Responding In Rhesus Monkeys Research Articles

Additive and subadditive antiallodynic interactions between μ-opioid agonists and N-methyl D-aspartate antagonists in male rhesus monkeys.

μ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of μ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of μ-agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (-)-nalbuphine, and (-)-oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of μ-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to μ-opioid agonists for thermal allodynic pain states.

Effects of lorcaserin on cocaine and methamphetamine self-administration and on reinstatement of extinguished responding in rhesus monkeys

Effects of lorcaserin on cocaine and methamphetamine self-administration and on reinstatement of extinguished responding in rhesus monkeys

An assessment of domain-general metacognitive responding in rhesus monkeys

Metacognition is the ability to monitor and control one’s cognition. Monitoring may involve either public cues or introspection of private cognitive states. We tested rhesus monkeys (Macaca mulatta) in a series of generalization tests to determine which type of cues control metacognition. In Experiment 1, monkeys learned a perceptual discrimination in which a “decline-test” response allowed them to avoid tests and receive a guaranteed small reward. Monkeys declined more difficult than easy tests. In Experiments 2–4, we evaluated whether monkeys generalized this metacognitive responding to new perceptual tests. Monkeys showed a trend toward generalization in Experiments 2 & 3, and reliable generalization in Experiment 4. In Experiments 5 & 6, we presented the decline-test response in a delayed matching-to-sample task. Memory tests differed from perceptual tests in that the appearance of the test display could not control metacognitive responding. In Experiment 6, monkeys made prospective metamemory judgments before seeing the tests. Generalization across perceptual tests with different visual properties and mixed generalization from perceptual to memory tests provide provisional evidence that domain-general, private cues controlled metacognition in some monkeys. We observed individual differences in generalization, suggesting that monkeys differ in use of public and private metacognitive cues.

Excitotoxic amygdala lesions disrupt reinforcer devaluation effects on instrumental responding in rhesus monkeys

Event Abstract Back to Event Excitotoxic amygdala lesions disrupt reinforcer devaluation effects on instrumental responding in rhesus monkeys Sarah Rhodes1* and Elisabeth Murray1 1 NIMH, NIH, Laboratory of Neuropsychology, United States The amygdala plays an important role in appetitive emotional learning and memory and its involvement in representing the current value of a food outcome is well documented. For example, studies in which the value of a reward is temporarily reduced via satiety-specific reinforcer devaluation have shown that rats with lesions of the basolateral amygdala (BLA) fail to show the reduction in responding normally seen for a devalued reward. This effect has been observed in both Pavlovian and instrumental paradigms [1] indicating the BLA plays an integral role in the ability of the current outcome value to modulate behavior that is guided by either stimulus-outcome (S-O) or response-outcome (R-O) associations. Monkeys with amygdala lesions likewise show a disruption of satiety-specific devaluation effects in the context of object choices [2]. In the monkey studies, however, the task design left unresolved whether the instrumental R-O associations or S-O driven Pavlovian approach responses were guiding performance. To investigate the role of the amygdala specifically in the control of goal-directed behavior, we designed a task in which responding relied on instrumental control of behavior and could not be explained via Pavlovian mechanisms. Rhesus monkeys were trained to perform two different instrumental responses (tap and hold) on a touch-sensitive screen for two different food rewards. After evaluation of responding in baseline conditions they were tested under extinction for the effect of satiety-specific devaluation. Whereas unoperated controls showed a reduction in performance of the response associated with a devalued outcome relative to the nondevalued outcome, monkeys with excitotoxic amygdala lesions failed to show this shift in response preference. These preliminary data support the idea that the amygdala is required for updating reward value and is therefore essential for goal-directed behavior in appetitive contexts.

Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys

Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate “agonist” medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys ( N = 3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032–0.01 mg/kg/hr) and RTI-113 (0.01–0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.

Effects of the selective delta opioid agonist SNC80 on cocaine- and food-maintained responding in rhesus monkeys

Delta agonists such as SNC80 ((+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide) produce some cocaine-like behavioral effects and warrant evaluation as candidate “agonist” medications for cocaine abuse. The present study examined acute and chronic effects of the systemically active delta agonist SNC80 on cocaine- and food-maintained responding in rhesus monkeys. Acute SNC80 (0.32–3.2 mg/kg, i.m.) pretreatment dose-dependently decreased cocaine self-administration (0.0032 mg/kg/injection), but doses of SNC80 that decreased cocaine self-administration also decreased food-maintained responding. In chronic studies, SNC80 (0.32–3.2 mg/kg/h, i.v.) was delivered for 7 days, and food or cocaine (0.01 mg/kg/injection) was available during 4 daily components of food availability and 4 daily components of drug availability. Chronic SNC80 (1.8 mg/kg/h) tended to decrease cocaine self-administration but produced greater reductions in food-maintained responding. A higher dose of 3.2 mg/kg/h SNC80 eliminated both cocaine- and food-maintained responding and produced profound sedation in one monkey and was not tested in other monkeys. These findings indicate that SNC80 produced dose-dependent and non-selective reductions in cocaine self-administration. These results suggest that SNC80 is unlikely to be useful as a treatment for cocaine dependence.

Effects of the selective delta opioid agonist SNC80 on cocaine‐ and food‐maintained responding in rhesus monkeys

Delta agonists such as SNC80 produce some cocaine-like behavioral effects and warrant evaluation as candidate “agonist” medications for cocaine abuse. The present study examined acute and chronic effects of SNC80 on cocaine- and food-maintained responding in rhesus monkeys. In acute studies, SNC80 (0.32–3.2 mg/kg, i.m.) was administered i.m. 15 min before 2 hr, multiple-component sessions during which food or cocaine was available under a FR30 schedule. SNC80 dose-dependently decreased cocaine self-administration, but doses of SNC80 that decreased cocaine self-administration also decreased food-maintained responding. In chronic studies, SNC80 (0.32–3.2 mg/kg/hr) was delivered by continuous i.v. infusion for 7 days, and food or cocaine (0.01 mg/kg/inj) were available during four daily 1hr food components and four 1hr drug components under a FR4(VR16:S) schedule. SNC80 doses up to 1.8 mg/kg/hr had little effect on cocaine self-administration, although 1.8 mg/kg/hr SNC80 transiently decreased food-maintained responding. A higher dose of 3.2 mg/kg/hr SNC80 eliminated all responding and produced profound sedation for 2 days in the first monkey tested. Further treatment was terminated in this monkey, and other monkeys were not tested. These findings indicate that SNC80 produced a dose-dependent and non-selective reduction in cocaine self-administration. These results contrast with the selective reductions in cocaine self-administration produced by other compounds (e.g. amphetamine, low-efficacy mu agonists) and suggest that SNC80 is unlikely to be useful as a treatment for cocaine dependence. Support: RO1-DA11460, RO1-DA02519 and K05-DA000101.

The effects of eticlopride and the selective D 3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D 3 receptor is mainly expressed in regions of the brain associated with the limbic system. D 3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D 2 receptors. The purpose of the present studies was to evaluate the effects of a selective D 3 receptor antagonist and a non-selective D 2/D 3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01–0.3 mg/kg/injection) presentation. In one experiment ( n = 4), the schedule was a fixed-interval (FI) 3-min and a second study ( n = 6) was conducted using a second-order fixed-ratio 5 (FI 6-min : S) schedule. The D 3 antagonist PNU 99194-A (0.3–3.0 mg/kg), which is 14-fold selective for D 3 relative to D 2 receptors, or the D 2/D 3 antagonist eticlopride (0.001–0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D 3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.

Effects of the mixed-action κ/μ opioid agonist 8-carboxamidocyclazocine on cocaine- and food-maintained responding in rhesus monkeys

The present study evaluated the effects of 8-carboxamidocyclazocine (8-CAC), a novel mixed-action κ/μ agonist with a long duration of action, on food- and cocaine-maintained responding in rhesus monkeys to assess the potential utility of 8-CAC as a medication for the treatment of cocaine dependence. The effects of acute and chronic (10 days) 8-CAC were examined in rhesus monkeys responding under a multiple schedule for both cocaine and food reinforcement. Acute 8-CAC (0.032–0.56 mg/kg, i.m.) dose-dependently eliminated cocaine-maintained responding in all three monkeys. However, doses of 8-CAC that decreased cocaine self-administration typically also decreased food-maintained responding, and 8-CAC-induced decreases in cocaine self-administration diminished during chronic 8-CAC treatment. These results confirm that 8-CAC acutely decreases cocaine self-administration. However, non-selective effects of 8-CAC on food-maintained responding and tolerance to 8-CAC effects on cocaine self-administration may limit its potential for the treatment of cocaine dependence.

Effects of chronic methadone treatment on cocaine- and food-maintained responding under second-order, progressive-ratio and concurrent-choice schedules in rhesus monkeys

The effects of chronic infusion with saline or methadone (0.032–1.0 mg/kg/h) were examined on cocaine- and food-maintained responding in rhesus monkeys using three procedures. In one procedure, cocaine injections (0.0032–0.032 mg/kg per injection) and food pellets were available under a second-order schedule during alternating daily sessions. During saline treatment, cocaine maintained a dose-dependent increase in the number of cocaine injections per day, and monkeys usually responded for the maximum number of pellets. Methadone dose-dependently decreased cocaine self-administration, and methadone doses that decreased cocaine self-administration had variable effects on food-maintained responding. In the second procedure, 0.032 mg/kg per injection cocaine or food pellets were available under a progressive-ratio schedule. During saline treatment, cocaine and food maintained similar break points. Methadone produced a dose-dependent and non-selective decrease in break points maintained by both cocaine and food. In the third procedure, cocaine injections (0–0.1 mg/kg per injection) and food pellets were available under a concurrent-choice schedule. During saline treatment, increasing unit doses of cocaine produced a dose-dependent increase in cocaine choice. Methadone had little effect on the cocaine choice dose-effect curve up to doses that eliminated responding. These results provide little evidence to suggest that chronic methadone altered the reinforcing effects of cocaine; rather methadone appeared to non-selectively decrease rates of operant responding.

Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys.

High-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed. The purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (-)2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design. Rhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1 g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003-0.3 mg/kg per injection) were determined. The effects of pretreatment with (-)PTT (0.001-0.056 mg/kg, i.v.) and cocaine (0.03-0.3 mg/kg, i.v.) were determined when the dose of cocaine that maintained peak response rates (0.03 mg/kg per injection) or saline was available. (-)PTT and cocaine reduced cocaine intake; (-)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (-)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures. These results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.

Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys

Effective treatment of opioid dependence with methadone and of tobacco dependence with nicotine illustrates the potential usefulness of agonist medications for drug abuse treatment. The monoamine-releaser d-amphetamine is one drug under consideration as an agonist pharmacotherapy for cocaine dependence. To assess the concordance between preclinical evaluations and ongoing clinical trials, the present study examined the effects of chronic treatment with saline or d-amphetamine on cocaine- and food-maintained responding in rhesus monkeys. Cocaine injections and food pellets were available under a second-order schedule during alternating daily sessions of cocaine and food availability. d-Amphetamine (0.01–0.1 mg/kg per h i.v. for 7 consecutive days) dose-dependently decreased self-administration of a unit dose of cocaine (0.01 mg/kg per injection) at the peak of the cocaine self-administration dose–effect curve. d-Amphetamine (0.032–0.1 mg/kg per h for 7 days) also decreased self-administration of a broad range of cocaine doses (0.0032–0.1 mg/kg per injection) and produced rightward and downward shifts in the cocaine dose–effect curve. Food-maintained responding was usually decreased less than cocaine self-administration, and few signs of toxicity were noted. To evaluate the effects of a longer treatment regimen, d-amphetamine (0.1 mg/kg per h) was administered for 28 consecutive days. d-Amphetamine nearly eliminated self-administration of cocaine (0.01 mg/kg per injection) throughout this treatment, whereas food-maintained responding returned to baseline levels after approximately 9 days. These preclinical findings are concordant with recent clinical studies and suggest that chronic d-amphetamine may selectively decrease cocaine-taking behavior in rhesus monkeys, possibly by producing a selective decrease in the reinforcing effects of cocaine.

Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys.

The present study examined how daily treatment with the benzodiazepine (BZ) diazepam modifies the effects of positive modulators acting at different sites on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABA(A) modulators were administered alone or in combination with acute or chronic diazepam to rhesus monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus-shock termination (SST). There was mutual antagonism between the rate-decreasing effects of diazepam (5.6 mg/kg, p.o.) and high efficacy BZ site negative modulators [ethyl beta-carboline-3-carboxylate (beta-CCE), methyl beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (DMCM)]. Antagonism of beta-CCE, beta-CCM, and DMCM by diazepam was markedly reduced in monkeys receiving diazepam daily. In contrast, daily diazepam treatment enhanced the rate-decreasing effects of Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and flumazenil. Chronic diazepam elicited cross-tolerance to the BZ triazolam and not to the barbiturate pentobarbital or the neuroactive steroid pregnanolone. These results suggest that tolerance to the rate-decreasing effects of BZs is not accompanied by cross-tolerance to positive GABA(A) modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABA(A) modulators during chronic diazepam treatment appeared to be related to negative efficacy and not clearly related to the precipitation of withdrawal for all drugs. These results indicate that changes in sensitivity to the behavioral effects of drugs that act at different sites on the GABA(A) receptor complex might be especially useful for identifying and characterizing the functional consequences of GABA(A) receptor heterogeneity.

Development of Long-Acting Dopamine Transporter Ligands as Potential Cocaine-Abuse Therapeutic Agents: Chiral Hydroxyl-Containing Derivatives of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine

In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909 and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The enantiomers of the 2-hydroxylated analogues displayed substantial enantioselectivity. The S enantiomers displayed higher dopamine transporter (DAT) affinity and the R enantiomers were found to interact at the serotonin transporter (SERT) with higher affinity. The two-carbon spacer between the hydroxyl group and the piperazine ring was essential for enantioselectivity, and the length of the alkyl chain between the phenyl group and the piperazine ring influenced binding affinity and selectivity for the DAT and SERT. Phenylethyl analogues had a higher binding affinity for the SERT and a weaker affinity and selectivity for the DAT than the corresponding phenylpropyl analogues. Thus, (S)-(+)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-3-phenylpropan-2-ol (6) displayed the highest affinity to the DAT, and (S)-(+)-1-[4-[2-(diphenylmethoxy)ethyl]piperazinyl]-3-phenylpropan-2-ol (8) had the highest selectivity. The latter (8) is one of the most DAT selective ligands known. In accord with the in vitro data, 6 showed greater potency than 7 in elevating extracellular dopamine levels in a microdialysis assay and in inhibiting cocaine-maintained responding in rhesus monkeys.

Tetrabenazine fails to antagonize a behavioral effect of cocaine in rhesus monkeys

For research and therapeutic purposes, a cocaine antagonist is an important drug development goal. The vesicular monoamine transport inhibitor tetrabenazine was tested for interaction with cocaine using food-reinforced responding in rhesus monkeys as an assay. Both tetrabenazine and cocaine suppressed food-maintained behavior individually. However, a low-dose tetrabenazine pretreatment did not alter the rate-suppressing effects of cocaine and cocaine did not alter the rate-suppressing effects of a high dose tetrabenazine pretreatment. Because tetrabenazine interacts with the monoamine oxidase inhibitor deprenyl in this assay, we conclude that cocaine does not produce an effect through vesicular catecholamines in this assay.

A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule

The dopamine reuptake inhibitor GBR 12909 and the dopamine releaser phentermine may have potential for the treatment of cocaine abuse in humans. Pre-session treatment with either drug can decrease cocaine-maintained responding in rhesus monkeys while not affecting food-maintained responding. Both drugs are self-administered, but in some reports the patterns of responding they maintain differ from typical cocaine-reinforced responding. This study compared self-administration of cocaine (1–100 μg/kg/inj), GBR 12909 (3–100 μg/kg/inj), and phentermine (10–170 μg/kg/inj) in rhesus monkeys on a progressive-ratio schedule. Individual unit doses of each drug were available across several consecutive sessions. Cocaine self-administration was typical: the average number of ratios completed per session was a bitonic (increasing/decreasing) function of unit dose. Phentermine self-administration was variable across subjects (two of four monkeys self-administered reliably); one subject exhibited clear signs of behavioral toxicity. Self-administration of GBR 12909 was similarly variable across subjects. In the two subjects that self-administered GBR 12909 reliably, self-administration of small to mid-sized unit doses was enhanced following exposure to large unit doses. These data indicate that differences in self-administration of these drugs can be observed under progressive ratio procedures. Further, the data add to existing evidence suggesting that phentermine and GBR 12909 have at least moderate potential to be abused by humans.

Quadazocine decreases responding reinforced by ethanol, sucrose, and phencyclidine fluid deliveries in rhesus monkeys: comparison to naltrexone's effects

The endogenous opioid system may mediate the reinforcing effects of ethanol as well as sweet-tasting solutions. For example, opioid antagonists, such as naltrexone, reduce ethanol- and sucrose-reinforced responding in rhesus monkeys. If these effects are due to blockade of the mu-receptor, then an opioid antagonist such as quadazocine with a receptor selectivity profile similar to that of naltrexone should reduce responding at doses correlated with its mu-selectivity. To determine whether quadazocine would reduce responding for ethanol and sucrose at mu-selective doses, and whether quadazocine and naltrexone would reduce responding for a bitter-tasting drug solution such as phencyclidine. Rhesus monkeys were given access to ethanol, sucrose, or phencyclidine concurrently with water. Prior to the drinking sessions, quadazocine (0.032-3.2 mg/kg) or saline was injected intramuscularly. During the phencyclidine experiment, naltrexone (0.1 and 0.32 mg/kg) was also tested. The highest quadazocine doses (1 and 3.2 mg/kg) reduced ethanol and sucrose fluid deliveries without affecting the concurrently available water. Quadazocine reduced the fluid deliveries of both phencyclidine and water when concurrently available. Naltrexone reduced only phencyclidine fluid deliveries. The opioid antagonist effect on oral-reinforced responding is not selective for ethanol or sweet-tasting solutions; responding for phencyclidine was reduced as well. Quadazocine and NTX may reduce responding by blocking the mu-receptor because the relative potency of these antagonists to reduce oral self-administration was similar to their relative potency to produce withdrawal in morphine-dependent monkeys. However, water responding was low in these experiments, and thus we cannot rule out rate-dependent effects of the antagonists.

Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol‐Reinforced Responding in Rhesus Monkeys

Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as "side effects" in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist-naive rhesus monkeys responded for solutions from a two-spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool-Aid solutions paired with either saline or naltrexone (0.32 mg/kg) given 30 min before the session. The monkeys then had seven choice sessions between the saline-paired solution or the naltrexone-paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone-paired solution maintained significantly less responding than did the saline-paired solution during the choice phase. In the next phase, the saline and naltrexone were given "unpaired" from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given "unpaired" from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol-, sucrose-, and phencyclidine-reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone-induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics.

Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol-Reinforced Responding in Rhesus Monkeys

Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as “side effects” in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist-naive rhesus monkeys responded for solutions from a two-spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool-Aid® solutions paired with either saline or naltrexone (0.32 mg/kg) given 30 min before the session. The monkeys then had seven choice sessions between the saline-paired solution or the naltrexone-paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone-paired solution maintained significantly less responding than did the saline-paired solution during the choice phase. In the next phase, the saline and naltrexone were given “unpaired” from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given “unpaired” from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol-, sucrose-, and phencyclidine-reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone-induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics.

Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol-Reinforced Responding in Rhesus Monkeys

Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol-Reinforced Responding in Rhesus Monkeys