Characterization of the discriminative stimulus effects of buprenorphine in pigeons

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine. Objective: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement. Methods and results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1–1.0 μg), the μ opioid agonist DAMGO (0.005 and 0.05 μg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1–1.0 μg) and the opioid antagonist CTOP (1 μg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine self-administration. Conclusions: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence. Electronic Publication     

Discriminative stimulus properties of alprazolam

Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality. Received: 7 March 1999 / Final version: 22 June 1999     

Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone

The opioid antagonist, naltrexone, was used to identify some of the receptor mechanisms responsible for the discriminative stimulus effects of cyclorphan in the pigeon. Subjects were trained to discriminate 10 mg/kg IM injections of either morphine or dextrorphan from saline injections in a two key drug discrimination procedure in which responding was maintained by food presentation. The dextrorphan-trained birds generalized tol-cyclorphan at 10 mg/kg; naltrexone did not alter thel-cyclorphan dose-response curve for this effect. In the morphine-trained group,l-cyclorphan produced only partial generalization, and naltrexone greatly increased the dose ofl-cyclorphan necessary to produced only These results are consistent with the conclusion that in morphine-trained pigeons the partial generalization tol-cyclorphan is mediated by opioid receptors. Moreover, limited intrinsic efficacy at mu opioid receptors may be the characteristic ofl-cyclorphan that prevents full generalization in morphine-trained pigeons.d-Cyclorphan produced partial generalization in both groups, but the involvement of opioid receptor mechanisms could not be confirmed, as 1 mg/kg naltrexone did not antagonized-cyclorphan in either group.     

Discriminative stimulus effects of flumazenil in untreated and in diazepam-treated rhesus monkeys

Rationale: Long-term use of benzodiazepine agonists can have adverse effects (e.g., development of dependence), thereby limiting their clinical usefulness. Objectives: The goal of the current study was to examine the discriminative stimulus effects of flumazenil in untreated and diazepam-treated monkeys to determine whether this type of procedure could be used to examine benzodiazepine dependence. Methods: Flumazenil (0.32 mg/kg s.c.) was established as a discriminative stimulus in eight monkeys receiving 5.6 mg/kg/day of diazepam (p.o.); four responded under a fixed ratio (FR)5 schedule of stimulus-shock termination (SST) and four responded under a FR5 schedule of food presentation. For comparison, 1.0 mg/kg flumazenil (s.c.) was established as a discriminative stimulus in four untreated monkeys responding under a FR5 schedule of SST. Results: Flumazenil dose-dependently increased responding on the flumazenil-appropriate lever in all monkeys. In diazepam-treated monkeys, Ro 15-4513, ethyl beta-carboline-3-carboxylate and bretazenil substituted for flumazenil with pentylenetetrazole substituting in some monkeys; other drugs failed to substitute for flumazenil. Acute administration of 10.0 mg/kg diazepam (s.c.) shifted the flumazenil dose–effect curve threefold to the right of the control dose–effect curve. Temporary suspension of diazepam treatment produced a time-related increase in flumazenil-lever responding that was reversed by diazepam. In untreated monkeys, midazolam substituted for flumazenil, with other drugs, including those with primary mechanisms of action at non-γ-aminobutyric acid_A receptors, substituting in some monkeys. Ro 15-4513 did not substitute in any untreated monkey. Conclusions: The flumazenil discriminative stimulus appears to be pharmacologically selective in treated monkeys with only negative and low efficacy positive modulators substituting for flumazenil; in contrast, a variety of drugs substitute for flumazenil in untreated monkeys. This apparent difference in selectivity suggests that diazepam treatment modifies the flumazenil discriminative stimulus perhaps due to the development of dependence. Received: 30 November 1998 / Final version: 25 May 1999     

Discriminative stimulus effects of melatonin in the rat

To provide initial information on the potential mechanisms underlying the discriminative stimulus effects of melatonin, rats were trained to discriminate melatonin (150 mg/kg, IP) from saline in a two-choice discrete-trial avoidance paradigm. Stimulus generalization curves for melatonin were steep; complete generalization with melatonin occurred at 100–150 mg/kg. Triazolam generalized completely with melatonin (n=7). Flurazepam generalized completely with melatonin in only two out of six rats; however, partial generalization was produced in the remaining four animals. The melatonin-appropriate responding produced by triazolam was antagonized completely (in six out of seven rats) by 0.3–10 mg/kg flumazenil (Ro 15–1788). In contrast, the dose of flumazenil sufficient to block completely the melatonin-like discriminative effects of triazolam failed to block the stimulus effects of the training dose of melatonin. Pentobarbital produced primarily melatonin-appropriate responding, with complete generalization with melatonin in five out of seven rats. Diphenhydramine generalized completely with melatonin in two out of seven rats; however, little or no partial generalization was observed in the remaining five rats. These results suggest that melatonin may produce its discriminative effects through sites on the GABA_A-benzodiazepine receptor complex distinct from the benzodiazepine binding sites.     

Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers

Rationale: Buprenorphine is an opioid agonist-antagonist under development in the United States as a sublingual medication for treatment of opioid dependence. Buprenorphine may be abused; therefore, tablets combining buprenorphine with naloxone have been developed with the intent of reducing the abuse risk in people physically dependent upon opioids. The characteristics and abuse potential of buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers have not been determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely in people who have less severe substance abuse disorders (e.g., are not physically dependent upon opioids). Objectives: To assess the abuse potential of sublingual buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers. Methods: Subjects (n=7) were tested with sublingual buprenorphine (4, 8, 16 mg), sublingual buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg), as well as intramuscular hydromorphone as an opioid agonist control (2, 4 mg) and placebo in laboratory sessions conducted twice per week. Dosing was double-blind and double-dummy. Results: The higher doses of both buprenorphine and buprenorphine/naloxone produced similar opioid agonist-like effects. The onset of these effects was slowed, consistent with the sublingual route of administration, and the magnitude of effects was moderate. There was no evidence to suggest the addition of naloxone attenuated buprenorphine’s opioid agonist effects in this population when buprenorphine was delivered by the sublingual route. Conclusions: These results suggest that sublingual buprenorphine and buprenorphine/naloxone may both be abused by opioid users who are not physically dependent upon opioids. Received: 15 April 1999 / Final version: 11 September 1999     

Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats

 The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED₅₀ for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED₅₀ for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED₅₀ for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED₅₀ for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist. Received: 17 September 1996 / Final version: 13 March 1997     

Discriminative stimulus effects of nicotine in rats trained under different schedules of reinforcement

There have been few comparisons between different schedules of reinforcement for establishing drugs as discriminative stimuli. Fixed-ratio (FR) 10 and tandem variable-interval 1-min FR-10 schedules have been compared directly in a conventional, nicotine-saline discrimination paradigm with food reinforcement in rats. The discrimination was acquired rapidly under both schedules, with stimulus control by nicotine (0.1 mg/kg SC) being very slightly superior under the FR schedule. In 5-min extinction tests with nicotine, rats maintained under the FR schedule yielded a clear dose-response curve with a bar-selection (quantal) index; in these rats, discrimination of nicotine appeared generally poor, and dose-response curves were shallow, when the percentage of drug-appropriate responding (quantitative index) was calculated. In contrast, rats under the tandem schedule yielded clear dose-response data with both indices. In tests with (+)-amphetamine full generalization was obtained with both schedules, and with both quantitative and quantal indices. Tests of generalization to morphine were negative regardless of the training schedule or index employed. In rats under the FR-10 schedule, overall response rates declined both within and across extinction tests; the relatively high rates of responding maintained by the tandem schedule were more sensitive to the response rate-decreasing effects of morphine and amphetamine. The results confirm that orderly data may be obtained with either a FR or a tandem schedule provided that an appropriate index of discriminative response is employed. The results generally support the validity of current practices, and there will probably be no marked differences between conclusions depending on which schedule is used.     

Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine

RATIONALE: Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy. OBJECTIVES: To test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine. METHODS: Residential subjects ( n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions. RESULTS: There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal. CONCLUSIONS: The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist.     

Discriminative stimulus effects of a low dose of apomorphine in the rat

The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other directacting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation.     

Discriminative stimulus effects of dextromethorphan in the rat

This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype ofsigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED₅₀ of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED₅₀s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested withsigma-site ligands,mu-opioid agonists, and naltrexone. Concurrent administration of naltrexone orsigma-site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by themu-opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor.     

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.     

Discriminative stimulus effects of spiradoline,a kappa-opioid agonist

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED₅₀s for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.     

Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine

 The present study was conducted to determine if the putative atypical antipsychotic olanzapine could be established as a discriminative stimulus in rats. Seven rats were successfully trained to discriminate olanzapine (0.5 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure (mean number of acquisition sessions=39.3). Generalization testing with olanzapine (0.0625–2.0 mg/kg) yielded an ED₅₀ of 0.170 mg/kg (95% confidence interval=0.118–0.246 mg/kg). The atypical antipsychotic clozapine (0.156–10.0 mg/kg) fully substituted for olanzapine in all rats at the 2.5 mg/kg dose with 99.0% drug-lever responding, in six rats at the 0.625 mg/kg dose, and in five rats at the 1.25 and 5.0 mg/kg doses (ED₅₀=0.259 mg/kg, 95% confidence interval=0.089–0.755 mg/kg). This study is the first demonstration that rats can be trained to discriminate olanzapine from vehicle in a two-lever drug discrimination procedure and that the olanzapine discrimination cue generalizes to clozapine. Received: 11 June 1996 / Final version: 19 July 1996     

Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey

Rationale. The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats. Objective. The purpose of this study was to extend observations to a non-human primate. Methods. Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR→NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL→NTX). Results. Seven subjects acquired the discrimination in an average of 108±14 sessions. MOR→NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56–1.7 mg/kg) and of naltrexone (0.01–10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR→NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR→NTX-appropriate responding. Conclusions. This is the first non-rodent study of the discriminative effects of MOR→NTX. MOR→NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs. Electronic Publication     

Discriminative effects of morphine in the pigeon

Pigeons were trained to discriminate between the effects of morphine (6 mg/kg) and saline injected IM, 45 min prior to training in a box equipped with 2 response keys which were mounted left and right on the front panel. Reinforcement (food) was contingent upon pecking (FR 15) on one key when trained under the influence of morphine (6 mg/kg) and the other key when trained with saline. After the choice of key (left or right) had become conditioned to the presence or absence of the effects of morphine, test sessions under new drug conditions were interspersed between the regular training sessions. The median effective dose of morphine and the time interval since the morphine injection in producing 50% morphine appropriate responding by the pigeons were respectively: 1.6 mg/kg and 6 hr post-injection. A stereoisomeric requirement for the discrimination was evident because treatment with levorphanol (2 mg/kg) resulted in responding on the morphine appropriate key while treatments with the enantiomer dextrorphan (1–10 mg/kg) predominantly while tests with 3 other psychotropic drugs Δ⁹-THC (0.25 and 0.50 mg/kg), d-LSD (0.04 and 0.08 mg/kg) and pentobarbital yielded responding on the saline appropriate key. In addition, methadone (3 and 6 mg/kg) substituted for morphine (4 and 8 mg/kg)) resulted in responding appropriate for the saline-induced training condition. The opioid antagonists naloxone and naltrexone blocked the stimulus effects of morphine (6 mg/kg). Naloxone appeared less potent in this respect than its congener, naltrexone, when the drugs were evaluated 45 min post-injection. Thus the discriminable effects of morphine in the pigeon are qualitatively similar to the results obtained in mammals (gerbils, rats, and squirrel monkeys) required to discriminate morphine from a nondrug condition.     

Discriminative stimulus effects of etorphine in rhesus monkeys

Two rhesus monkeys were trained to discriminate the IM injection of etorphine (0.001 mg/kg) from saline in a task in which 20 consecutive responses on one of two levers resulted in food delivery. In both monkeys, etorphine (0.0001–0.0018), meperidine (0.1–1.0 mg/kg), morphine (0.1–3.2 mg/kg), and codeine (0.3–3.2) produced dose-related increases in the percentage of total session responses that occurred on the etorphine-appropriate lever. In contrast, ethylketazocine, SKF-10047, and pentazocine, at doses up to and including those that suppressed response rates, produced responses primarily on the saline-appropriate lever. Thus, etorphine-like narcotics, including morphine, have discriminative stimulus effects in rhesus monkeys which can be distinguished from those produced by narcotics with nonmorphine-like actions such as ethylketazocine, SKF-10047, and pentazocine.     

Discriminative stimulus properties of cocaine: enhancement by ββ-adrenergic receptor antagonists

 Although many of the behavioral effects of cocaine are widely believed to be mediated by blockade of dopamine transporters, recent studies suggest that norepinephrine (NE) may play a modulatory role. In this study, selective and nonselective β-adrenergic receptor antagonists were administered alone or in combination with cocaine (2.5 mg/kg, IP) to rats trained to discriminate a low dose (2.5 mg/kg) from a high dose of cocaine (10 mg/kg) in a two-lever, FR10 drug discrimination procedure. The central β₂/β₁-adrenergic antagonists (–)-propranolol and tertatolol, and the β₂-adrenergic antagonist, ICI 118,551, produced high-dose appropriate responding in a dose-related manner when administered (IP) in combination with the low training dose of cocaine. In contrast, neither the peripheral β₂/β₁-adrenergic antagonist, nadolol, nor the central β₁-adrenergic antagonist, betaxolol enhanced the behavioral effects of the low dose of cocaine in a manner comparable with that produced by compounds with central β₂-adrenergic antagonist properties. Also in contrast to findings obtained using β-adrenergic antagonists, neither the α₁-adrenergic agonist cirazoline, nor the α₂-adrenergic ligands (±)-efaroxan and UK-14304 enhanced the behavioral effects of the low dose of cocaine. Overall, these results suggest that central β₂-adrenergic receptors may play a modulatory role in the discriminative stimulus effects of cocaine. Received: 29 October 1996 / Final version: 4 February 1997     

Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids

Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. Objectives: In vivo apparent pA₂ analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA₂ analyses were used to evaluate receptor mechanisms of stimulus control. Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA₂ values of 7.6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA₂ values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization. Received: 16 February 1999 / Final version: 31 August 1999     

Characterization of the discriminative stimulus effects of centrally administered morphine in the rat

The discriminative stimulus effects of centrally administered morphine were characterized in rats trained to discriminate 3.0 mg/kg SC morphine from saline in a two-choice discrete-trial avoidance paradigm. The intracerebroventricular (ICV) administration of 0.3–10 g morphine engendered morphine-appropriate responding, morphine administered ICV being nearly 1000 times as potent as morphine administered SC. Cannula implantation itself did not affect the sensitivity of the rats to the discriminative effects of morphine. The onset of the discriminative stimulus effects of ICV morphine was not immediate; stimulus generalization comparable to that produced by 3.0 mg/kg morphine occurred 30–60 min after the injection of 1.0 or 10 g ICV morphine and persisted for 90 and 150 min, respectively. Naltrexone blocked the discriminative stimulus effects of 10 g ICV morphine in a dose-related manner. Complete antagonism of the stimulus effects of this dose of morphine was obtained with 0.01–0.03 mg/kg SC naltrexone. When administered centrally, the relatively lipid insoluble naltrexone methobromide completely antagonized the discriminative effects of 3.0 mg/kg morphine at a median effective dose of 0.3 g. In contrast, when injected systemically at a dose of 1.0 mg/kg (approximately 500 g), naltrexone methobromide failed to block the discriminative stimulus effects of either 10 g ICV morphine or the SC training dose. Thus, periventricular brain sites appear to be involved in mediating the discriminative stimulus effects of morphine in the rat.