Medical Care |

Medical Care




Ilar523toc 1.2

The Neurobehavioral Pharmacology of Ketamine: Implications for Drug Abuse, Addiction, and Psychiatric Disorders Keith A. Trujillo, Monique L. Smith, Brian Sullivan, Colleen Y. Heller, Cynthia Garcia, and Melvin Bates Ketamine was initially developed in the 1960s as a safer alternative to phencyclidine (PCP1) for anes- Ketamine was developed in the early 1960s as an anesthetic thetic procedures. It produces a state of dissociation and has been used for medical and veterinary procedures similar to PCP but is shorter-acting, less potent, and less since then. Its unique profi le of effects has led to its use at likely to induce agitation and violence (Gill and Stajic 2000; subanesthetic doses for a variety of other purposes: it is an Krystal et al. 1994; Newcomer et al. 1999). The dissociative effective analgesic and can prevent certain types of patho- state allows ketamine-treated patients to be conscious but logical pain; it produces schizophrenia-like effects and so is cognitively separated from the environment and unrespon- used in both clinical studies and preclinical animal models to sive to pain. Because of these unique qualities ketamine is better understand this disorder; it has rapid-acting and long- ideal for treating burn victims as well as for use in emergency lasting antidepressant effects; and it is popular as a drug of surgical procedures and in acute trauma situations (Bergman abuse both among young people at dance parties and raves 1999; Craven 2007; Domino 2010; Haas and Harper 1992; and among spiritual seekers. In this article we summarize Sinner and Graf 2008). recent research that provides insight into the myriad uses of In addition to its use as an anesthetic in both animals and ketamine. Clinical research is discussed, but the focus is on humans, ketamine is increasingly used for a variety of other preclinical animal research, including recent fi ndings from purposes (Domino 2010; Jansen 2000; Sinner and Graf 2008; our own laboratory. Of particular note, although ketamine is Wolff and Winstock 2006). Refl ecting the increased uses of normally considered a locomotor stimulant at subanesthetic ketamine, the attention given to the drug in published papers doses, we have found locomotor depressant effects at very has escalated tremendously. A PubMed search reveals that in low subanesthetic doses. Thus, rather than a monotonic dose- 1969 only 19 published articles used "ketamine" as a key dependent increase in activity, ketamine produces a more word and that the number has increased over the years to complex dose response. Additional work explores the mech- well over 500 in 2008–2009 (Figure 1). anism of action of ketamine, ketamine-induced neuroadapta- This review presents a summary of recent research on tions, and ketamine reward. The fi ndings described will the uses and effects of ketamine at subanesthetic doses. The inform future research on ketamine and lead to a better un- focus is on preclinical animal research as a means to better derstanding of both its clinical uses and its abuse. understand its myriad effects, both in its clinical and preclini-cal use for various disorders and conditions and in its in- Key Words: analgesia; anesthesia; animal model; antide-
creasingly popular abuse. pressant; drug abuse; glutamate; ketamine; reward; schizo-phrenia Uses of Ketamine
Anesthesia and Analgesia Keith A. Trujillo, PhD, is Professor of Psychology and Director of the Offi ce for Biomedical Research and Training at California State University A complete discussion of the anesthetic and analgesic ef- (CSU) San Marcos. Monique L. Smith, BA, was a graduate student in the fects of ketamine is beyond the scope of this article. How- Department of Psychology at CSU San Marcos and is now at Oregon Health & Science University; Brian Sullivan, BA, was a graduate student in the ever, it is important to mention these effects as they are the Department of Psychology at CSU San Marcos and is now at the University clinical actions for which ketamine is most often used. of Texas at El Paso; Colleen Y. Heller, BA, is a postbaccalaureate student in The fi rst publication on ketamine (called CI-581 at the the Department of Psychology at CSU San Marcos; Cynthia Garcia, BA, time) described it as a potent anesthetic that did not produce was an undergraduate student in the Department of Psychology at CSU San Marcos and is now at Washington University in St. Louis, Missouri; and Melvin Bates, BA, was a graduate student in the Department of Psychology at CSU San Marcos and is now at Texas A&M University. 1Abbreviations that appear ≥3x throughout this article: AMPA, α-amino-3- Address correspondence and reprint requests to Dr. Keith A. Trujillo, hydroxy-5methyl-4-isoxazoleproprionic acid; AMPAR, AMPA receptor; Department of Psychology, California State University San Marcos, 333 South CPP, conditioned place preference; NMDA, N-methyl-d-aspartate; PCP, Twin Oaks Valley Road, San Marcos, CA 92096 or email [email protected].
ILAR Journal Although early work focused on relatively high doses of ketamine for analgesia, recent discoveries have led to the use of subanesthetic doses for pain relief (for review, Kronenberg 2002; Visser and Schug 2006). For example, certain types of pathological pain result from a process known as "central sensitization," in which pain responses become hypersensi-tive (Latremoliere and Woolf 2009; Woolf 2011). The devel-opment of central sensitization involves N-methyl-d-aspartate (NMDA1) receptors. Because, as described below, ketamine is an effective NMDA receptor antagonist, it has been used in the treatment of certain types of pathological pain condi-tions that involve central sensitization (Craven 2007; Haas and Harper 1992; Hocking and Cousins 2003; Latremoliere and Woolf 2009; Mao 1999; Sinner and Graf 2008; Subramaniam et al. 2004; Woolf 2011). In the early 1990s it was discovered that ketamine, along with other NMDA receptor antagonists, can inhibit the de-velopment of opiate tolerance (Trujillo and Akil 1991, 1994), a fi nding that has been confi rmed by many others (for re-view, Trujillo 2000). Furthermore, a number of preclinical Figure 1 Number of publications on ketamine indexed in PubMed
each year from 1969 to 2009, based on key word "ketamine" and
studies have found that ketamine enhances opiate analgesia publication date. A total of 19 publications appeared in 1969; the (Baker et al. 2002; Dambisya and Lee 1994; Hoffmann et al. number remained below 200 per year through the 1970s, and began 2003; Holtman et al. 2003; Joo et al. 2000; Kosson et al. an upward trend in the early 1980s. By 2007–2009 publications on 2008; Nadeson et al. 2002; Pellissier et al. 2003), leading to ketamine exceeded 500/year. its use in combination therapy for pain. Clinical studies show that combinations of ketamine and opioids result in more ef-fective pain relief (and/or lower doses of opiates) and thus fewer respiratory depression at anesthetic doses (McCarthy et al. side effects (Bell 2009; Bell et al. 2003, 2005; Subramaniam 1965). This feature, which distinguishes ketamine from more traditional central nervous system (CNS) depressant anes-thetics, makes it particularly useful for emergency situations (such as battlefi eld injuries) and procedures in which breath- Antidepressant Effects ing assistance is unavailable or contraindicated. Among the other features of ketamine that make it par- Ketamine has recently been studied for its relevance to the ticularly useful are its rapid onset and predictable duration of treatment of major depression. Exciting evidence in humans action; its analgesic, anxiolytic, and amnestic effects; and its demonstrates that ketamine has very rapid and long-lasting mild effects on cardiovascular function (Domino 1990; Haas antidepressant effects when administered at subanesthetic and Harper 1992; White et al. 1982).
doses (Berman et al. 2000; Diazgranados et al. 2011; Zarate Given these qualities, ketamine soon became, and re- et al. 2006). This evidence is supported by research using mains, an important tool in the armamentarium of surgeons animal models involving learned helplessness, inescapable and anesthesiologists as well as veterinarians. In fact, one of stress, forced swim, and tail suspension (for review, Paul and the biggest sources of ketamine for recreational use is diver- Skolnick 2003; Skolnick 1999; Skolnick et al. 2009). sion from veterinary sources (Freese et al. 2002; Ross 2008; Remarkably, ketamine's antidepressant action is evident Wolff and Winstock 2006). within hours and lasts for up to 2 weeks postadministration, The analgesic properties of ketamine in humans were de- a fi nding that has been replicated in humans (Zarate et al. scribed soon after its discovery. Domino and colleagues 2006) and rodent models (Yilmaz et al. 2002; Maeng et al. (1965) reported a numbness of the entire body and a com- 2008) (however, Popik et al. 2008 were unable to replicate plete lack of reaction to "pain-inducing procedures" (includ- the long-lasting antidepressant effect of ketamine in a rodent ing skin crush with hemostats), although sensation to touch model). Ketamine's rapid and long-lasting antidepressant was unaffected. But the analgesia was accompanied by strong effects are unusual: currently used medications, such as tri- psychoactive effects, such as changes in mood and body im- cyclic antidepressants and selective serotonin reuptake in- age, vivid dreams and hallucinations, and a psychological hibitors (SSRIs), have a 3- to 6-week delay in onset and state in which subjects appeared to be disconnected from require daily administration to achieve and maintain antide- their surrounding environment. The latter prompted Domino pressant effects (Schatzberg and Nemeroff 2009). However, and colleagues (1965) to coin the term "dissociative" to de- currently used antidepressants act primarily on monoamine scribe ketamine and related drugs, apparently inspired by neurotransmitter systems, whereas ketamine acts on glutamate Domino's wife (Domino 2010). (see details below), resulting in the emergence of theories Volume 52, Number 3 2011 about the role of glutamate in major depressive disorder effects, some people use it for psychic exploration, aiming for (Hashimoto 2009; Machado-Vieira et al. 2009; Skolnick mystical experiences, self-transcendence, and spiritual growth 1999; Skolnick et al. 2009). (Jansen 2000; Jansen and Darracot-Cankovic 2001).
Unfortunately, the usefulness of ketamine as an antide- On the streets, ketamine is known as "Special K," "Vi- pressant is limited because of adverse side effects, including tamin K," "cat valium," or "K." It is commercially avail- the psychotomimetic effects described above. Further research able as an injectable liquid but most commonly abused in is necessary to better understand the mechanisms and antide- a powder form and either snorted or smoked, although pressant effects of ketamine and to explore the development some use it orally or via intramuscular or intravenous in- of antidepressant glutamatergic compounds that have fewer jection (Dillon et al. 2003; Freese et al. 2002; Smith et al. side effects.
Ketamine abusers claim that the drug is rewarding and can produce a variety of psychoactive effects. At relatively Models of Schizophrenia low doses, users report stimulation and excitement, eupho-ria, sensory distortions, lucid intoxication, and heightened Early clinical studies on ketamine and PCP led researchers feelings of empathy (Dillon et al. 2003; Jansen 2000; Jansen to believe that these drugs were psychotomimetic and could and Darracot-Cankovic 2001). At higher doses, ketamine offer insight into schizophrenia (Davies and Beech 1960; produces a hallucinatory state referred to as a "K-hole," an Domino et al. 1965; Luby et al. 1959). Effects of subanes- intense dissociative experience that includes visions and dis- thetic doses include cognitive dysfunction and perceptual tortion of time, sense, and identity, and sometimes out-of- changes in healthy volunteers, and exacerbation of symp- body, near death, or rebirth experiences. Users often report toms in schizophrenic patients (Adler et al. 1998, 1999; the K-hole as a frightening or aversive experience (Dillon Krystal et al. 1994; Lahti et al. 1995, 2001; Malhotra et al. et al. 2003).
1997b; van Berckel et al. 1998). Ketamine's ability to pro- The rise in ketamine abuse is associated with an in- duce both negative and positive symptoms of schizophrenia, crease in ketamine-related emergency room visits (Dillon as well as cognitive dysfunction, is noteworthy as more tra- et al. 2003; Jansen 2000; Jansen and Darracot-Cankovic ditional stimulant models induce primarily positive symp- 2001). Because of the drug's dissociative state, burns, falls, toms and thus provide an incomplete model of schizophrenia drowning, traffi c accidents, and "date rape" are some of the symptomology (Angrist et al. 1974; Janowsky and Risch 1979; consequences linked to ketamine-related impairment (Dillon Krystal et al. 2005b). et al. 2003; Freese et al. 2002; Jansen 2000; Smith et al. The effects in humans have led to the use of ketamine (as 2002). Despite such aversive experiences, case reports of well as PCP and related drugs) in animal models of schizo- ketamine addiction indicate that ketamine seeking can be- phrenia, and to the related theory that glutamatergic dys- come compulsive, and users often express concern about function is involved in schizophrenia (more on glutamatergic the potential for addiction and dependence (Dillon et al. hypotheses below). In rodent models, the ability of drugs to 2003; Jansen and Darracot-Cankovic 2001; Muetzelfeldt block the behavioral actions of ketamine is often used as a et al. 2008).
preclinical assay of antipsychotic effects (Becker et al. 2003; The potential dangers and increased abuse of ketamine Gilmour et al. 2009; Jentsch and Roth 1999; Lees et al. 2004; prompted the US Drug Enforcement Administration (DEA) Neill et al. 2010). Notably, atypical antipsychotics (drugs to classify ketamine as a schedule III2 drug in 1999 (DEA such as clozapine, olanzapine, and risperidone, which pro- duce fewer motoric side effects than traditional antipsychotics) are effective at blocking ketamine's behavioral effects in both humans and rodents (Krystal et al. 1999, 2005a; Malhotra Neurochemical Effects of Ketamine
These fi ndings provide evidence for the use of ketamine NMDA Receptors and Glutamate in schizophrenia research, and are leading to a better under-standing of the disorder and the development of novel Glutamatergic transmission is mediated by three ionotropic glutamate receptors: AMPA1 (α-amino-3-hydroxy-5methyl-4-isoxazoleproprionic acid), NMDA, and kainate. It wasn't until the 1980s, nearly 20 years after its discovery, that ket- amine was found to exert its physiological and behavioral effects as an antagonist of NMDA receptors (Anis et al. In the 1980s and the 1990s there was a dramatic increase in 1983; Lodge et al. 1982). the recreational use of ketamine (Dillon et al. 2003; Freese et al. 2002; Jansen 1993; Ross 2008; Smith et al. 2002), espe-cially at raves and dance parties, leading to its classifi cation 2According to the DEA website, "Substances in this schedule have a as a "club drug" (Freese et al. 2002; Jansen 2000; Jansen and potential for abuse, [which] may lead to moderate or low physical Darracot-Cankovic 2001; Kelly et al. 2006; Smith et al. dependence or high psychological dependence" (www.deadiversion.usdoj.
2002). In addition, because of its unique psychoactive gov/schedules; accessed on June 3, 2011). ILAR Journal NMDA receptors are ligand-gated cation channels that and Andersen 1993; Hauber and Waldenmeier 1994; Li et al. open in response to the binding of glutamate and glycine 2010; Maeng et al. 2008; Takahata and Moghaddam 2003). (Collingridge and Watkins 1995; Yamakura and Shimoji 1999). Together, these results suggest that NMDA receptor block- This opening leads to an infl ux of calcium, which can act in ade leads to the release of glutamate, which acts on AMPA a second messenger cascade and is essential to NMDA re- receptors to evoke behavioral effects of the dissociatives. ceptor function. A role for AMPAR mediation (after glutamate release) PCP and ketamine are NMDA antagonists and selec- has been found for the antidepressant effects of ketamine. tively bind to the "PCP site," which is located in the NMDA When administered before a forced swim test in mice, ket- ion channel (Collingridge and Watkins 1995; Sinner and amine and other NMDA receptor antagonists decrease im- Graf 2008; Wood et al. 1990; Yamakura and Shimoji 1999). mobility (such a decrease is a sign of antidepressant action), Because of their ability to block NMDA receptor function and this effect can be blocked by pretreatment with the without inhibiting the binding of glutamate, these drugs are AMPAR blocker NBQX (Maeng et al. 2008), as can down- referred to as noncompetitive antagonists. Specifi cally, ket- stream consequences of ketamine action (Li et al. 2010).
amine blocks the open ion channel, reduces the amount of The glutamate hyperactivity hypothesis has been investi- open time, and decreases the frequency of channel openings gated indirectly, using drugs that act on different aspects of (for review see Sinner and Graf 2008). However, ketamine glutamate function. For example, as noted above, AMPAR binds to this site with a lower affi nity than PCP (Collingridge antagonists have been found to inhibit specifi c effects of ket- and Watkins 1995), refl ecting its decreased behavioral ef- amine and PCP, suggesting a role for AMPAR activation in fects relative to PCP. the actions of these drugs. Furthermore, group II metabotro-pic receptor agonists (which can lower glutamate release) can decrease certain motor and cognitive effects of PCP Hypo- or Hyperglutamatergic? (Krystal et al. 2005a; Lorrain et al. 2003a,b; Moghaddam and Adams 1998). The reigning explanation for the actions of ketamine is the Although the studies described above suggest that en- hypoglutamatergic hypothesis: ketamine produces its effects hanced glutamate release is involved in the effects of disso- by blocking the ability of glutamate to activate NMDA re- ciatives, other studies, using compounds that inhibit glutamate ceptors. More recently, however, it has been suggested that release, suggest that the hypothesis is incomplete. the subjective and behavioral effects of ketamine may result from more complex effects on glutamatergic signaling. Ac-cording to this hypothesis, ketamine, PCP, and related dis- Inconsistent Research Results about the Role sociatives may actually increase glutamate in certain brain areas and thereby produce some of the drugs' behavioral ef- fects (Adams and Moghaddam 1998; Farber et al. 2002a,b; Krystal et al. 2003; Maeng et al. 2008; Moghaddam et al. and riluzole (2-amino-6-trigluromethoxy benzothiazole) are 1997; Olney et al. 1999). Thus, rather than producing their two compounds that inhibit release of glutamate, and both effects via a hypoglutamatergic mechanism, dissociatives are seeing increased use as potential therapies for psychiat- may act via hyperglutamatergic actions. ric disorders, including depression, bipolar disorder, and In alignment with the glutamate hyperactivity hypothe- schizophrenia (Amann et al. 2010; Goff 2009; Kugaya and sis, researchers have demonstrated that NMDA receptor Sanacora 2005; Large et al. 2005; Mathew et al. 2008; Pittenger blockade induced by PCP or ketamine results in release of et al. 2008; Premkumar and Pick 2006; Zarate and Manji glutamate in the cerebral cortex (Adams and Moghaddam 1998, 2001; Lorrain et al. 2003a,b; Moghaddam et al. 1997; If the glutamate hyperactivity hypothesis is correct, then Razoux et al. 2007; Takahata and Moghaddam 2003). riluzole and lamotrigine should inhibit the behavioral ac- GABAergic neurons normally inhibit glutamatergic inputs to tions of dissociatives. However, studies of the effects of these the cortex; however, blockade of NMDA receptors on these drugs on ketamine-induced behavior have yielded confl ict- GABAergic neurons by the dissociatives blocks the inhibi- ing results. For example, in a study using human participants tion, resulting in activation of the glutamatergic neurons and Anand and colleagues (2000) found that lamotrigine de- increased glutamate release. The increased glutamate concen- creased ketamine-induced symptoms of schizophrenia and trations produce stimulation of non-NMDA glutamate recep- impairments in learning and memory, but increased the im- tors (AMPA receptors) and the drugs' cognitive and behavioral mediate mood-elevating effects of ketamine. Similarly, Brody and colleagues (2003) demonstrated in rats that lamo- In support of this idea, PCP and ketamine have been trigine prevented ketamine-induced disruptions in prepulse shown to increase glutamatergic neurotransmission at AMPA inhibition; however, this fi nding was not replicated in later receptors (Adams and Moghaddam 1998; Moghaddam et al. research (Cilia et al. 2007). Another study demonstrated 1997; Razoux et al. 2007), and studies have shown that that lamotrigine increased PCP-induced hyperlocomotion AMPA receptor (AMPAR1) antagonists attenuate certain be- (Williams et al. 2006), an effect that is opposite to the gluta- havioral and neurochemical effects of dissociatives (Hauber mate hyperactivity hypothesis. In related work, Lourenço Da Volume 52, Number 3 2011 Silva and colleagues (2003) found no effect of riluzole on the ade of NMDA receptors, and yet others mediated by neu- locomotor stimulation produced by MK-801, a potent dis- rotransmitters other than glutamate. sociative drug. Thus, while some studies have obtained fi nd-ings that are consistent with the hypothesis, others are in contradiction. Behavioral Effects of Ketamine:
In our laboratory we have performed a series of studies to systematically assess the ability of riluzole and lamotri-gine to affect the locomotor stimulant actions of ketamine Locomotor activation in rodents is an important target in and PCP. Extensive dose response experiments have revealed models of drug abuse and certain psychiatric disorders, such no consistent effects of these drugs on ketamine- or PCP- as schizophrenia. The effects of ketamine on locomotor be- induced hyperlocomotion, stereotypy, or ataxia (Trujillo, havior have been well characterized, beginning with the Smith, and Heller, unpublished results). 1965 paper reporting that subanesthetic doses of ketamine In addition, we tested the same hypothesis using the produced locomotor stimulation accompanied by ataxia in AMPA antagonist GYKI-52466, reasoning that AMPAR mice and rats (McCarthy et al. 1965). Since then, innumer- blockade should attenuate any behaviors that were due to able studies have replicated the ability of ketamine and re- increased availability of glutamate at AMPA receptors. As lated drugs to produce locomotor stimulation, ataxia, and with the riluzole and lamotrigine, GYKI-52466 had no effect stereotypy at subanesthetic doses. on ketamine- or PCP-induced hyperlocomotion, stereotypy, Because subanesthetic doses of ketamine can induce a or ataxia at a dose that did not, by itself, inhibit locomotor schizophrenia-like syndrome in humans, it was a natural ex- behavior (Trujillo and Smith, unpublished results). tension to consider locomotor activation as a marker of the Thus, the fi ndings do not consistently support the gluta- psychoactive effects of the drug in rodent models of schizo- mate hyperactivity hypothesis. One potential explanation for phrenia. Consequently, the ability of a drug to block the loco- these mixed fi ndings is that only certain behavioral effects of motor effects of ketamine has been used to identify potential ketamine are mediated by an increase in glutamate release antipsychotics. Atypical antipsychotics are particularly effec- and subsequent AMPAR activation, and others are mediated tive at blocking ketamine-induced locomotion. by NMDA receptor blockade. This possibility is consistent Locomotor activation has also been associated with posi- with the fi ndings of Anand and colleagues (2000), who found tive reinforcing effects of drugs, leading to a psychomotor that lamotrigine decreased certain effects of ketamine and stimulant theory of drug reward (Robinson and Berridge increased others. Furthermore, the ketamine-induced in- 2001, 2002; Trujillo et al. 1993; Wise 1988; Wise and Bozarth crease in glutamate release appears delayed relative to the 1987). Drug-induced locomotor activation has therefore some- locomotor stimulant effects of ketamine. For example, gluta- times been used as a surrogate marker of drug reward (more mate release increases signifi cantly only 40 to 60 minutes on ketamine and reward below). postadministration (Lorrain et al. 2003a; Moghaddam et al. Data from our laboratory illustrate increases in activity, 1997), whereas the locomotor stimulant effects, stereotypy, ataxia, and stereotypy associated with ketamine administra- and ataxia induced by moderate doses of ketamine occur im- tion (Figure 2). At a low, subanesthetic dose (15.8 mg/kg), mediately and subside within 20 minutes (Garcia and Trujillo ketamine produces increases in ambulatory activity accom- 2007; Heller and Trujillo 2007; Sullivan and Trujillo 2007). panied by mild ataxia and stereotypy; at a higher dose This time discrepancy, along with results of studies using (50 mg/kg), stimulation, ataxia, and stereotypy dramatically riluzole and lamotrigine, suggests that the motor effects of increase. As anesthetic doses are approached (100 mg/kg ketamine are independent of glutamate release. and higher), ataxia overwhelms the locomotor activation, re-sulting in a complex progression from low levels of activity to considerable ataxia, stereotypy, and locomotor activation Other Neurochemical Effects of Ketamine as the anesthesia wears off (not shown). We have assessed the locomotor responses of Sprague- Ketamine affects many neurotransmitter systems other than Dawley rats at subanesthetic doses of ketamine and obtained glutamate. There is, for example, considerable interest in the quite surprising results at the low end of the dose range. We interactions between ketamine and dopamine as well as ket- found that the drug reliably depresses locomotor activity, amine and endogenous opioids. A full consideration of these relative to control animals, at doses of 10 mg/kg or less (ad- effects is beyond the scope of this article; summaries are ministered by intraperitoneal [i.p.] injection) (Figure 3). The available (Bergman 1999; Seeman 2009; Sinner and Graf locomotor depressant effects were not accompanied by no- 2008; White and Ryan 1996).
ticeable incoordination or ataxia. Therefore, rather than a Together, the results discussed in this section suggest monotonic increase in activity reported by most laboratories, that the psychoactive and behavioral effects of ketamine may ketamine produces more complex dose-dependent effects, be more complex than either the glutamate hypo- or hyper- with decreases in activity at very low subanesthetic doses activity hypothesis suggests, with perhaps only a subset of (5–10 mg/kg), increases at higher doses (15–50 mg/kg), and responses mediated by an increase in glutamate release and decreases again at anesthetic levels (100 mg/kg and higher). AMPAR activation, others mediated more directly by block- Moreover, even at stimulant doses, the increase in activity ILAR Journal was followed by a rebound decrease in behavior, relative to control animals, as the stimulant effect abated (Garcia and Trujillo 2007; Mercado et al. 2009). In examining the literature, we found at least one refer- ence to locomotor depressant effects of subanesthetic doses of ketamine. Becker and colleagues (2003), in attempting to develop a ketamine-based rodent model of schizophrenia, noted a locomotor depressant effect of the drug at 30 mg/kg (a dose that frequently produces stimulation). However, this result was not studied systematically and was presented as a single fi gure among others characterizing different behav-ioral responses to the drug. Ketamine in Combination with Other Drugs The locomotor depressant effects of ketamine are most evident when it is administered with other psychomotor stimulants. We examined the interaction of ketamine with methamphet-amine, a potent and widely abused psychomotor stimulant that is often used in combination with ketamine (Dillon et al. 2003). The behavioral effects of this combination are largely unknown. To better understand the effects of ketamine and metham- phetamine combined, we explored the locomotor effects of each drug alone and of both mixed together in a "cocktail." We hypothesized that the combination would produce an effect greater than either drug alone, similar to the "speedball" effect seen with combinations of opiates and psychomotor stimulants (Leri et al. 2003). Methamphetamine administration produced the expected psychomotor stimulation, while ketamine pro-duced a mild depressant effect at lower doses (5 and 10 mg/kg, subcutaneous [s.c.] administration) and stimulation followed by locomotor depression at a higher dose (20 mg/kg s.c.). In con-trast to our hypothesis, at all doses ketamine potently inhibited the locomotor stimulant effect of methamphetamine. Studies of the combined effects of cocaine and ketamine confi rm that ketamine can attenuate the behavioral effects of psychostimulants. Uzbay and colleagues (2000) examined the impact of ketamine on cocaine-induced locomotor stim-ulation and showed that ketamine produced a dose-dependent inhibition of the stimulant effect of cocaine. These results, together with our observations, suggest that ketamine pro-duces potent locomotor depression, an effect that is particu-larly evident when the drug is administered with psychomotor stimulants. Figure 2 Dose-dependent effects of ketamine (Ket) on motor be-
Research Implications havior in laboratory rats. Adult male Sprague-Dawley rats (n = 6/group) were placed in photocell locomotor chambers (Kinder Sci- The fi nding that ketamine produces locomotor depression at entifi c Open Field Motor Monitor) for a 30-minute habituation, fol- low doses has important implications for preclinical research lowed by injection of saline (1 ml/kg) or ketamine (15.6 or 50 mg/ on the drug. For example, as noted above, locomotor stimu- kg). Ataxia and stereotypy were assessed according to Castellani lation in rodents is used as an index of the psychotomimetic and Adams (1981). Locomotor activity represents the mean (+ effects of ketamine, but this effect occurs only at moderate to SEM) total photocell counts (basic movements) for 60 min after injection in each group. Ataxia and stereotypy are the mean (+ high doses, whereas the doses used in clinical studies to in- SEM) peak scores for each group. SEM, standard error of the duce such effects in humans are quite low (Krystal et al. 1994; van Berckel et al. 1998). Volume 52, Number 3 2011 Tolerance and Sensitization Tolerance is a decrease in response after repeated use of a drug and sensitization is "reverse tolerance," or an increase in response. An individual may develop tolerance to some psychoactive and behavioral effects of a drug, and sensitiza-tion to others. Furthermore, the development of tolerance and sensitization can be infl uenced by a variety of factors, such as dose, the interval between doses, and environmental infl uences. Tolerance and sensitization are important to the clinical use of drugs as well as drug abuse and addiction. Tolerance to the therapeutic effect of a drug will make it less effective over time, while sensitization to a side effect will produce escalating problems with repeated use. Similarly, tolerance to the desired effect of an abused drug may lead to increases in use to overcome the decreased effect, while sensitization has been linked to the craving that is prominent in addiction. Early studies on repeated use of ketamine focused on changes induced by high doses and reported that tolerance developed to the anesthetic effect of the drug (Douglas and Dagirmanjian 1975; Hance et al. 1989; Livingston and Waterman 1978; Winters et al. 1988). Follow-up studies on Figure 3 Locomotor depressant effects of low-dose ketamine (Ket)
subanesthetic doses of ketamine left an unclear picture of in laboratory rats. Adult male Sprague-Dawley rats (n = 6/group) neuroadaptations, with some reports of tolerance, others of were injected with saline (1 ml/kg) or ketamine (5 or 10 mg/kg) and sensitization, and others showing no change after repeated immediately placed in photocell locomotor chambers (Kinder Sci- administration (Becker et al. 2003; Lannes et al. 1991; Leccese entifi c Cage Rack Monitors). Locomotor activity represents the mean (± SEM) percent saline control for 15 min after injection in et al. 1986; Nelson et al. 2002; Rocha et al. 1996; Uchihashi each group. SEM, standard error of the mean In light of the inconsistent results, we have begun to ex- amine the changes that take place with repeated administration of subanesthetic doses of ketamine. Our studies demonstrate This discrepancy raises the question of whether the low- potent sensitization to the locomotor effects of ketamine. dose depressant effects in rats may more accurately refl ect Sensitization occurs at short or long treatment intervals and the clinical research and lead to a better animal model of at a broad range of doses, and, like other drugs of abuse, is schizophrenia. Indeed, studies that have examined prepulse enhanced in the presence of specifi c environmental cues inhibition of startle in rats to model schizophrenia-related (Heller and Trujillo 2007). Other studies have also reported defi cits in sensorimotor gating have typically used ketamine sensitization to ketamine locomotion (Popik et al. 2008; doses in the range that we have found to depress behavior Uchihashi et al. 1993; Wiley et al. 2008). (10 mg/kg or less) (Imre et al. 2006; Mansbach et al. 2001; Because sensitization has been linked to addiction Mansbach and Geyer 1991; Ong et al. 2005; Swerdlow et al. (Robinson and Berridge 1993, 2001), these results offer in- sight into the potential addictive properties of ketamine and The lower end of the dose range may also be a better demonstrate that repeated use can lead to long-term changes target in animal studies of the rewarding effects of ketamine. in brain function. Studies using conditioned place preference in laboratory rats (see below) have found rewarding effects at low doses, com-parable to those that produce locomotor depression. And in- Research Implications of Ketamine dividuals who use ketamine to enhance their experience at dance clubs and raves aim for doses that do not produce sig-nifi cant incoordination or ataxia. Together, the fi ndings sug- The development of sensitization to ketamine in some stud- gest that research should be aimed at better understanding ies and tolerance in others raises an important methodologi- the low-dose depressant effects of ketamine. cal concern for research on the behavioral pharmacology of dissociative drugs. Ketamine is the anesthetic of choice for a variety of sur- gical procedures in laboratory animals. Animals that require Repeated administration of psychoactive drugs typically leads surgery before testing, such as those receiving catheter im- to neuroadaptations in the form of tolerance or sensitization. plants for self-administration, often receive high doses of the ILAR Journal drug before behavioral testing. As a result, these animals infl uences. De Luca and Badiani (2011) found that rats read- are experienced with the drug and may have undergone sig- ily self-administered ketamine when sessions occurred in an nifi cant brain changes that can infl uence the outcome of experimental cage, but reduced their self-administration when sessions occurred in the home cage. These results are We recommend the use, when possible, of an alternative similar to recent work from our laboratory demonstrating anesthetic for animals involved in studies of ketamine or much greater ketamine sensitization when the drug was ad- other dissociatives to avoid potentially confounding effects ministered in an experimental cage than in a home cage related to tolerance or sensitization. (Heller and Trujillo 2007). Thus environment is an important factor in the psychoactive effects of ketamine and can mod- ify ketamine reward and neuroadaptations. Future studies should pay attention to environment when evaluating the be-havioral and psychoactive effects of ketamine. There are many reasons drugs are abused, but reward is con- Research on self-administration of ketamine is not ex- sidered to be an essential aspect of addiction (Robinson and tensive, but the similar pattern of ketamine self-administration Berridge 2000, 2001, 2003; Trujillo and Akil 1995). Two in comparison with other drugs of abuse leads to the conclu- widely used and effective measures of reward in animal sion that ketamine is rewarding to laboratory animals. This models involve self-administration and conditioned place fi nding is in contrast to other classes of psychedelic drugs, preference (CPP1). such as LSD, which are used by humans but are not self- administered by laboratory animals (for review, Fantegrossi In self-administration models, an animal performs a task, such as pressing a lever, to obtain a drug; an increase in the Conditioned Place Preference frequency of task performance is an index of the reinforcing properties of the drug. There is a high correspondence be- Conditioned place preference is particularly useful in as- tween drugs that are readily self-administered by experimen- sessing drug reward (Bozarth 1987; Mucha et al. 1982; tal animals and those that are abused by humans (Bozarth Tzschentke 1998, 2007). This approach uses an experimen- 1987; Collins et al. 1984). tal chamber with two compartments distinguished by differ- The earliest preclinical studies of the rewarding effects ent cues (visual and/or tactile and/or olfactory). A test drug of ketamine focused on the propensity for animals to self- is reliably paired with one compartment and a placebo with administer the drug and showed that ketamine was reinforc- the other. If, after conditioning, the animal spends more time ing in a small but signifi cant number of self-administration in the drug-associated environment, the drug is considered experiments, the fi rst of which involved nonhuman primates. rewarding. As with self-administration there is a high corre- McCarthy and Harrigan (1977) and Moreton and colleagues spondence between drugs that produce CPP and those abused (1977) found that rhesus monkeys self-administered ket- amine in a dose-dependent manner, and the pattern of self- Only in the past 10 years have there been any reported administration behavior was similar to that seen with other fi ndings regarding the ability of ketamine to produce a con- drugs of abuse, such as methamphetamine, cocaine, mor- ditioned place preference (Gao et al. 2003; Li et al. 2008; phine, and heroin. Subsequent studies have replicated the Suzuki et al. 2000; van der Kam et al. 2009a; Xu et al. 2006). fi nding that nonhuman primates self-administer ketamine The earliest work examining ketamine did not focus on its (Broadbear et al. 2004; Carroll and Stotz 1983; Marquis and ability to produce a place preference but rather its interaction Moreton 1987; Risner 1982; Winger et al. 1989; Young and with other drugs. For example, it was reported that ketamine alone (3 and 10 mg/kg i.p.) produced a signifi cant place pref- One potential criticism of this early work is that the ani- erence (Gao et al. 2003; Suzuki et al. 2000) but (at 10 mg/kg mals in these investigations nearly always had considerable i.p.) blocked the development of morphine place preference. experience self-administering other drugs, so it might be In contrast, ketamine (10 mg/kg) produced CPP both alone argued that they were sensitized or primed for drug self- and in combination with methamphetamine (Xu et al. 2006). administration. But similar ketamine self-administration has In each of these studies, the place conditioning produced by been observed in monkeys without a history of drug self- ketamine was statistically signifi cant, but typically less pro- administration (Young and Woods 1981). Self-administration nounced than that induced by other drugs in the studies, such of ketamine has also been replicated in other species, includ- as morphine (Gao et al. 2003; Suzuki et al. 2000) and MK- ing dogs (Risner 1982), baboons (Lukas et al. 1984), and rats 801 (Suzuki et al. 1999, 2000). (Collins and Woods 2007; Collins et al. 1984; De Luca and More recently van der Kam and colleagues (2009a) Badiani 2011; Marquis et al. 1989; Marquis and Moreton assessed a variety of doses of ketamine (3.16, 10.0, and 1987; Rocha et al. 1996; van der Kam et al. 2007, 2009b). 31.6 mg/kg) in place conditioning. Consistent with the pre- A very recent relevant fi nding is that ketamine self- vious studies, they noted the development of CPP at 10.0 and administration is highly dependent on environmental 31.6 mg/kg. However, the conditioning was quite modest, Volume 52, Number 3 2011 with animals spending only marginally greater time in the nisms that underlie its unique effects, there is still much drug-paired compartment than the vehicle-paired compart- more to be learned. Given the drug's popularity both in clini- ment (although the difference was statistically signifi cant).3 cal use and among recreational users, research on ketamine We have begun to examine place conditioning to ketamine using both human subjects and animal models will undoubtedly in laboratory rats and, like van der Kam and colleagues remain a focus of intense investigation well into the future. (2009a), have found that it is modest at best and very sensi-tive to the specifi c approaches used. In a series of studies, we were able to show only marginally more time spent in the ketamine-paired (10 mg/kg) compartment relative to the This work was supported by the National Institutes of saline-paired compartment (Sullivan and Trujillo 2010). Yet Health's National Institute of General Medical Sciences despite the low levels of conditioning, animals became sen- (GM081069, GM008807, and GM064783). sitized to the ketamine they received during conditioning. Thus, ketamine sensitization was robust and reliable, while ketamine place conditioning was modest and unreliable.
The results of the studies described here suggest a con- Adams B, Moghaddam B. 1998. Corticolimbic dopamine neurotransmis- flict between those that have used self-administration to sion is temporally dissociated from the cognitive and locomotor effects study ketamine reward and those that used conditioned place of phencyclidine. J Neurosci 18:5545-5554.
preference. There are several possible explanations for this Adams BW, Moghaddam B. 2001. Effect of clozapine, haloperidol, or discrepancy. One likely explanation is that ketamine reward M100907 on phencyclidine-activated glutamate effl ux in the prefrontal cortex. Biol Psychiatry 50:750-757.
is accompanied by aversive effects that become apparent in Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A. 1998. Effects of ketamine on thought disorder, working memory, and semantic memory Users of ketamine for recreational purposes often report in healthy volunteers. Biol Psychiatry 43:811-816.
a mix of reward and aversion (Dillon et al. 2003; Jansen Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A. 2000; Jansen and Darracot-Cankovic 2001), an effect that 1999. Comparison of ketamine-induced thought disorder in healthy vol-unteers and thought disorder in schizophrenia. Am J Psychiatry has also been seen in human clinical studies with subanes- thetic doses of ketamine (Krystal et al. 1994; van Berckel Amann B, Born C, Crespo JM, Pomarol-Clotet E, McKenna P. 2010. Lam- et al. 1998). Self-administration studies typically use very low otrigine: When and where does it act in affective disorders? A system- doses administered intravenously, with repeated administra- atic review. J Psychopharmacol (Sep 7; epub ahead of print).
tions during a single session. Conditioned place preference Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH. 2000. Attenuation of the neuropsychiatric effects of ket- studies typically use higher doses, with only one i.p. or s.c. amine with lamotrigine: Support for hyperglutamatergic effects of administration during a session. The conditions used in self- N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry administration may lead to a bias toward ketamine reward, while CPP methods produce a more balanced expression of Angrist B, Sathananthan G, Wilk S, Gershon S. 1974. Amphetamine psy- reward and aversion. chosis: Behavioral and biochemical aspects. J Psychiatr Res 11:13-23.
Anis NA, Berry SC, Burton NR, Lodge D. 1983. The dissociative anaesthet- Further research on ketamine self-administration, condi- ics, ketamine and phencyclidine, selectively reduce excitation of central tioned place preference, and other approaches will enhance mammalian neurones by n-methyl-aspartate. Br J Pharmacol 79:565- understanding of ketamine reward and its role in ketamine abuse and addiction. Baker AK, Hoffmann VL, Meert TF. 2002. Interactions of NMDA antago- nists and an alpha 2 agonist with mu, delta and kappa opioids in an acute nociception assay. Acta Anaesthesiol Belg 53:203-212.
Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G. 2003. Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:687- Ketamine is a fascinating drug that has captured the attention of anesthesiologists, psychiatrists, spiritual seekers, dance Bell RF. 2009. Ketamine for chronic non-cancer pain. Pain 141:210-214.
partiers, and scientists. In this review we have identifi ed a Bell RF, Eccleston C, Kalso E. 2003. Ketamine as adjuvant to opioids for few aspects of particular interest in current research: the drug's cancer pain: A qualitative systematic review. J Pain Symptom Manage unique anesthetic profi le, its analgesic effects across a variety Bell RF, Dahl JB, Moore RA, Kalso E. 2005. Peri-operative ketamine for of doses and its ability to prevent pathological pain, its abil- acute post-operative pain: A quantitative and qualitative systematic re- ity to mimic key symptoms of schizophrenia, its rapid and view (Cochrane review). Acta Anaesthesiol Scand 49:1405-1428.
long-lasting antidepressant effects, its ability to evoke mysti- Bergman SA. 1999. Ketamine: Review of its pharmacology and its use in cal or spiritual feelings and insight, and its euphorigenic and pediatric anesthesia. Anesth Prog 46:10-20.
rewarding effects. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. 2000. Antidepressant effects of ketamine in depressed pa- Although much is known about ketamine's actions, and tients. Biol Psychiatry 47:351-354.
there has been progress in efforts to understand the mecha- Bozarth MA, ed. 1987. Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer-Verlag.
Broadbear JH, Winger G, Woods JH. 2004. Self-administration of fentanyl, 3In contrast to all of these studies, Li and colleagues (2008) reported very cocaine and ketamine: Effects on the pituitary-adrenal axis in rhesus strong place conditioning to ketamine (10 mg/kg) in rats. monkeys. Psychopharmacology (Berl) 176:398-406.
ILAR Journal Brody SA, Geyer MA, Large CH. 2003. Lamotrigine prevents ketamine but posite behavioural effects of NMDA receptor antagonists in rats: Impli- not amphetamine-induced defi cits in prepulse inhibition in mice. Psy- cations for "NMDA antagonist modeling" of schizophrenia. chopharmacology (Berl) 169:240-246.
Psychopharmacology (Berl) 205:203-216.
Carroll ME, Stotz DC. 1983. Oral d-amphetamine and ketamine self- Goff DC. 2009. Review: Lamotrigine may be an effective treatment for clo- administration by rhesus monkeys: Effects of food deprivation. J Pharma- zapine resistant schizophrenia. Evid Based Ment Health 12:111.
col Exp Ther 227:28-34.
Haas DA, Harper DG. 1992. Ketamine: A review of its pharmacologic prop- Castellani S, Adams PM. 1981. Acute and chronic phencyclidine effects on erties and use in ambulatory anesthesia. Anesth Prog 39:61-68.
locomotor activity, stereotypy and ataxia in rats. Eur J Pharmacol Hance AJ, Winters WD, Quam DD, Benthuysen JL, Cadd GG. 1989. Cata- lepsy induced by combinations of ketamine and morphine: Potentiation, Cilia J, Hatcher P, Reavill C, Jones DN. 2007. (+/-) ketamine-induced pre- antagonism, tolerance and cross-tolerance in the rat. Neuropharmacol- pulse inhibition defi cits of an acoustic startle response in rats are not ogy 28:109-116.
reversed by antipsychotics. J Psychopharmacol 21:302-311.
Hashimoto K. 2009. Emerging role of glutamate in the pathophysiology of Collingridge GL, Watkins JC, eds. 1995. The NMDA Receptor. New York: major depressive disorder. Brain Res Rev 61:105-123.
Oxford University Press.
Hauber W, Andersen R. 1993. The non-NMDA glutamate receptor antago- Collins GT, Woods JH. 2007. Drug and reinforcement history as determi- nist GYKI 52466 counteracts locomotor stimulation and anticataleptic nants of the response-maintaining effects of quinpirole in the rat. J Phar- activity induced by the NMDA antagonist dizocilpine. Naunyn Schmie- macol Exp Ther 323:599-605.
debergs Arch Pharmacol 348:486-490.
Collins RJ, Weeks JR, Cooper MM, Good PI, Russell RR. 1984. Prediction Hauber W, Waldenmeier MT. 1994. The AMPA receptor antagonist GYKI of abuse liability of drugs using IV self-administration by rats. Psycho- 52466 reverses the anti-cataleptic effects of the competitive NMDA re- pharmacology (Berl) 82:6-13.
ceptor antagonist CGP 37849. Eur J Pharmacol 256:339-342.
Craven R. 2007. Ketamine. Anaesthesia 62 Suppl 1:48-53.
Heller CY, Trujillo KA. 2007. Sensitization to ketamine ("Special K"): Ef- Dambisya YM, Lee TL. 1994. Antinociceptive effects of ketamine-opioid fects of injection interval and environmental conditioning. Soc Neurosci combinations in the mouse tail fl ick test. Methods Find Exp Clin Phar- Annu Conf Abstr #813.3.
macol 16:179-184. Hocking G, Cousins MJ. 2003. Ketamine in chronic pain management: An Davies BM, Beech HR 1960. The effect of 1-arylcylohexylamine (sernyl) evidence-based review. Anesth Analg 97:1730-1739.
on twelve normal volunteers. J Ment Sci 106:912-924.
Hoffmann VL, Baker AK, Vercauteren MP, Adriaensen HF, Meert TF. 2003. DEA [Drug Enforcement Administration]. 1999. News release: DEA to Epidural ketamine potentiates epidural morphine but not fentanyl in control "Special K" for the fi rst time. Available online (www.usdoj.
acute nociception in rats. Eur J Pain 7:121-130.
gov:80/dea/pubs/pressrel/pr071399.htm), accessed on October 14, Holtman JR, Jing X, Wala EP. 2003. Sex-related differences in the enhance- ment of morphine antinociception by NMDA receptor antagonists in De Luca MT, Badiani A. 2011. Ketamine self-administration in the rat: rats. Pharmacol Biochem Behav 76:285-293. Evidence for a critical role of setting. Psychopharmacology (Berl) Imre G, Fokkema DS, Den Boer JA, Ter Horst GJ. 2006. Dose-response characteristics of ketamine effect on locomotion, cognitive function and Diazgranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Lucken- central neuronal activity. Brain Res Bull 69:338-345.
baugh DA, Machado-Vieira R, Zarate CA Jr. 2010. Rapid resolution of Janowsky DS, Risch C. 1979. Amphetamine psychosis and psychotic symp- suicidal ideation after a single infusion of an N-methyl-D-aspartate an- toms. Psychopharmacology 65:73-77.
tagonist in patients with treatment-resistant major depressive disorder. J Jansen KL. 1993. Non-medical use of ketamine. BMJ 306:601-602.
Clin Psychiatry 71:1605-1611.
Jansen KL. 2000. A review of the nonmedical use of ketamine: Use, users Dillon P, Copeland J, Jansen K. 2003. Patterns of use and harms associated and consequences. J Psychoact Drugs 32:419-433.
with non-medical ketamine use. Drug Alcohol Depend 69:23-28.
Jansen KL, Darracot-Cankovic R. 2001. The nonmedical use of ketamine, Domino EF, ed. 1990. Status of Ketamine in Anesthesiology. Ann Arbor: part two: A review of problem use and dependence. J Psychoact Drugs Domino EF. 2010. Taming the ketamine tiger. Anesthesiology 113:678- Jentsch JD, Roth RH. 1999. The neuropsychopharmacology of phencycli- dine: From NMDA receptor hypofunction to the dopamine hypothesis Domino EF, Chodoff P, Corssen G. 1965. Pharmacologic effects of CI-581, of schizophrenia. Neuropsychopharmacology 20:201-225.
a new dissociative anesthetic, in man. Clin Pharmacol Ther 6:279-291.
Joo G, Horvath G, Klimscha W, Kekesi G, Dobos I, Szikszay M, Benedek Douglas BG, Dagirmanjian R. 1975. The effects of magnesium defi ciency G. 2000. The effects of ketamine and its enantiomers on the morphine- of ketamine sleeping times in the rat. Br J Anaesth 47:336-340.
or dexmedetomidine-induced antinociception after intrathecal adminis- Fantegrossi WE, Murnane KS, Reissig CJ. 2008. The behavioral pharma- tration in rats. Anesthesiology 93:231-241.
cology of hallucinogens. Biochem Pharmacol 75:17-33.
Kelly BC, Parsons JT, Wells BE. 2006. Prevalence and predictors of club Farber NB, Jiang XP, Heinkel C, Nemmers B. 2002a. Antiepileptic drugs drug use among club-going young adults in New York City. J Urban and agents that inhibit voltage-gated sodium channels prevent NMDA Health 83:884-895.
antagonist neurotoxicity. Mol Psychiatry 7:726-733.
Kosson D, Klinowiecka A, Kosson P, Bonney I, Carr DB, Mayzner- Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C. 2002b. Receptor Zawadzka E, Lipkowski AW. 2008. Intrathecal antinociceptive interac- mechanisms and circuitry underlying NMDA antagonist neurotoxicity. tion between the NMDA antagonist ketamine and the opioids, morphine Mol Psychiatry 7:32-43.
and biphalin. Eur J Pain 12:611-616.
Freese TE, Miotto K, Reback CJ. 2002. The effects and consequences of Kronenberg, RH. 2002. Ketamine as an analgesic: parenteral, oral, rectal, selected club drugs. J Subst Abuse Treat 23:151-156.
subcutaneous, transdermal and intranasal administration. J Pain Pallia- Gao C, Che LW, Chen J, Xu XJ, Chi ZQ. 2003. Ohmefentanyl stereoiso- tive Care Pharmacother 16:27-35.
mers induce changes of CREB phosphorylation in hippocampus of mice Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, in conditioned place preference paradigm. Cell Res 13:29-34.
Heninger GR, Bowers MB Jr, Charney DS. 1994. Subanesthetic effects Garcia C, Trujillo KA. 2007. Club drug interactions: Effects of ketamine of the noncompetitive NMDA antagonist, ketamine, in humans: Psy- and methamphetamine combinations on locomotor behavior in rats. Soc chotomimetic, perceptual, cognitive, and neuroendocrine responses. Neurosci Annu Conf Abstr #813.15.
Arch Gen Psychiatry 51:199-214.
Gill JR, Stajic M. 2000. Ketamine in non-hospital and hospital deaths in Krystal JH, D'Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab New York City. J Forensic Sci 45:655-658.
D, Cassello K, Bowers MB Jr, Vegso S, Heninger GR, Charney DS. Gilmour G, Pioli EY, Dix SL, Smith JW, Conway MW, Jones WT, Loomis 1999. Interactive effects of subanesthetic ketamine and haloperidol in S, Mason R, Shahabi S, Tricklebank MD. 2009. Diverse and often op- healthy humans. Psychopharmacology (Berl) 145:193-204.
Volume 52, Number 3 2011 Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. Lukas SE, Griffi ths RR, Brady JV, Wurster RM. 1984. Phencyclidine-ana- 2003. NMDA receptor antagonist effects, cortical glutamatergic func- logue self-injection by the baboon. Psychopharmacology (Berl) 83:316- tion, and schizophrenia: Toward a paradigm shift in medication devel- opment. Psychopharmacology (Berl) 169:215-233.
Machado-Vieira R, Manji HK, Zarate CA. 2009. The role of the tripartite Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R, glutamatergic synapse in the pathophysiology and therapeutics of mood McDougall L, Hunsberger T, Belger A, Levine L, Breier A. 2005a. Pre- disorders. Neuroscientist 15:525-539.
liminary evidence of attenuation of the disruptive effects of the NMDA Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji glutamate receptor antagonist, ketamine, on working memory by pre- HK. 2008. Cellular mechanisms underlying the antidepressant effects of treatment with the group II metabotropic glutamate receptor agonist, ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propi- ly354740, in healthy human subjects. Psychopharmacology (Berl) onic acid receptors. Biol Psychiatry 63:349-352.
Malhotra AK, Adler CM, Kennison SD, Elman I, Pickar D, Breier A. 1997a. Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi- Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D'Souza DC. A study with ketamine. Biol Psychiatry 42:664-668.
2005b. Comparative and interactive human psychopharmacologic ef- Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A. fects of ketamine and amphetamine: Implications for glutamatergic and 1997b. Ketamine-induced exacerbation of psychotic symptoms and dopaminergic model psychoses and cognitive function. Arch Gen Psy- cognitive impairment in neuroleptic-free schizophrenics. Neuropsy- chiatry 62:985-994. Kugaya A, Sanacora G. 2005. Beyond monoamines: Glutamatergic func- Mansbach RS, Geyer MA. 1991. Parametric determinants in pre-stimulus tion in mood disorders. CNS Spectr 10:808-819.
modifi cation of acoustic startle: Interaction with ketamine. Psychophar- Lahti AC, Koffel B, LaPorte D, Tamminga CA. 1995. Subanesthetic doses macology (Berl) 105:162-168.
of ketamine stimulate psychosis in schizophrenia. Neuropsychopharma- Mansbach RS, Carver J, Zorn SH. 2001. Blockade of drug-induced defi cits cology 13:9-19.
in prepulse inhibition of acoustic startle by ziprasidone. Pharmacol Bio- Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. chem Behav 69:535-542.
2001. Effects of ketamine in normal and schizophrenic volunteers. Neu- Mao J. 1999. NMDA and opioid receptors: Their interactions in antinocicep- tion, tolerance and neuroplasticity. Brain Res Rev 30:289-304.
Lannes B, Micheletti G, Warter JM, Kempf E, Di Scala G. 1991. Behav- Marquis KL, Moreton JE. 1987. Animal models of intravenous phencycli- ioural, pharmacological and biochemical effects of acute and chronic noid self-administration. Pharmacol Biochem Behav 27:385-389.
administration of ketamine in the rat. Neurosci Lett 128:177-181.
Marquis KL, Gussio R, Webb MG, Moreton JE. 1989. Cortical EEG Large CH, Webster EL, Goff DC. 2005. The potential role of lamotrigine in changes during the self-administration of phencyclinoids. Neurophar- schizophrenia. Psychopharmacology (Berl) 181:415-436.
Latremoliere A, Woolf CJ. 2009. Central sensitization: A generator of pain Mathew SJ, Manji HK, Charney DS. 2008. Novel drugs and therapeutic hypersensitivity by central neural plasticity. J Pain 10:895-926.
targets for severe mood disorders. Neuropsychopharmacology 33:2080- Leccese AP, Marquis KL, Mattia A, Moreton JE. 1986. The anticonvulsant and behavioral effects of phencyclidine and ketamine following chronic McCarthy DA, Harrigan SE. 1977. Dependence-producing capacity of treatment in rats. Behav Brain Res 22:257-264.
ketamine in macaca mulatta. In: Hülz E, Sanchez-Hernandez JA, Lees J, Hallak JE, Deakin JF, Dursun SM. 2004. Gender differences and the Vasconcelos G, Lunn JN. Anaesthesiology: Proceedings of the VI World effects of ketamine in healthy volunteers. J Psychopharmacol 18:337-339.
Congress of Anaesthesiology, Mexico City, April 24-30, 1976. Amster- Leri F, Bruneau J, Stewart J. 2003. Understanding polydrug use: Review of dam: Excerpta Medica. p 160-168.
heroin and cocaine co-use. Addiction 98:7-22.
McCarthy DA, Chen G, Kaump DH, Ensor C. 1965. General anesthetic and Li F, Fang Q, Liu Y, Zhao M, Li D, Wang J, Lu L. 2008. Cannabinoid CB(1) other pharmacological properties of 2-(o-chlorophenyl)-2-methylamino receptor antagonist rimonabant attenuates reinstatement of ketamine cyclohexanone HCL (CI-581). J New Drugs 28:21-33.
conditioned place preference in rats. Eur J Pharmacol 589:122-126.
Mercado E, Garcia C, Trujillo KA. 2009. Low dose depressant effects of Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, ketamine and interaction with other drugs of abuse. Soc Neurosci Ann Duman RS. 2010. mTOR-dependent synapse formation underlies the rapid Conf Abstr #551.17.
antidepressant effects of NMDA antagonists. Science 329:959-964.
Moghaddam B, Adams BW. 1998. Reversal of phencyclidine effects by a Livingston A, Waterman AE. 1978. The development of tolerance to ket- group II metabotropic glutamate receptor agonist in rats. Science amine in rats and the signifi cance of hepatic metabolism. Br J Pharma- col 64:63-69.
Moghaddam B, Adams B, Verma A, Daly D. 1997. Activation of gluta- Lodge D, Anis NA, Burton NR. 1982. Effects of optical isomers of ket- matergic neurotransmission by ketamine: A novel step in the pathway amine on excitation of cat and rat spinal neurones by amino acids and from NMDA receptor blockade to dopaminergic and cognitive disrup- acetylcholine. Neurosci Lett 29:281-286.
tions associated with the prefrontal cortex. J Neurosci 17:2921-2927.
Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA. 2003a. Ef- Moreton JE, Meisch RA, Stark L, Thompson T. 1977. Ketamine self- fects of ketamine and N-methyl-D-aspartate on glutamate and dopamine administration by the rhesus monkey. J Pharmacol Exp Ther 203:303- release in the rat prefrontal cortex: Modulation by a group II selective metabotropic glutamate receptor agonist ly379268. Neuroscience Mucha RF, van der Kooy D, O'Shaughnessy M, Bucenieks P. 1982. Drug reinforcement studied by the use of place conditioning in rat. Brain Res Lorrain DS, Schaffhauser H, Campbell UC, Baccei CS, Correa LD, Rowe B, Rodriguez DE, Anderson JJ, Varney MA, Pinkerton AB, Vernier JM, Muetzelfeldt L, Kamboj SK, Rees H, Taylor J, Morgan CJ, Curran HV. Bristow LJ. 2003b. Group II MGLU receptor activation suppresses nor- 2008. Journey through the k-hole: Phenomenological aspects of ket- epinephrine release in the ventral hippocampus and locomotor responses amine use. Drug Alcohol Depend 95:219-229.
to acute ketamine challenge. Neuropsychopharmacology 28:1622- Nadeson R, Tucker A, Bajunaki E, Goodchild CS. 2002. Potentiation by ketamine of fentanyl antinociception. I. An experimental study in rats Lourenço Da Silva A, Hoffmann A, Dietrich MO, Dall'Igna OP, Souza DO, showing that ketamine administered by non-spinal routes targets spinal Lara DR. 2003. Effect of riluzole on MK-801 and amphetamine-induced cord antinociceptive systems. Br J Anaesth 88:685-691.
Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. 1959. Study of Rajagopal L, Harte MK. 2010 Animal models of cognitive dysfunction a new schizophrenomimetic drug, sernyl. AMA Arch Neurol Psychiatry and negative symptoms of schizophrenia: Focus on NMDA receptor an- tagonism. Pharmacol Ther 128:419-432.
ILAR Journal Nelson CL, Burk JA, Bruno JP, Sarter M. 2002. Effects of acute and re- Suzuki T, Kato H, Aoki T, Tsuda M, Narita M, Misawa M. 2000. Effects of peated systemic administration of ketamine on prefrontal acetylcholine the non-competitive NMDA receptor antagonist ketamine on morphine- release and sustained attention performance in rats. Psychopharmacol- induced place preference in mice. Life Sci 67:383-389.
ogy (Berl) 161:168-179.
Swerdlow NR, Bakshi V, Waikar M, Taaid N, Geyer MA. 1998. Seroquel, Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, clozapine and chlorpromazine restore sensorimotor gating in ketamine- Hershey T, Craft S, Olney JW. 1999. Ketamine-induced NMDA recep- treated rats. Psychopharmacology (Berl) 140:75-80.
tor hypofunction as a model of memory impairment and psychosis. Takahata R, Moghaddam B. 2003. Activation of glutamate neurotransmis- sion in the prefrontal cortex sustains the motoric and dopaminergic Olney JW, Newcomer JW, Farber NB. 1999. NMDA receptor hypofunction effects of phencyclidine. Neuropsychopharmacology 28:1117-1124.
model of schizophrenia. J Psychiatr Res 33:523-533.
Trujillo KA. 2000. Are NMDA receptors involved in opiate-induced neural Ong JC, Brody SA, Large CH, Geyer MA. 2005. An investigation of the and behavioral plasticity? A review of preclinical studies. Psychophar- effi cacy of mood stabilizers in rodent models of prepulse inhibition. J macology (Berl) 151:121-141.
Pharmacol Exp Ther 315:1163-1171.
Trujillo KA, Akil H. 1991. Inhibition of morphine tolerance and depen- Paul IA, Skolnick P. 2003. Glutamate and depression: Clinical and preclini- dence by the NMDA receptor antagonist MK-801. Science cal studies. Ann N Y Acad Sci 1003:250-272.
Pellissier T, Laurido C, Kramer V, Hernandez A, Paelle C. 2003. Antinoci- Trujillo KA, Akil H. 1994. Inhibition of opiate tolerance by non-competitive ceptive interactions of ketamine with morphine or methadone in monon- N-methyl-D-aspartate receptor antagonists. Brain Res 633:178-188.
europathic rats. Eur J Pharmacol 477:23-28. Trujillo KA, Herman JP, Schäfer MK-H, Mansour A, Meador-Woodruff J, Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. 2008. Watson SJ, Akil H. 1993. Drug reward and brain circuitry: Recent advances Riluzole in the treatment of mood and anxiety disorders. CNS Drugs and future directions. In: Korenman SG, Barchas JD. Biological Basis of Substance Abuse. New York: Oxford University Press. p 119-142.
Popik P, Kos T, Sowa-Kucma M, Nowak G. 2008. Lack of persistent effects Trujillo KA, Zamora JJ, Warmoth KP. 2008. Increased response to ketamine of ketamine in rodent models of depression. Psychopharmacology following treatment at long intervals: Implications for intermittent use. (Berl) 198:421-430.
Biol Psychiatry 63:178-183.
Premkumar TS, Pick J. 2006. Lamotrigine for schizophrenia. Cochrane Da- Tzschentke TM. 1998. Measuring reward with the conditioned place prefer- tabase Syst Rev:CD005962.
ence paradigm: A comprehensive review of drug effects, recent progress Razoux F, Garcia R, Lena I. 2007. Ketamine, at a dose that disrupts motor and new issues. Prog Neurobiol 56:613-672.
behavior and latent inhibition, enhances prefrontal cortex synaptic effi - Tzschentke TM. 2007. Measuring reward with the conditioned place prefer- cacy and glutamate release in the nucleus accumbens. Neuropsycho- ence (CPP) paradigm: Update of the last decade. Addict Biol 12:227- Risner ME. 1982. Intravenous self-administration of phencyclidine and re- Uchihashi Y, Kuribara H, Morita T, Fujita T. 1993. The repeated administra- lated compounds in the dog. J Pharmacol Exp Ther 221:637-644.
tion of ketamine induces an enhancement of its stimulant action in mice. Robinson TE, Berridge KC. 1993. The neural basis of drug craving: An in- Jpn J Pharmacol 61:149-151.
centive-sensitization theory of addiction. Brain Res Brain Res Rev Uzbay IT, Wallis CJ, Lal H, Forster MJ. 2000. Effects of NMDA receptor blockers on cocaine-stimulated locomotor activity in mice. Behav Brain Robinson TE, Berridge KC. 2001. Incentive-sensitization and addiction. Res 108:57-61.
van Berckel BN, Oranje B, van Ree JM, Verbaten MN, Kahn RS. 1998. The Robinson TE, Berridge KC. 2002. Addiction. Annu Rev Psychol 14:14.
effects of low dose ketamine on sensory gating, neuroendocrine secre- Rocha BA, Ward AS, Egilmez Y, Lytle DA, Emmett-Oglesby MW. 1996. tion and behavior in healthy human subjects. Psychopharmacology Tolerance to the discriminative stimulus and reinforcing effects of ket- (Berl) 137:271-281.
amine. Behav Pharmacol 7:160-168.
van der Kam EL, de Vry J, Tzschentke TM. 2007. Effect of 2-methyl-6- Ross S. 2008. Ketamine and addiction. Primary Psychiatry 15:61-69.
(phenylethynyl) pyridine on intravenous self-administration of ketamine Schatzberg AF, Nemeroff CB, eds. 2009. Textbook of Psychopharmacol- and heroin in the rat. Behav Pharmacol 18:717-724.
ogy. Arlington VA: American Psychiatric Publishing.
van der Kam EL, De Vry J, Tzschentke TM. 2009a. 2-methyl-6- Seeman P. 2009. Glutamate and dopamine components in schizophrenia. J (phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin re- Psychiatr Neurosci 34:143-149.
ward as assessed by acquisition, extinction, and reinstatement of Sinner B, Graf BM. 2008. Ketamine. Handb Exp Pharmacol:313-333.
conditioned place preference in the rat. Eur J Pharmacol 606:94-101.
Skolnick P. 1999. Antidepressants for the new millennium. Eur J Pharmacol van der Kam EL, De Vry J, Tzschentke TM. 2009b. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intra- Skolnick P, Popik P, Trullas R. 2009. Glutamate-based antidepressants: 20 venous self-administration and induces conditioned place preference in years on. Trends Pharmacol Sci 30:563-569.
the rat. Eur J Pharmacol 607:114-120.
Smith KM, Larive LL, Romanelli F. 2002. Club drugs: Methylene- Visser E, Schug SA. 2006. The role of ketamine in pain management. dioxymethamphetamine, fl unitrazepam, ketamine hydrochloride, Biomed Pharmacother 60:341-348.
and gamma-hydroxybutyrate. Am J Health Syst Pharm 59:1067- White JM, Ryan CF. 1996. Pharmacological properties of ketamine. Drug Alcohol Rev 15:145-155.
Subramaniam K, Subramaniam B, Steinbrook RA. 2004. Ketamine as adju- White PF, Way WL, Trevor AJ. 1982. Ketamine: Its pharmacology and vant analgesic to opioids: A quantitative and qualitative systematic re- therapeutic uses. Anesthesiology 56:119-136.
view. Anesth Analg 99:482-495, table of contents.
Wiley JL, Evans RL, Grainger DB, Nicholson KL. 2008. Age-dependent Sullivan B, Trujillo KA. 2007. Sensitization to ketamine in a "bump" model: differences in sensitivity and sensitization to cannabinoids and "club Robust effect following different patterns of administration. Soc Neuro- drugs" in male adolescent and adult rats. Addict Biol 13:277-286.
sci Ann Conf Abstr #813.13.
Williams HJ, Zamzow CR, Robertson H, Dursun SM. 2006. Effects of clo- Sullivan B, Trujillo KA. 2010. Modest motivational effects of ketamine as zapine plus lamotrigine on phencyclidine-induced hyperactivity. Prog demonstrated by conditioned place preference. Soc Neurosci Ann Conf Neuropsychopharmacol Biol Psychiatry 30:239-243.
Abstr #67.17.
Winger G, Palmer RK, Woods JH. 1989. Drug-reinforced responding: Suzuki T, Aoki T, Kato H, Yamazaki M, Misawa M. 1999. Effects of the Rapid determination of dose-response functions. Drug Alcohol Depend 5-ht(3) receptor antagonist ondansetron on the ketamine- and dizo- cilpine-induced place preferences in mice. Eur J Pharmacol 385:99- Winters WD, Hance AJ, Cadd GG, Quam DD, Benthuysen JL. 1988. Ket- amine- and morphine-induced analgesia and catalepsy. I. Tolerance, Volume 52, Number 3 2011 cross-tolerance, potentiation, residual morphine levels and naloxone ac- preference and NR1 receptor phosphorylation in rats. Neurosignals tion in the rat. J Pharmacol Exp Ther 244:51-57.
Wise RA. 1988. Psychomotor stimulant properties of addictive drugs. Ann Yamakura T, Shimoji K. 1999. Subunit- and site-specifi c pharmacology of N Y Acad Sci 537:228-234.
the NMDA receptor channel. Prog Neurobiol 59:279-298.
Wise RA, Bozarth MA. 1987. A psychomotor stimulant theory of addiction. Yilmaz A, Schulz D, Aksoy A, Canbeyli R. 2002. Prolonged effect of an Psychol Rev 94:469-492.
anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Wolff K, Winstock AR. 2006. Ketamine: From medicine to misuse. CNS Behav 71:341-344.
Drugs 20:199-218.
Young AM, Woods JH. 1981. Maintenance of behavior by ketamine and Wood PL, Rao TS, Iyengar S, Lanthorn T, Monahan J, Cordi A, Sun E, related compounds in rhesus monkeys with different self-administration Vazquez M, Gray N, Contreras P. 1990. A review of the in vitro and in histories. J Pharmacol Exp Ther 218:720-727.
vivo neurochemical characterization of the NMDA/PCP/glycine/ion Zarate CA, Manji HK. 2008. Riluzole in psychiatry: A systematic review of channel receptor macrocomplex. Neurochem Res 15:217-230.
the literature. Expert Opin Drug Metab Toxicol 4:1223-1234.
Woolf CJ. 2011. Central sensitization: Implications for the diagnosis and Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh treatment of pain. Pain 152(3 Suppl):S2-S15. DA, Charney DS, Manji HK. 2006. A randomized trial of an N-methyl- Xu DD, Mo ZX, Yung KK, Yang Y, Leung AW. 2006. Individual and com- D-aspartate antagonist in treatment-resistant major depression. Arch bined effects of methamphetamine and ketamine on conditioned place Gen Psychiatry 63:856-864. ILAR Journal


Contents The Minister for Defence and the Department of Defence 1.1 The Minister The Constitution vests supreme command of the Defence Forces in the President and also provides that the exercise of such command shall be regulated by law. The governing legislation is contained in the Defence Acts, 1954-2011, which provide that military


The Effect of Inhaled Fluticasone Propionate inthe Treatment of Young Asthmatic ChildrenA Dose Comparison Study HANS BISGAARD, JOHN GILLIES, MARCELLE GROENEWALD, and CLAIRE MADENon behalf of an International Study Group Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Hamilton, New Zealand; Pretoria, South Africa;and Glaxo Wellcome Research and Development, Greenford, United Kingdom