Modulation of the discriminative stimulus effects of d-amphetamine by mu and kappa opioids in squirrel monkeys

It has been reported that the discriminative stimulus effects of cocaine in squirrel monkeys can be potentiated by mu opioid agonists and attenuated by kappa opioid agonists. The purpose of this study was to extend these observations by examining the effects of mu and kappa opioids agonists on the discriminative stimulus effects of d-amphetamine (AMPH). Five squirrel monkeys were trained to discriminate 0.3 mg/kg of AMPH (i.m.) from saline using a stimulus termination/avoidance task. AMPH and cocaine substituted dose dependently for the AMPH training stimulus in all five monkeys. The AMPH training dose was completely antagonized by 0.1 mg/kg of the D1 dopamine antagonist SCH 39166. When administered alone, the kappa agonist U69,593 substituted partially or completely for AMPH in four of five monkeys, the kappa agonist enadoline substituted completely for AMPH in two of five monkeys, and morphine substituted completely for AMPH in one monkey. In all five monkeys, pretreatment with some doses of U69,593 or enadoline attenuated the discriminative stimulus effects of AMPH; however, some doses of U69,593 and enadoline also potentiated the effects of AMPH in at least two monkeys. Morphine pretreatment potentiated the discriminative stimulus effects of AMPH in three monkeys and either attenuated or did not alter these effects in two monkeys. Morphine pretreatment did not significantly alter the discriminative stimulus effects of cocaine except in one monkey. These data indicate large individual differences in the abilities of mu and kappa opioid agonists to alter the discriminative stimulus effects of AMPH.     

Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats

Rationale. Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear. Objective. The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine. Methods. One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline. Results. In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01–0.56 mg/kg) produced full, dose-related substitution; nornicotine (1–5.6 mg/kg) substituted only partially, and lobeline (2.71–15.34 mg/kg) and pilocarpine (0.26–2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1–5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2–26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48–0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine. Conclusions. Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine. Electronic Publication     

Pharmacological analysis of the rate-decreasing effects of mu and kappa opioids in pigeons

The present study investigated the rate-decreasing effects of several mu (morphine andl-methadone) and kappa (bremazocine, U69,593 and U50,488) opioid agonists in pigeons. Mu and kappa agonists were examined alone, in combination with naltrexone or the mu-selective opioid antagonist, -funaltrexamine (-FNA), and in pigeons treated chronically with U50,488. Naltrexone was equipotent in shifting the morphine,l-methadone and bremazocine dose-effect curves to the right, but was less potent in shifting the U69,593 dose-effect curve and did not shift the U50,488 dose-effect curve. -FNA shifted thel-methadone dose-effect curve to the right but did not shift the bremazocine, U69,593 or U50,488 dose-effect curves. Pigeons that developed tolerance to U50,488 following daily administration were cross-tolerant to bremazocine but not tol-methadone. Taken together, these experiments indicate that the rate-decreasing effects of morphine andl-methadone are mediated by mu opioid receptors, whereas the rate-decreasing effects of bremazocine, U69,593 and U50,488 in pigeons differ depending on the pharmacological procedures used to assess their effects.This work was supported by US Public Health Service Grant DA 02749 from the National Institute on Drug Abuse. L.A.D. is the recipient of Research Scientist Award DA 00033 and AJM of a Research Supplement for Minority Graduate Research Assistants. Portions of this research were submitted by the first author in partial fulfilment of the requirements for the degree of Doctor of Philosophy     

Delta opioid-like discriminative stimulus effects of mu opioids in pigeons discriminating the delta opioid BW373U86 from saline

The purpose of this experiment was to examine the substitution patterns produced by opioids with activity at the mu receptor in pigeons trained to discriminate the delta opioid BW373U86 from saline. A low dose of naltrindole (0.1 mg/kg) produced at least a 16-fold rightward shift in the dose-effect curve for the stimulus effects of BW373U86 (yielding a pK(B) = 7.9), whereas a relatively high dose of naloxone (1.0 mg/kg) produced only a 2-fold rightward shift (yielding a pK(B) = 5.6). The delta opioid SNC80 and the mixed mu/kappa opioids ethylketocyclazocine and ketocyclazocine substituted completely for the BW373U86 stimulus. Various opioids with activity at the mu receptor (levallorphan, [-]-cyclazocine, [-]-n-allylnormetazocine, morphine, butorphanol, nalbuphine, [+]-propoxyphene, etorphine, fentanyl) substituted partially for the BW373U86 stimulus. There was no relationship between the substitution patterns produced by these opioids and their relative intrinsic efficacy at the mu receptor, their relative selectivity for the mu receptor or their relative affinity for the delta receptor. Naloxone (1.0 mg/kg) was considerably more effective than naltrindole (0.1 mg/kg) in antagonizing the substitution patterns produced by etorphine, ethylketocyclazocine, ketocyclazocine and butorphanol, suggesting that these effects were not mediated by activity at the delta receptor. There was no evidence that these opioids antagonized the BW373U86 stimulus, suggesting that they were not functioning as low efficacy agonists at the delta receptor. The kappa opioids bremazocine and U50,488, as well as the non-opioids cocaine and pentobarbital, failed to produce appreciable levels of BW373U86 responding. The present findings indicate that in pigeons mu opioids most likely produce delta-like discriminative stimulus effects by activation of mu rather than delta or kappa receptors.     

Discriminative stimulus and subjective effects of opioids with mu and kappa activity: data from laboratory animals and human subjects

 Although a large and rich body of data is available regarding the discriminative stimulus effects of opioids in laboratory animals and human subjects, it has been difficult to reconcile the data obtained from these two different sources. Therefore, the purpose of this review is to bring together data from both animal and human laboratories and systematically to compare the discriminative stimulus effects of opioids, in particular those with activity at both mu and kappa opioid receptor types (i.e., the mixed action opioids). The data that can be collected from laboratory animals differ from the data that can be collected in human subjects. In general, the advantage of studies in laboratory animals is that they can investigate very broad dose ranges of opioids as well as some very selective opioids that are not available for investigation in human subjects. Although investigations in human subjects are limited by the compounds and doses available for examination, the advantage of these studies is that they can examine the subjective as well as the discriminative stimulus effects of opioids. Taken together, studies conducted in laboratory animals and human subjects indicate that the mixed action opioids are best classified as intermediate efficacy mu agonists with additional activity through other non-mu, possibly kappa opioid systems. Received: 9 May 1996 / Final version: 1 November 1996     

Nicotine-like discriminative stimulus effects of bupropion in rats

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine; however, nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effects through a different mechanism than nicotine. Given bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission.     

Phencyclidine-like discriminative stimulus properties of opioids in the squirrel monkey

The opioids SKF 10047, dl-cyclazocine, and dextrorphan have been shown to have phencyclidine (PCP)-like discriminative stimulus properties in the rat. In order to extend the generality of this observation, the stimulus effects of these and other opioids were evaluated in squirrel monkeys trained to discriminate between IM injections of saline and 0.25 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Stimulus control of behavior was characterized by the reliable completion of at least 22 trials of a 25-trial session on the appropriate choice lever after an injection of saline or PCP. In tests of stimulus generalization, SKF 10047, d-cyclazocine, dextrorphan, normetazocine, dl-cyclazocine, l-cyclazocine, and dextromethorphan occasioned dose-related increases in PCP-appropriate responding. The first four of these compounds and, under some conditions, l- and dl-cyclazocine, produced stimulus control of behavior comparable to that produced by the PCP training dose. Six other opioids occasioned responding only on the saline-appropriate lever: ethylketocyclazocine, ketocyclazocine, levorphanol, levallorphan, pentazocine, naltrexone. Naltrexone (1.0 or 4.0 mg/kg) attenuated slightly the PCP-like stimulus effects of SKF 10047 and dextrorphan, but increased PCP-appropriate responding with l- and dl-cyclazocine and levorphanol by enabling higher doses of these drugs to be tested without disruption of responding. The PCP-like stimulus effects of certain opioids appear to be mediated at neuronal substrates acted upon by PCP rather than at sites typically associated with opiate activity. These neuronal sites of action common to opioids and PCP may correspond to the sigma opiate receptor.     

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT_1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The ratedecreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT_1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.     

Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats

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

Effects of mu, kappa and sigma opioids on fixed consecutive number responding in rats

Responding in rats was maintained under a fixed consecutive number 20 schedule. Under this schedule, at least 20 consecutive responses were required on one lever before a response on a second lever produced food. Morphine, buprenorphine, ethylketocyclazocine (ECK), N-allylnormetazocine (NANM) and d-cyclazocine all caused dose-dependent decreases in response rate. With the exception of buprenorphine and EKC, each drug also produced a decrease in the percent of reinforced runs. Differences among the drugs were more apparent, however, on the basis of the conditional probability of switching to the second lever after any given run length on the first lever. Morphine increased the probability of premature switching and decreased the probability of switching after run lengths greater than 20. Buprenorphine decreased the probability of switching at all run lengths and EKC produced occasional increases in premature switching. In sharp contrast to the other opioids tested, NANM and d-cyclazocine generally increased the probability of switching at all run lengths. Thus, it appears that the fixed consecutive number schedule may be a sensitive procedure for distinguishing among the behavioral effects of various opioid agonists.     

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.     

Dopaminergic mediation of the discriminative stimulus effects of bupropion in rats

Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever when injected IP with bupropion (17.0 mg/kg), and another lever when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU 19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic dopamine uptake blocker benztropine produced limited partial substitution. A series of dopamine D₁-like and D₂-like receptor agonists were also tested: only the D₂-like agonist RU 24213 fully substituted; three other D₂-like agonists and four D₁-like agonists partially substituted (50% < drug responding < 80%). Antagonism of the discriminative effects of bupropion was obtained with a D₁- and a D₂-like dopamine antagonist. The results demonstrate strong similarities with those obtained using other dopamine uptake inhibitors as training drugs, and support the view that the behavioural effects of bupropion are primarily mediated by dopaminergic mechanisms. Received: 29 May 1997/Final version: 6 June 1997     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys

This study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys.     

Behavioral sensitization to the discriminative stimulus effects of methamphetamine in rats

Sensitization to the discriminative stimulus effects of psychostimulants is not fully understood. Therefore, the present study was designed to investigate the development of sensitization to the discriminative stimulus of methamphetamine in rats. A dose-response curve for methamphetamine and a generalization test for cocaine were recorded in rats trained to discriminate between 1.0 mg/kg methamphetamine and saline. A significant leftward shift of the dose-response curve for methamphetamine and of the dose-generalization curve for cocaine was observed following repeated administration of methamphetamine (2.0 mg/kg) instead of saline. These findings suggest that repeated administration of methamphetamine can produce behavioral sensitization to the discriminative stimulus effects of methamphetamine in rats.     

The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats

The discriminative stimulus effects of two competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10-60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebroventricular (i.c.v.) administration of APH (1.5-30 micrograms). Systemic and central administration of CPP (3-30 mg/kg i.p.; 0.1-10 micrograms i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5-30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.     

Serotonin1B receptor ligands in the nucleus accumbens shell do not affect the discriminative stimulus effects of amphetamine in rats

Enhanced dopamine neurotransmission particularly, in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc), seems to be critical for the behavioral effects of amphetamine in rodents. Nonetheless, recent findings have also demonstrated a modulatory role of 5-hydroxytryptamine (5-HT; serotonin) in these effects. In the present study, we examined whether 5-HT1B receptors in the NAc shell are engaged in the discriminative stimulus of amphetamine. To this end male Wistar rats were trained to discriminate amphetamine (1 mg/kg, ip) from saline (ip) in a two-lever, water reinforced fixed ratio (FR) 20 task. After acquiring the amphetamine-saline discrimination, rats were stereotaxically implanted with bilateral cannulae aimed at the NAc shell and then infused with selective 5-HT1B receptor ligands. The ability of these drugs to substitute for or to alter (enhance or antagonize) the discriminative stimulus effects of amphetamine was examined. When given systemically, amphetamine (0.125-1 mg/kg) produced a dose-dependent increase in drug-lever responding. In substitution studies, microinjection of the 5-HT1B receptor agonist CP 93129 (1-10 microg/side) or the 5-HTIB receptor antagonist GR 55562 (1-10 microg/side) into the NAc shell did not evoke amphetamine-lever responding. Combination tests of 5-HT1B receptor ligands demonstrated that local injection with fixed doses of CP 93129 (1 or 10 microg/side) or GR 55562 (1 or 10 microg/side) with the submaximal doses of amphetamine (0.125-0.5 mg/kg) did not modify dose-response curves of the psychostimulant, nor did it affect its ED50 value. Our results seem to exclude a role for the NAc shell 5-HT1B receptors in the control of the discriminative stimulus effects of amphetamine. These findings also show that pharmacological stimulation of those receptors does not affect the amphetamine discrimination in rats.     

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABA_A agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABA_B agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABA_A agonists, PB and diazepam, although similar to one another, differ from those of direct GABA_A receptor agonists, which produced only partial substitution for PB. The GABA_B agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.     

Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's relative intrinsic efficacy at the mu receptor

Rats were trained to discriminate 3.0mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30- to 1000-fold differences were obtained with nalbuphine and levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and levallorphan were also sensitive to the antinociceptive effects of nalbuphine, levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at the mu receptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.     

Multiple dopamine receptors mediate the discriminative stimulus effects of dihydrexidine in rats

The dopamine D(1) receptor agonist dihydrexidine (DHX) [(±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride] has shown efficacy in animal models of Parkinson's disease and improved cerebral blood flow and working memory of schizophrenic patients. Although the discriminative stimulus effects of DHX, an in-vivo predictor of human subjective effect profile, have only been characterized with respect to activity at D(1) receptors, DHX also has significant affinity for D(2) receptors. This study was designed to characterize the role of D(1) and D(2)/D(3) receptors in mediating the discriminative stimulus effects of DHX. Rats were trained to discriminate DHX [3 mg/kg, intraperitoneally (i.p.)] from the vehicle. The selective dopamine D(1) receptor partial agonist SKF 38393 was fully substituted for DHX. The D(1) receptor antagonist SCH 23390 (0.1 mg/kg, s.c.) and the D(3)-selective antagonist U99194 (10 mg/kg, i.p.) significantly attenuated the discriminative stimulus effects of the training dose of DHX by 80 and 60%, respectively, suggesting that both D(1) and D(3) receptors mediate the discriminative stimulus effects of DHX. In contrast, raclopride (1 mg/kg, i.p.) did not significantly alter the discriminative stimulus effects of DHX, indicating a lack of D(2)-mediated effects. The D(2)/D(3) receptor preferring agonists, quinpirole and (+)-PD 128907 were fully substituted, whereas (+)-7-OH-DPAT was partially substituted for DHX. The DHX bound to D(2) receptors with a Ki of 4.3+0.7 nmol/l was compared with 33.7+4.6 nmol/l at D(3) receptors. Determinations of activity at second messenger systems revealed that DHX functioned as a full agonist at D(3) receptors and a partial agonist at D(2) receptors in vitro. These activities at D(2)/D(3) receptors have shown effects in some preclinical models and clinical disease states. Therefore, the prominent in-vivo agonist activity of DHX at both D(1) receptors and D(2)/D(3) receptors should be considered while making predictions of effects in humans.     

Sensitization to the morphine-like discriminative stimulus effects of buprenorphine in rats.

An experiment was performed to determine whether chronic non-contingent administration of morphine would produce cross-sensitization to the cueing properties of buprenorphine or D-amphetamine. To this end the sensitivity to the discriminative stimulus effects of morphine, buprenorphine and D-amphetamine was determined in rats trained to discriminate 10 mg kg(-1)morphine from saline in a food-reinforced operant task. Seven rats were given repeated non-contingent treatments with morphine (20 mg kg(-1)on saline or no-test days and 10 mg kg(-1)on drug days) starting 20 days before the beginning of discrimination training; another six animals received injections of saline. Chronic administration of morphine resulted in sensitization to the discriminative stimulus effect of this drug and in cross-sensitization to the discriminative stimulus effect of buprenorphine. D-Amphetamine produced only saline lever selection in all rats. In conclusion, the present results confirm that the stimulus properties of opioid drugs may be enhanced, rather than decreased, in animals with a history of repeated non-contingent treatment with morphine. Sensitization to central-acting drugs is thought to play a role in the psychopathology of drug abuse. Hence, the present results point out the necessity of considering the effects of drugs which show tolerance, and those which show sensitization, under any particular drug regimen.