Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.     

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.     

Effects of nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats

RATIONALE: Nitric oxide synthase (NOS) inhibitors may modulate the discriminative stimulus effects of cocaine because they alter dopamine (DA) release. OBJECTIVES: The effects of the NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitro-indazole (7-NI) were examined in experiments designed to better understand the mechanisms that may underlie the interactions between NOS inhibitors and cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline, and then substitution and pretreatment tests with L-NAME and 7-NI were conducted. To determine if the combined effects of NOS inhibitors and cocaine might be related to DA mechanisms and/or to N-methyl-D-aspartate (NMDA) receptor mechanisms, substitution tests with other indirect DA agonists and NMDA antagonists were carried out in the presence and absence of L-NAME. In addition, the roles of the D1 and D2 families of DA receptors in mediating the cocaine-altering effects of L-NAME and 7-NI were examined in antagonism tests using SCH 23390 and haloperidol, respectively. RESULTS: The results demonstrated that neither NOS inhibitor alone substituted for the 10 mg/kg cocaine training dose, but when given as a pretreatment, 100 mg/kg L-NAME as well as 10 mg/kg 7-NI enhanced the discriminative stimulus and rate-decreasing effects of cocaine. L-NAME pretreatment also enhanced the potency of (+)-amphetamine and GBR 12909, but not MK-801, phencyclidine, or NPC 17742, for producing discriminative stimulus and rate-decreasing effects in substitution tests. Further testing showed that the cocaine-enhancing effects of L-NAME and 7-NI were attenuated by doses of haloperidol and SCH 23390 that minimally altered the effects of cocaine alone. CONCLUSIONS: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition.     

Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats

The discriminative stimulus (DS) properties ofd-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N=8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0–5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.     

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.     

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     

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.     

Diverse effects of GABA-mimetic drugs on cocaine-evoked self-administration and discriminative stimulus effects in rats

Rationale Recent data indicate that γ-aminobutyric acid (GABA) is a modulator of behavioral responses to cocaine. Objective The efficacy of gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (an inhibitor of GABA transaminase and reuptake) to alter cocaine-seeking behavior and discriminative effects was examined in rats. Materials and methods Rats were trained to press a lever for cocaine (0.5 mg/kg per infusion) paired with a cue (light + tone) using a fixed ratio (FR) 5 schedule of reinforcement. After extinction, the cocaine-seeking behavior was reinstated by cocaine priming (10 mg/kg). Another group of rats was trained to discriminate cocaine (10 mg/kg) from saline in a two-lever FR 20 task. Results Vigabatrin (150–250 mg/kg) decreased cocaine-maintained responding, whereas tiagabine (10 mg/kg) significantly reduced responses on the “active” lever. Vigabatrin (150–250 mg/kg) significantly decreased responding to the cocaine-priming dose and a nonsignificant attenuation of cocaine-induced reinstatement was seen after tiagabine (5–10 mg/kg). Gabapentin (10–30 mg/kg) failed to alter maintenance of cocaine self-administration or drug-induced reinstatement. Pretreatment with either gabapentin, tiagabine, or vigabatrin resulted in neither reinstatement of cocaine seeking nor alterations in cocaine discrimination. Conclusions Our study demonstrates that vigabatrin (only at the 150 mg/kg dose) exerted inhibitory actions on cocaine-maintained responding and attenuated the reinstatement of extinguishing responding more effectively than gabapentin or tiagabine and with less evidence of motor impairment than the latter drugs. Present findings do not support a role for gabapentin or tiagabine for the possible treatment of cocaine relapse, whereas albeit limited effects of vigabatrin may be seen. This research was supported by the grant no. 033/P05/2001 from the Ministry of Education and Science (Warsaw, Poland) and by the Institute of Pharmacology, Polish Academy of Sciences (Kraków, Poland).     

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.     

Effects of central dopamine depletion on thed-amphetamine discriminative stimulus in rats

The discriminative stimulus properties ofd-amphetamine, cocaine, and apomorphine were assessed in rats trained in a two-lever, food-reinforced drug discrimination paradigm to discriminate 1.0 mg/kgd-amphetamine from saline. After determination of these dose-response relationships, the rats were divided into two groups. One group (6-OHDA) was given injections of desmethylimipramine (DMI, 30 mg/kg, IP) and 6-hydroxydopamine (6-OHDA, 100 g/10 l each ventricle), while the other group (sham) was given the same dose of DMI and 6-OHDA vehicle (intraventricularly). Beginning approximately 45 days after intraventricular injections, dose-response relationships were redetermined for all three drugs. Larger doses ofd-amphetamine were required to elicit the same response in the 6-OHDA group (i.e. the dose-response relationship was shifted to the right), while no change was observed in the sham group. Any changes in the dose-response relationships for cocaine and apomorphine were comparable in the 6-OHDA and sham group. The rate-decreasing effects were not altered in either group for any of the drugs. Upon sacrifice, dopamine (DA) was found to be significantly depleted in the accumbens, caudate and rest of brain of the 6-OHDA group. Levels of norepinephrine and serotonin were unaltered. These data suggest that central DA-containing neurons play a role in the discriminative stimulus properties of psychomotor stimulants 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.     

Effects of H(1)-antagonists on discriminative stimulus effects of cocaine and methamphetamine in rats

The effects of H(1)-antagonists, such as tripelennamine, chlorpheniramine and pyrilamine, on the discriminative stimulus effects of cocaine and methamphetamine in rats were examined. Rats were trained to discriminate between cocaine (10mg/kg, i.p.) or methamphetamine (1.0mg/kg, i.p.) and saline, with responses maintained under a fixed-ratio 10 (FR10) schedule of food delivery. In generalization tests, tripelennamine generalized to the discriminative stimulus effects of cocaine and methamphetamine, while chlorpheniramine only generalized to cocaine. These generalizations of tripelennamine and chlorpheniramine were attenuated by the dopamine receptor antagonist haloperidol. Furthermore, tripelennamine and chlorpheniramine, but not pyrilamine, potentiated the discriminative stimulus effects of cocaine and methamphetamine. These results suggest that some H(1)-antagonists possess cocaine- and/or methamphetamine-like discriminative stimulus effects which may be mediated by the dopaminergic system, and as a result the discriminative stimulus effects of cocaine and methamphetamine were potentiated by these H(1)-antagonists.     

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D₂ against LY-171555 (0.05–0.25 mg/kg); but not to the D₁ agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D₁ antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D₂ antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D₁ or D₂ receptor activation; for example, the stimulus properties of this substance might involve both D₁ and D₂ receptor activation.Some of these results were presented at the meeting of the Society for Neuroscience, Toronto, 1988     

Effects of the nicotinic receptor partial agonists varenicline and cytisine on the discriminative stimulus effects of nicotine in rats

The nicotinic partial agonist varenicline (VCL) is a recently approved medication for the treatment of tobacco dependence, yet very little preclinical research on this drug has been published. The present experiment examined the nicotinic partial agonist properties of VCL and its parent compound, cytisine (CYT), in a nicotine discrimination assay. Rats were trained to discriminate nicotine (0.4 mg/kg, s.c.) from saline using a two-lever discrimination procedure, followed by generalization and antagonism tests with VCL and CYT. Antagonism was examined across a range of nicotine doses. In generalization tests, VCL produced a maximum of 63% responding on the nicotine-appropriate lever, indicating partial generalization. In antagonism tests, VCL decreased the % responding on the nicotine-appropriate lever at 0.2 and 0.4 mg/kg nicotine, indicating antagonism of nicotine's discriminative stimulus effects. No dose of VCL produced significant effects on response rate. The two highest doses of CYT weakly substituted for nicotine, producing a maximum of 23% nicotine-appropriate responding. CYT produced a weak antagonism of the discrimination of moderate nicotine doses, but not of the training dose. These results demonstrate that VCL and CYT partially generalize to and partially antagonize nicotine's discriminative stimulus effects, consistent with a partial agonist mechanism of action.     

Extended blockade of the discriminative stimulus effects of nicotine with low doses of ethanol

The aim of the present study was to further evaluate effects of ethanol on nicotine discrimination and to correlate these effects with blood ethanol levels. Rats were trained to discriminate 0.3 mg/kg nicotine from its vehicle in the standard two-lever operant procedure. In antagonism tests, small doses of ethanol (0.25-0.5 g/kg) were injected either 5 or 50 min before nicotine. Both doses of ethanol partially antagonized the nicotine cue regardless of the pre-treatment time. Ethanol attenuated also inhibitory effects of nicotine on the rate of responding. Suppression of the cueing effects of nicotine was noted even 60 min after the injection of 0.25 g/kg ethanol, i.e. at the time point when the blood ethanol level was close to zero. Ethanol-induced antagonism of the nicotine cue disappeared when longer time (110 min) was allowed to elapse between the ethanol (0.5 g/kg) and nicotine injection. Concluding, the present results may indicate that the effects of ethanol on nicotine discrimination are not primarily related to blood ethanol levels.     

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.     

Amphetamine-like discriminative stimulus effects of ephedrine and its stereoisomers in pigeons

This study assessed the discriminative stimulus effects of (+/-)-ephedrine and its stereoisomers in pigeons discriminating 1.0 mg/kg of amphetamine from saline. Amphetamine, (+/-)-, (-)-, and (+)-ephedrine, and cocaine occasioned greater than 80% drug-key responding with the following rank order of potency: amphetamine > cocaine > (-)-ephedrine > or = (+/-)-ephedrine > or = (+)-ephedrine. Neither the alpha-adrenergic antagonist, phentolamine, nor the beta-adrenergic antagonist, propranolol, antagonized the effects of amphetamine or (+/-)-ephedrine. In contrast, the dopamine receptor antagonist, haloperidol, antagonized the discriminative stimulus effects of amphetamine and (+/-)-ephedrine as well as those of (-)- and (+)-ephedrine. These results indicate that, like cocaine, (+/-)-ephedrine and its stereoisomers share discriminative stimulus effects with amphetamine. Moreover, these effects appear to be the result of increased activity in dopaminergic systems.     

Cocaine-like discriminative stimulus effects of procaine,dimethocaine and lidocaine in rats

The discriminative stimulus effects of several local anesthetics and (+)-amphetamine were assessed in a drug discrimination based on the psychomotor stimulant cocaine. Two groups of adult male Sprague-Dawley rats were trained in two-lever operant chambers in a cocaine versus saline discrimination, or a cocaine versus procaine or saline discrimination, using a fixed ratio 20 schedule of food reinforcement. Cocaine, (+)-amphetamine and dimethocaine all dose-dependently substituted for the training dose of cocaine (10 mg/kg) in both procedures. While procaine and lidocaine showed partial substitution in the cocaine versus saline procedure, much less substitution occurred in the cocaine versus procaine or saline discrimination. These data demonstrate that it is possible to train rats to discriminate between cocaine and another local anesthetic procaine, resulting in an increased pharmacological specificity of cocaine discrimination. The fact that dimethocaine fully substituted for cocaine in both procedures indicates that this local anesthetic has more cocaine-like effects than others so far tested, which is consistent with results from other behavioral and neurochemical studies with this compound.     

Serotonin involvement in the discriminative stimulus effects of mu and kappa opioids in rats

The role of serotonin (5-HT) in the discriminative stimulus effects of opioids was examined using a two-lever, food-reinforced drug discrimination procedure. The effects of the 5-HT(1A) full agonist 8-OH-DPAT, the 5-HT(1A) partial agonist buspirone and the 5-HT(2) antagonist ketanserin were evaluated in rats trained to discriminate the mu opioid agonist morphine, or the kappa opioid agonist U50, 488 from saline. In rats trained to discriminate 5.6mg/kg of morphine from saline, morphine dose-dependently substituted (produced >/= 80% morphine-appropriate responding) for the morphine stimulus. In contrast, U50,488, 8-OH-DPAT and ketanserin did not substitute for morphine, and buspirone produced only a small degree of substitution (approx. 40% morphine-appropriate responding). When administered in combination with morphine, 8-OH-DPAT, but not buspirone and ketanserin, attenuated the discriminative stimulus effects of higher doses of morphine. In rats trained to discriminate 5.6mg/kg of U50, 488 from saline, U50, 488 dose-dependently substituted for the U50, 488 stimulus. When administered alone, 8-OH-DPAT and buspirone partially substituted (produced between 40% and 79% U50, 488-appropriate responding) for the U50,488 stimulus, whereas morphine and ketanserin did not substitute for U50,488. The opioid antagonist naltrexone failed to antagonize the effects of 8-OH-DPAT and buspirone suggesting that the effects of these drugs in U50,488-trained rats were not mediated by opioid receptors. When administered in combination with U50,488, 8-OH-DPAT, but not buspirone or ketanserin, attenuated the discriminative stimulus effects of the training dose of U50,488. These results suggest that the 5-HT system is involved in the discriminative stimulus effects of both morphine and U50,488, although the exact nature of this 5-HT involvement is not clear.