Relative reinforcing effects of cocaine, remifentanil, and their combination in rhesus monkeys.

Human polydrug abusers often take combinations of opioids and stimulants, but it is not clear why. Behavioral economics with demand curve analysis is uniquely able to separate two of the possibilities: that the drug combination increases the reinforcing potency of the component drugs or that the drug combination is a more effective reinforcer than either drug alone. Rhesus monkeys self-administered a range of doses of cocaine, remifentanil, and combinations of the drugs through indwelling intravenous catheters; the number of responses required for each drug infusion increased across drug-availability sessions. Combining small doses of cocaine and remifentanil that by themselves resulted in very low rates of responding yielded rates of responding that were higher than the maximum maintained by any dose of the constituent drugs. Nevertheless, demand curve analysis demonstrated that the drug combination was equally elastic as the component drugs, indicating that it was not more effective as a reinforcer than either cocaine or remifentanil alone. This suggests that enhanced self-administration of this particular drug combination is due primarily to the drug enhancement of the potency of the other drug.

Reinforcing and discriminative stimulus effects of 1-benzylpiperazine and trifluoromethylphenylpiperazine in rhesus monkeys.

1-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two designer drugs that are often sold in combination tablets via the internet. The discriminative stimulus properties and reinforcing effects of these compounds have not previously been assessed in laboratory primates. In this regard, the reinforcing effects of BZP and TFMPP (alone, and in combination) were assessed via intravenous self-administration in rhesus monkeys previously trained to self-administer cocaine, while the discriminative stimulus effects of these compounds were determined in rhesus monkeys trained to discriminate amphetamine (AMPH) from saline. BZP was an effective reinforcer in self-administration tests, and appeared to induce long-lasting direct effects on behavior following sessions where BZP intakes were large. Additionally, BZP occasioned AMPH-appropriate responding in a dose-dependent manner, and produced full generalization in all monkeys tested. In contrast, TFMPP was not self-administered by any subjects and occasioned essentially no AMPH-appropriate responding at any dose tested. Non-contingent TFMPP administration had direct effects on behavior and abolished subsequent cocaine-maintained responding. Similarly, self-administration of various ratios of BZP:TFMPP combinations engendered less responding than did BZP alone. The present results suggest that BZP has abuse liability of the amphetamine type, but that such effects are not shared by TFMPP.

Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys.

Relatively few studies have assessed the reinforcing effects of hallucinogenic compounds, and no such studies have attempted to engender contingent responding for these compounds in animals with behavioral histories that include experience with serotonergically mediated reinforcing effects. The objectives of the present study were to investigate the capacity of several hallucinogenic compounds to maintain self-administration behavior in rhesus monkeys with a previous history of 3,4-methylenedioxymethamphetamine (MDMA) self-administration, and to compare these effects across a range of doses of drugs from two structural classes (indolealkylamines and phenylisopropylamines). The results indicate that no compound generated reliable responding and that no subject ever self-administered 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) at rates above those engendered by contingent saline. However, 3 out of 4 subjects did respond at rates between 0.75 and 3.0 responses/s in one or more sessions where N,N-dimethyltryptamine (DMT), mescaline or psilocybin were available. During some of these sessions in which self-administration was maintained, animals earned a majority of all available infusions and appeared intoxicated by the end of the session. This pattern of transient self-administration may indicate that these compounds have weak reinforcing effects, or mixed reinforcing and aversive effects.

Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys.

RATIONALE: The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. OBJECTIVES: The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. METHODS: The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. RESULTS: Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. CONCLUSIONS: The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement.

Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action.

The potential contribution of onset and duration of pharmacological action to the reinforcing strength of three intravenously delivered N-methyl-D-aspartate antagonists was evaluated in this study. The onsets and durations of action of ketamine, phencyclidine, and dizocilpine were evaluated by observation and tabulation of their behavioral effects in rhesus monkeys after i.v. administration. The reinforcing effects of each drug were tested in a paradigm in which the fixed ratio requirements for i.v. drug injection were increased systematically. The peak observable effect of ketamine occurred immediately after its administration. There were some immediately observable effects of phencyclidine, although the peak effect of phencyclidine was delayed for 3 to 10 min. Dizocilpine had few immediate effects and a peak effect 32 min after administration. Ketamine had the shortest duration of action, followed by phencyclidine and dizocilpine. Analysis of demand curves and response output curves that were normalized to account for potency differences among the drugs revealed that ketamine and phencyclidine were equally effective as reinforcers, and they were both much stronger reinforcers than was dizocilpine. The data therefore suggest that a fast onset of action increases the reinforcing strength of drugs, although duration of action may play a role as well.

Relative reinforcing effects of three opioids with different durations of action.

The role of duration of action on the relative reinforcing effects of three opioid drugs (fentanyl, alfentanil, and remifentanil) was evaluated. Duration and onset of action were determined using measures of respiratory depression and antinociception after i.v. administration. Effects on minute volume of respiration indicated that each of the three opioids had immediate onsets of action after i.v. administration. Fentanyl's duration of suppression of respiration and antinociception was longer than that of alfentanil, which was longer than that of remifentanil. Reinforcing strength was measured in i.v. self-administration studies in which the fixed ratio resulting in drug administration was increased from one session to the next. Comparisons were made of the behavioral economic variables P(max) and area under the demand curve (O(max)). Remifentanil maintained higher rates of responding than did alfentanil, and alfentanil maintained higher rates of responding than did fentanyl. When normalized demand functions were compared, however, the drugs did not differ significantly from each other in terms of P(max) or O(max). These data agree with those of others who have suggested that duration of action is not an important contributor to drugs' reinforcing strength.

Reinforcing and discriminative-stimulus effects of ephedrine isomers in rhesus monkeys.

Ephedrine is a sympathomimetic drug that is currently found in many over-the-counter preparations. This compound exists as four isomers which, in addition to a racemic mixture, were evaluated for their positive reinforcing effects and for their similarity to (+)-amphetamine as a discriminative stimulus. Rhesus monkeys (N=3) with intravenous cocaine (0.1 mg/kg/inj) or saline as a consequence for lever pressing were shown to self-administer all of the ephedrine compounds (range tested: 0.03-3.0 mg/kg/inj), with the exception of (-)-pseudoephedrine, when each drug/dose was substituted for cocaine or saline during test sessions. However, the (-)-pseudoephedrine isomer was evaluated within a limited dose range due to solubility limitations. Systematically increasing the number of responses required for an injection indicated that these isomers were not as effective as reinforcers as was cocaine. Rhesus monkeys (N=3) trained to discriminate intragastric 1.0 mg/kg (+)-amphetamine from saline were given substitution tests with the ephedrine isomers and the racemic mixture. When given intragastrically, at least one dose of all the ephedrine isomers substituted for the (+)-amphetamine discriminative stimulus in at least one of the subjects tested. However, (+)-amphetamine-like effects were not systematically related to dose. When the discriminative-stimulus effects of (-)-ephedrine were also compared with those of (+)-amphetamine across three different routes of administration, full, dose-related, (+)-amphetamine-like responding was observed with both the intramuscular and intravenous routes. Taken together, these results suggest that the ephedrines have psychomotor stimulant-like abuse potential, lower than that of cocaine. Parenteral administration may enhance psychomotor-stimulant-like effects.

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys.

The reinforcing effects of intravenously delivered cocaine, alfentanil, morphine, heroin, nalbuphine, or buprenorphine were evaluated in four rhesus monkeys before, during, and after daily administration of 3.2 mg/kg morphine. Morphine was given 21 h prior to measures of the reinforcing effects of each of the drugs. No changes in the potency of cocaine or the high efficacy mu agonist alfentanil were detectable during the period of chronic morphine administration. Small (1/2-1) log unit decreases in the reinforcing potency of intermediate efficacy mu agonists morphine and heroin occurred during chronic morphine administration. Larger decreases in both the potency and effectiveness of low-efficacy mu agonists nalbuphine and buprenorphine developed during this time. These data suggest that the amount of tolerance that develops to the reinforcing effects of opioids depends on the efficacy of the drugs used to maintain responding.

Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors.

RATIONALE AND OBJECTIVE: Sufficiently high doses of beta-phenylethylamine (beta-PEA), a trace amine that is rapidly metabolized by monoamine oxidase-type B (MAO-B), can produce effects comparable to those of cocaine or methamphetamine (MA). The present experiments were conducted to study how the discriminative-stimulus (S(D)) and reinforcing-stimulus (S(R)) effects of beta-PEA in monkeys are modified by treatment with inhibitors of MAO-B [R-(-)-deprenyl and MDL 72974]. METHODS AND RESULTS: In studies of its S(D) effects, doses of beta-PEA up to 30 mg/kg engendered only sporadic responding on the drug-associated lever in squirrel monkeys that discriminated intramuscular injections of 0.3 mg/kg MA from vehicle whereas lower doses of 0.3-1.0 mg/kg beta-PEA produced full substitution when administered after either R-(-)-deprenyl or MDL 72974 (0.3 mg/kg). The MA-like S(D) effects of beta-PEA were attenuated by either dopamine D(1) or D(2) receptor blockers. In studies of its S(R) effects, high doses of beta-PEA maintained responding in two of three monkeys under a second-order fixed-interval schedule (3.0 or 10 mg/kg per injection) and two of three monkeys under a simple fixed ratio (FR) schedule (0.3-1.0 mg/kg per injection) of intravenous (i.v.) self-administration. MAO-B inhibition by R-(-)-deprenyl or MDL 72974 enhanced the S(R) effects of beta-PEA in all monkeys and, under the FR schedule, induced a 30-fold or greater leftward shift in the dose-response function for its i.v. self-administration. Based on time-course determinations, the enhanced S(R) effects of beta-PEA under the FR schedule were long-lasting and dissipated gradually over 3-7 days. CONCLUSIONS: These results show that inhibition of MAO-B enhances S(D) and S(R) effects of beta-PEA in monkeys, presumably by delaying its inactivation. MAO-B inhibition leading to increased levels of beta-PEA may be useful, alone or in combination with other therapeutic agents, in the pharmacological management of selected aspects of drug dependence.

Natural and artificial enzymes against cocaine. I. Monoclonal antibody 15A10 and the reinforcing effects of cocaine in rats.

Recent reports have indicated the potential usefulness of anticocaine catalytic monoclonal antibodies in reducing cocaine's toxic and reinforcing effects by altering its pharmacokinetics to favor increased metabolism to the systemically inert products ecgonine methylester and benzoic acid. The present study was designed to further these findings by evaluating the hypothesis that administration of the anticocaine catalytic monoclonal antibody mAb 15A10 would dose and time dependently reduce behavior maintained by a range of doses of i.v. cocaine. Male Sprague-Dawley rats were trained in daily 8-h sessions to self-administer i.v. cocaine. A within-session multiple-dose protocol was used wherein rats were allowed access to saline or one of six doses of cocaine [0 (saline), 0.015, 0.03, 0.06, 0 (saline), 0.125, 0.25, or 0.5 mg/kg/injection] each hour in the order stated. After demonstrating stable dose-response curves over 3 consecutive days, rats were given 30-min pretreatments of saline or mAb 15A10, (10, 30, or 100 mg/kg i.v.). Antibody, but not saline, pretreatments significantly altered dose-response curves for cocaine self-administration in a dose- and time-dependent manner, resulting in downward and rightward shifts in rates of responding across the cocaine dose range. These effects were apparently not attributable to general behavioral suppression, because operant behavior for an alternative reinforcer was not likewise affected. The present data extend previous work indicating that pharmacokinetic approaches may be of worth in the search for clinically effective cocaine antagonists.

Methoclocinnamox: time course of changes in alfentanil-reinforced responding in rhesus monkeys.

RATIONALE: Methoclocinnamox (MC-CAM) possesses initial partial micro-opioid agonist activity with subsequent long-lasting micro-antagonist effects. This profile of activity is similar to that of buprenorphine, a compound with proposed use in the treatment of opioid abuse, suggesting a possible therapeutic use for MC-CAM as well. OBJECTIVE: The current study assessed the time course of the ability of MC-CAM and buprenorphine to antagonize the reinforcing effects of alfentanil and compared this with that of buprenorphine. METHODS: Rhesus monkeys self-administered a range of doses of alfentanil (0.03-1 microg/kg per injection) under a fixed-ratio 30, time-out 45 s schedule of i.v. drug delivery. MC-CAM was substituted for alfentanil on occasion, and a dose of 1.0 mg/kg MC-CAM or buprenorphine was given prior to sessions in which alfentanil was available. In the pretreatment studies, a wider range of alfentanil doses was utilized (0.03-30 microg/kg per injection). RESULTS: MC-CAM maintained self-administration behavior and was nearly equipotent with buprenorphine as a reinforcer in this paradigm. Both drugs, when given prior to a session in which alfentanil was available, produced a decrease in the reinforcing potency of alfentanil. The antagonist effects of the pretreatments were largest 30 min following administration and decreased over the next several days. The duration of MC-CAM's antagonism of alfentanil was approximately 4 days: the duration of buprenorphine as an antagonist was approximately 2 days. CONCLUSION: These data suggest that MC-CAM has a longer duration of antagonist effects than buprenorphine and it may therefore have an advantage in the treatment of opioid abuse.

Application of artificial enzymes to the problem of cocaine.

Cocaine mediates its reinforcing and toxic actions through a "loss of function" effect at multiple receptors. The difficulties inherent in blocking a pleiotropic blocker pose a great obstacle for the classical receptor-antagonist approach and have contributed to the failure-to-date to devise specific treatments for cocaine overdose and addiction. As an alternative, we have embarked on an investigation of catalytic antibodies, a programmable class of artificial enzyme, as "peripheral blockers"--agents designed to bind and degrade cocaine in the circulation before it partitions into the central nervous system to exert reinforcing or toxic effects. We synthesized transition-state analogs of cocaine's hydrolysis at its benzoyl ester, immunized mice, prepared hybridomas, and developed the first anti-cocaine catalytic antibodies with the capacity to degrade cocaine to non-reinforcing, non-toxic products. We subsequently identified several families of anti-cocaine catalytic antibodies and found that out most potent antibody, Mab15A10, possessed sufficient activity to block cocaine-induced reinforcement and sudden death in rodent models of addiction and overdose, respectively. With the potential to promote cessation of use, prolong abstinence, and provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine.

Glucocorticoid-reinforced responding in the rhesus monkey.

RATIONALE: Glucocorticoids have been reported to have rewarding effects in rats and may lead to drug-seeking behavior in humans under some circumstances. OBJECTIVES: The present study investigated whether glucocorticoids would be self-administered intravenously by rhesus monkeys (Macaca mulatta). METHODS: Ten monkeys, 7 male and 3 female, were maintained on a fixed ratio 10 (30 or 100), time-out 10-s schedule for 0.1 mg/kg methohexital or saline injections. Dexamethasone (0.03-0.3 mg/kg), methylprednisolone (0.1-1.0 mg/kg) and hydrocortisone (0.3-3.0 mg/kg) were periodically substituted for methohexital or saline. RESULTS: Dexamethasone (0.3 mg/kg) was self-administered by all of the male monkeys on the first, but not on subsequent occasions. It was hypothesized that suppression of hypothalamic-pituitary-adrenal (HPA) activity by these exogenous glucocorticoids following their first presentation may have interfered with their reinforcing effects on subsequent evaluation. Subsequently, plasma adrenocorticotropin and cortisol were measured in four male monkeys to ascertain that normal basal HPA activity had resumed prior to each glucocorticoid substitution. Of the ten monkeys that were tested, only one reliably self-administered dexamethasone, methylprednisolone and hydrocortisone, and he did so regardless of whether his basal HPA activity was suppressed. This monkey differed from some of the other monkeys both behaviorally and in his response to intravenous corticotropin releasing hormone. None of the three female monkeys that were tested with selected glucocorticoid doses showed any evidence of glucocorticoid reinforcement on any occasion. CONCLUSIONS: The results indicate that glucocorticoids were not reinforcing to the majority of monkeys in this study; nevertheless, large individual differences may exist in proclivity of monkeys to self-inject these compounds.

Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys.

RATIONALE AND OBJECTIVES: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and the orally bioavailable, water-soluble neuroactive steroid pro-drug Co 8-7071 (3alpha,21-dihydroxy-3beta-trifluoromethyl-5beta-pregnan-20- one, 21-hemisuccinate). METHODS: Four rhesus monkeys were prepared with chronic intravenous (i.v.) catheters and trained to press a lever under a ten-response fixed-ratio (FR) schedule of methohexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trained to discriminate intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination. RESULTS: At least two doses of pregnanolone (0.003-0.1 mg/kg per injection) maintained injections per session above saline levels in the four monkeys tested, whereas Co 8-7071 (0.01-1.0 mg/kg per injection) maintained injections per session above saline levels in two of four monkeys at relatively low levels of injections per session. In rhesus monkeys trained to discriminate pentobarbital, i.v. pregnanolone injections (0.1-1.7 mg/kg, 5-min presession) dose-dependently reproduced the discriminative stimulus effects of pentobarbital in all monkeys tested. Intravenous administration of Co 8-7071 (1-10 mg/kg, 5-min presession) resulted in a dose-dependent increase to >80% pentobarbital-appropriate responding in two of three monkeys tested. Following intragastric infusions of Co 8-7071 (1.0-30 mg/kg), > or =80% pentobarbital-appropriate responding occurred in one out of three monkeys at 10 mg/kg when administered 60 min before the session. When administered 120 min before the session, however, 10-30 mg/kg Co 8-7071 reproduced the discriminative stimulus effects of pentobarbital in each of the three monkeys tested. CONCLUSIONS: These data demonstrate barbiturate-like abuse-related effects that differed between two pregnane steroids. Whereas pregnanolone functioned as a reinforcer, suggesting that this compound has abuse potential, Co 8-7071 did not, despite having pentobarbital-like discriminative effects.

Cocaine-reinforced responding in rhesus monkeys: pharmacological attenuation of the hypothalamic-pituitary-adrenal axis response.

Intravenously self-administered cocaine produces a dose-dependent release of adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. This study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypothalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate and ketoconazole, both of which are cortisol synthesis inhibitors; astressin, a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF(1) receptors predominantly in the pituitary gland; and dexamethasone, a highly selective glucocorticoid receptor agonist whose long-lasting effects reduce or abolish the endogenous release of ACTH and cortisol. The reinforcing effects of a range of cocaine doses, with or without pretreatment with an HPA inhibitor, were evaluated using a fixed ratio 30 time-out 10-min schedule of reinforcement in six male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine increased plasma cortisol and ACTH. Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine-induced rise in cortisol and, at the highest doses, produced a compensatory increase in ACTH release. Astressin and dexamethasone attenuated or abolished cocaine-induced cortisol and ACTH release. Despite the efficacy exhibited by these pretreatments and the variety of mechanisms by which they inhibited the HPA axis, there was no evidence for any change in cocaine-reinforced behavior (response rate or infusion number), an indication that acute changes in the ACTH or cortisol response to cocaine do not play a direct role in modulating cocaine-seeking behavior under these behavioral circumstances.

Effects of response contingent and noncontingent cocaine injection on hypothalamic-pituitary-adrenal activity in rhesus monkeys.

Earlier studies of cocaine's effects on the hypothalamic-pituitary-adrenal (HPA) axis used nonresponse-contingent designs in which the investigator determined dose, timing, and route of administration. It is important to evaluate whether "control" over cocaine delivery is a significant determinant of cocaine's HPA axis effect. This study measured cocaine's effects on plasma adrenocorticotropic hormone and cortisol, using nonresponse-contingent injections followed later by response-contingent cocaine delivery. In addition, the effects of cocaine history on the HPA response to a noncontingent injection of 1 mg/kg of cocaine were measured. HPA effects of corticotropin-releasing hormone (CRF) were also measured. Male and female rhesus monkeys, with surgically placed venous catheters, were tested in their home cages. Up to 13 injections of saline and cocaine (0.01-, 0.03-, 0.1-, and 0.3-mg/kg/injection) were administered at 10-min intervals (nonresponse-contingent condition) and on a fixed ratio 30, time out 10-min schedule of reinforcement. Overall, cocaine delivered response contingently produced larger, more dose-dependent HPA responses than did noncontingent delivery. The HPA response to a 1 mg/kg cocaine infusion in cocaine-naive monkeys was not predictive of the HPA effect of this dose subsequent to acquisition of cocaine self-administration. Overall, male monkeys had larger HPA responses to cocaine than did female monkeys. Finally, the HPA effects of CRF were significantly correlated with those of large cocaine doses delivered nonresponse contingently, but not with response-contingent administration.

Effects of self-administered cocaine on plasma adrenocorticotropic hormone and cortisol in male rhesus monkeys.

This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially, basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured in singly housed male and female monkeys (n = 9) over a 24-h period using plasma samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels in both male and female rhesus monkeys demonstrated a circadian pattern of release, with peak levels for cortisol (19.60 +/- 2.16 microgram/dl) and ACTH (19.63 +/- 2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27 +/- 0.62 pg/ml) occurred at 6:00 PM, preceding the cortisol nadir (5.55 +/- 1.21 microgram/dl) at 9:00 PM. The reinforcing effects of saline, 0.01, 0.03, 0.1, and 0.3 mg/kg/injection cocaine were then evaluated using a fixed-ratio 30, time-out 10-min schedule of reinforcement in seven male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine produced dose-dependent increases in cortisol and ACTH. One dose of cocaine (0.03 mg/kg/injection), although reliably self-administered, did not produce a significant increase in HPA axis activity. These results indicate that although cocaine dose-dependently increases HPA axis activity, the HPA effect is more likely a consequence of overall cocaine intake than it is an indicator of cocaine doses that are sufficient to maintain self-administration behavior.

Evaluation of the reinforcing and discriminative stimulus effects of gamma-hydroxybutyrate in rhesus monkeys.

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate D-amphetamine (AMPH; n = 4), pentobarbital (PB; n = 3) or triazolam (n = 3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n = 2). GHB (0.01-10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0-178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

Naltrexone reduces ethanol- and sucrose-reinforced responding in rhesus monkeys.

These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and i.v. ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032-0.32 mg/kg) or saline was given i.m. 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol i.v. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection). The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol.