Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders. METHOD: In this randomized, double-blind, placebo-controlled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007. RESULTS: Differences were statistically significant (P < .05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P < .05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group). CONCLUSIONS: Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00369577.

Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers.

The objective of this randomized, double-blind, placebo-controlled, dose escalation study was to determine the pharmacokinetic characteristics, safety, and tolerability of single doses of inhaled loxapine aerosol in healthy volunteers. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Fifty participants were randomized to receive 0.625, 1.25, 2.5, 5.0, or 10 mg of loxapine aerosol or placebo. Following inhalation, the t(max) median (25%, 75%) was 2 (1, 3) minutes. The loxapine AUC(infinity) was dose proportional across all doses with slope (90% confidence interval) of log AUC(infinity) versus log dose = 0.909 (0.832, 0.987). No clinically meaningful changes were noted in hematology results, blood chemistry, vital signs, or respiratory function. The most common adverse events were dizziness, somnolence, and bad taste. The inhalation of Staccato loxapine represents a safe, well-tolerated means for rapidly achieving therapeutic plasma concentrations of loxapine.

Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant.

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.

Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation.

A deficiency of most current drug products for treatment of acute conditions is slow onset of action. A promising means of accelerating drug action is through rapid systemic drug administration via deep lung inhalation. The speed of pulmonary drug absorption depends on the site of aerosol deposition within the lung and the dissolution rate and drug content of the deposited particles. Alveolar delivery of fast-dissolving, pure drug particles should in theory enable very rapid absorption. We have previously shown that heating of thin drug films generates vapor-phase drug that subsequently cools and condenses into pure drug particles of optimal size for alveolar delivery. Here we present a hand held, disposable, breath-actuated device incorporating this thermal aerosol technology, and its application to the delivery of alprazolam, an anti-panic agent, and prochlorperazine, an anti-emetic with recently discovered anti-migraine properties. Thermal aerosol particles of these drugs exist in an amorphous state, which results in remarkably rapid drug absorption from the lung into the systemic circulation, with peak left ventricular concentrations achieved within 20 s, even quicker than following rapid (5 s) intravenous infusion. Absorption of the thermal aerosol is nearly complete, with >80% absolute bioavailability found in both dogs and human normal volunteers.

Attenuation of nicotine's discriminative stimulus effects in rats and its locomotor activity effects in mice by serotonergic 5-HT2A/2C receptor agonists.

RATIONALE: Reports have indicated that administration of nicotine inhibits, while withdrawal of chronically administered nicotine augments effects of serotonergic 5HT2A/2C agonists. OBJECTIVE: It was our objective to determine whether 5HT2A/2C agonists can modulate the discriminative stimulus effects of nicotine in rats or its locomotor activity effects in mice. METHODS: Adult male Sprague-Dawley rats were trained to discriminate 0.3 mg/kg nicotine base from saline in a two-lever, fixed-ratio (FR10), food-reinforced, operant-conditioning task during daily (Monday-Friday) 15-min experimental sessions. After characterizing a dose-response curve for nicotine, we tested the ability of the 5HT(2A/2C) agonists (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCL (DOI; 0.18-1.0 mg/kg) and 1-(4-bromo-2, 5-dimethoxyphenyl)-2-aminopropane (DOB; 0.1-1.0 mg/kg), the 5HT2C agonist 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride (MK 212; 0.1 mg/kg-1.0 mg/kg), and the 5HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.01 mg/kg-1.0 mg/kg) to modulate nicotine's discriminative stimulus effects. After finding that DOI was able to attenuate the percentage nicotine lever responding (%NLR), we tested for it to also reverse nicotine's effects on locomotor activity in mice. RESULTS: The 5HT2A/2C agonists-in particular DOI-dose dependently attenuated %NLR. The effects of DOI were reversed by the 5HT2A/2C antagonist ketanserin. MK 212 and 8-OH-DPAT had irregular effects among rats and only reduced %NLR to below 50% levels at doses markedly suppressing responding. DOI also dose dependently blocked nicotine's acute rate-lowering locomotor activity effects. CONCLUSIONS: These results indicate that activation of serotonin 5HT2A/2C receptors can blunt the discriminative stimulus and locomotor activity effects of nicotine and presents the possibility that activation of these receptors might also be able to attenuate other effects of nicotine.

Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats.

Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetamine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetamine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole.

Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release.

Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.

The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys.

RATIONALE: Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since Delta(9)-tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates. OBJECTIVES: To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys. METHODS: Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03-0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2-8 microg/kg per injection) were studied. RESULTS: Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions. CONCLUSIONS: Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.

Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats.

Adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that nonselective adenosine receptor antagonists (caffeine and 3,7-dimethyl-1-propargylxanthine) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A1 receptor agonist N6-cyclopentyladenosine (CPA; 0.01-0.1 mg/kg) and antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.3-23.7 mg/kg) and the A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; 0.03-0.18 mg/kg) and antagonist 3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthin phosphate disodium salt (MSX-3; 1-56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A1 and A2A receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A2A receptor agonist CGS 21680 also produced drug-appropriate responding (although at lower levels) when substituted for the cocaine-training stimulus, and both CGS 21680 and the A1 receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast, both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetamine-training stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A1 and A2A receptors appear to play important but differential roles in the modulation of the discriminative-stimulus effects of methamphetamine and cocaine.

Evaluation of the novel antiepileptic drug, AWD 131-138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys.

AWD 131-138 [1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one], a new low-affinity partial benzodiazepine receptor agonist with potent anticonvulsant and anxiolytic properties in rodent models, was studied in squirrel monkeys trained to discriminate intramuscular (i.m.) injections of midazolam (0.3 mg/kg) from injections of vehicle. Diazepam produced midazolam-like responding at cumulative doses of 1.0 and 3.0 mg/kg i.m. and decreased rates of responding at 3.0 mg/kg (plasma levels of about 400 ng/ml). In contrast, AWD 131-138 did not produce midazolam-like responding or alter response rates at cumulative doses up to 18.0 mg/kg i.m. (plasma levels over 2100 ng/ml). Other monkeys were trained to intravenously (i.v.) self-administer cocaine (56.0 microg/kg/injection). When AWD 131-138 (10-100 microg/kg/injection) was studied by substitution, responding declined to vehicle substitution levels within three sessions. At the dose of 100 microg/kg i.v. AWD 131-138, sufficient drug was self-administered during the first session (about 3.5 mg/kg) to produce plasma levels above 1000 ng/ml, yet responding over the next two sessions dropped to vehicle levels. The failure of AWD 131-138 to produce benzodiazepine-like discriminative effects and the absence of drug self-administration behavior when substituted for cocaine suggest that its abuse liability is low.

Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine.

The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence.

Caffeine potentiates the discriminative-stimulus effects of nicotine in rats.

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.

Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats.

RATIONALE: A(1) and A(2A) adenosine receptors are co-localized with dopamine D(1) and D(2) receptors, respectively, and their stimulation attenuates dopaminergic functioning. OBJECTIVE: To test whether adenosine antagonists with different selectivities for A(1) and A(2A) receptors mimic the discriminative-stimulus effects of dopamine releaser methamphetamine. METHODS: Effects of the A(1) antagonist DPCPX, the preferential A(2A) antagonist DMPX and the non-selective adenosine antagonist caffeine were evaluated in Sprague-Dawley rats trained to discriminate 1.0 mg/kg, IP, methamphetamine from saline under a fixed-ratio 10 schedule of food presentation. RESULTS: The A(1) antagonist DPCPX (1.0-10.0 mg/kg) failed to substitute for methamphetamine. However, 5.6 mg/kg DPCPX shifted the methamphetamine dose-response curve to the left. The A(2A) antagonist DMPX (1.8-18.0 mg/kg) produced about 70% methamphetamine-appropriate responding and the non-selective antagonist caffeine (3.0-56.0 mg/kg) about 50% methamphetamine-appropriate responding at the highest tested doses. Both DMPX (5.6 mg/kg) and caffeine (30.0 mg/kg) shifted the methamphetamine dose-response curve to the left. Methamphetamine-like effects of DMPX were blocked fully by the D(2) antagonist spiperone (0.18 mg/kg) and partially by the D(1) antagonist SCH-23390 (0.018 mg/kg). CONCLUSIONS: Antagonism at A(2A) adenosine receptors directly mimics the discriminative-stimulus effects of methamphetamine through the interaction with dopamine receptors. Antagonism at A(1) adenosine receptors potentiates effects of lower methamphetamine doses and thus plays a rather indirect, modulatory role.

Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats.

RATIONALE: Tetracycline antibiotics share some neuroprotective and CNS effects with N-methyl- D-aspartate (NMDA) receptor antagonists. OBJECTIVES: The acute effects of two tetracycline antibiotics were compared to those of the prototypic NMDA antagonist phencyclidine (PCP). METHODS: The effects of minocycline (10-56 mg/kg) and doxycycline (10-56 mg/kg) were evaluated in Sprague-Dawley rats trained to discriminate 2.0 mg/kg IP of PCP from saline under a fixed ratio schedule of food presentation. RESULTS: Even though minocycline and doxycycline did not substitute for PCP, pretreatment with 32 mg/kg of either drug produced leftward shifts in the PCP dose-response curve. The 32 mg/kg dose of minocycline also produced a leftward shift in the dose-response curve for dizocilpine (MK-801), another NMDA channel blocker, in the same subjects. CONCLUSIONS: Tetracycline antibiotics may interact either directly or indirectly with NMDA receptors. This suggests that they might be utilized in treatment of brain disorders in which NMDA receptor over-activation has been implicated.

Differential involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine and methamphetamine.

Involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine versus methamphetamine was studied in Sprague Dawley rats (n=10) trained to discriminate 10 mg/kg cocaine, i.p., from saline under a fixed-ratio 10 (FR10) schedule of food presentation. The ability of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, and ketanserin, a 5-HT(2A) receptor antagonist, to either substitute for or block the discriminative-stimulus effects of cocaine, or to shift the cocaine dose-response curve, was evaluated. DOI (0.18-1.0 mg/kg) partially substituted for the training dose of 10 mg/kg cocaine, but only at doses that decreased rates of responding. At the highest dose of DOI tested (1.0 mg/kg), there was about 65% cocaine-appropriate responding. Substitution of DOI for cocaine and DOI-induced decreases in rates of responding were completely reversed by ketanserin (3.0 mg/kg). Ketanserin (3.0 mg/kg) also produced a significant shift to the right of the cocaine dose-response curve and antagonized increases in rates of responding produced by lower doses of cocaine. Ketanserin (1.0-10.0 mg/kg), however, did not block the discriminative-stimulus effects of the training dose of cocaine. When DOI (0.3 mg/kg) was co-administered with different doses of cocaine, there was a slight leftward shift in the cocaine dose-response curve, which was not significant and appeared to reflect simple additive effects of DOI and cocaine. In contrast, the same dose of DOI (0.3 mg/kg) produced a marked and highly significant shift to the left of the methamphetamine (0.18-1.0 mg/kg) dose-response curve in the same subjects and the effects of DOI and methamphetamine were clearly more than additive. The present findings provide new evidence that there is some serotonergic modulation of cocaine's discriminative-stimulus actions, which appears to involve stimulation of 5-HT(2A) receptors. However, involvement of 5-HT(2A) receptor activity in the discriminative-stimulus actions of cocaine appears to be less pronounced than in similar actions of methamphetamine.

Evaluation of the reinforcing effects of the cannabinoid CB1 receptor antagonist, SR141716, in rhesus monkeys.

The abuse liability of a selective cannabinoid CB1 receptor antagonist, SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), was evaluated in rhesus monkeys. Four rhesus monkeys with chronically indwelling venous catheters were initially trained to self-administer cocaine (30 microg/kg/injection) during daily 1-h sessions under a fixed ratio 50 (FR50) schedule of reinforcement. SR141716 was subsequently substituted for cocaine, and SR141716 dose was varied from 1 to 100 microg/kg/injection. Each dose of SR141716 was tested for four consecutive sessions and each unit dose was separated by at least three sessions of cocaine self-administration. Substitution of SR141716 for cocaine resulted in rapid extinction of lever pressing and none of the doses of SR141716 tested was self-administered above the vehicle levels. When the highest dose of SR141716 (100 microg/kg/injection) was evaluated, self-administration behavior was suppressed below vehicle levels suggesting that behaviorally active doses were evaluated. Since positive results in self-administration tests are generally predictive of abuse potential, the negative results with SR141716 suggest that this drug would likely have low abuse liability.