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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.
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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

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