The D3 antagonist PNU-99194A potentiates the discriminative cue produced by the D3 agonist 7-OH-DPAT

Based on correlations between potencies of various dopamine D2/D3 agonists to substitute for the 7-OH-DPAT discriminative cue and their in vitro (mitogenesis test) potencies, it has been suggested that the 7-OH-DPAT cue is mediated by activity at the D3 subtype. We sought to verify that the 7-OH-DPAT cue could be blocked by PNU-99194A, a commercially available preferential D3 antagonist. Rats were trained (FR10 two-lever, food-reinforced schedule) to press one lever following 7-OH-DPAT (0.1 mg/kg i.p.) and the other lever following saline. Rats were then tested with various doses of 7-OH-DPAT alone or in combination with PNU-99194A. 7-OH-DPAT (0.003 to 0.3 mg/kg) engendered dose-dependent substitution; PNU-99194A (1 to 10 mg/kg) failed to antagonize the cue induced by 0.1 mg/kg of 7-OH-DPAT and, at 10 mg/kg, given in combination with 0.003 to 0.1 mg/kg of 7-OH-DPAT, PNU-99194A markedly shifted the 7-OH-DPAT dose-effect curve to the left, i.e., potentiated the 7-OH-DPAT cue. If PNU-99194A is a preferential D3 antagonist, the present data do not confirm the previous hypothesis that the 7-OH-DPAT cue is mediated by the D3 subtype.     

Assessment of D3 versus D2 receptor modulation of the discriminative stimulus effects of (+)-7-OH-DPAT in rats

Although there are presently no highly selective agonists for the D3 dopamine receptor, a number of compounds reported to bind with moderate selectivity to D3 receptors are currently employed to investigate the importance of D3 receptors in the behavioral effects of psychostimulant drugs. For example, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) has been used extensively to investigate the role of D3 receptors in the reinforcing and discriminative stimulus properties of cocaine and d-amphetamine. However, recent investigations with a relatively selective D3 antagonist, PNU-99194A, have led us to question the importance of D3 receptors in the discriminative stimulus effects of 7-OH-DPAT. In the present study, 16 male Sprague-Dawley rats were trained to discriminate (+)-7-OH-DPAT (0.03 mg/kg, subcutaneously (s.c.)) from saline in a two-choice operant procedure using a fixed-ratio 20 schedule of water reinforcement. Consistent with previous findings, PNU-99194A appeared to attenuate only partially (+)-7-OH-DPAT discrimination at a dose that disrupted responding in most subjects. Moreover, a highly selective D2 agonist, PNU-91356A, substituted completely and in a dose-dependent manner for (+)-7-OH-DPAT, while d-amphetamine produced only partial substitution for the training drug. These data indicate that D2 receptor actions appear to be more important than D3 receptor actions in exerting the discriminative stimulus effects of (+)-7-OH-DPAT. Continued efforts to determine the relative importance of D2 vs D3 receptor actions in the modulation of the discriminative stimulus effects of (+)-7-OH-DPAT are discussed.     

Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A

 It was recently documented that the relatively selective dopamine D₃ receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23–78). In substitution tests, the non-selective D₂ receptor antagonist, halo- peridol (0.01– 0.1 mg/kg), and the mixed D₂/D₃ antagonists, amisulpiride (3.2–32 mg/kg) and sulpiride (32–200 mg/kg), failed to produce stimulus generalization, while the D₃-preferring antagonists, (–)-DS121 (1–10 mg/kg) and (+)-AJ76 (3.2–32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01–0.32 mg/kg) and d-amphetamine (0.1–1 mg/kg), the D₁ agonist SKF-38393 (10–100 mg/kg), the D₂ selective agonist PNU-95666E (0.32–3.2 mg/kg) and the D₃-preferring agonist pramipexole (0.032–1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D₃ receptor antagonism. Received: 3 September 1997 / Final version: 21 January 1998     

(+)-3-PPP antagonizes the discriminative stimulus effects of (+)-N-allylnormetazocine

The functional significance of the reported affinity of (+)-3-PPP and (+)-N-allylnormetazocine (NANM) for the same binding site in rat brain membranes was assessed by studying (+)-3-PPP as a agonist and antagonist of (+)-NANM in rats trained to discriminate 5.0 mg/kg (+)-NANM from saline. Over a wide dose range, (+)-3-PPP was able to block the discriminative stimulus effects of (+)-NANM, with complete antagonism at 1.0 mg/kg i.p. Since (+)-NANM is a prototype sigma-opioid agonist, (+)-3-PPP is a good candidate for being a competitive sigma antagonist.     

Reevaluation of PNU-99194A discriminative stimulus effects: potentiation by both a D2 antagonist and a D3/D2 agonist

This study evaluated the relative importance of D(3) receptor antagonism in the discriminative stimulus effects of the putative D(3) receptor antagonist PNU-99194A. Eight male Sprague-Dawley rats were trained to discriminate PNU-99194A (10 mg/kg sc) from vehicle in a two-choice drug discrimination procedure under a FR 20 schedule of food reinforcement. The selective D(3) antagonists PD 152255 and S14297 were examined for stimulus generalization. The D(2) antagonist haloperidol and the D(2)/D(3) receptor agonist (+)-7-OH-DPAT were also assessed for antagonism of PNU-99194A discrimination. PD 152255 (1.0-3.0 mg/kg) engendered no generalization to PNU-99194A. Due to its markedly rate-suppressive effects, PD 152255 could not be tested at higher doses. S-14297 produced partial substitution (66%) for PNU-99194A at both 3.0 and 8.0 mg/kg. Neither haloperidol nor (+)-7-OH-DPAT blocked the discrimination of PNU-99194A and, surprisingly, actually appeared to potentiate its effects. These data, along with other recent findings, suggest that the discriminative stimulus effects of PNU-99194A appear to involve complex pharmacological actions and are not solely mediated by D(3) receptor antagonism.     

Antagonism of the discriminative stimulus effects of the kappa-opioid agonist spiradoline

This study compared the potency of mixed-action opioids (i.e., agonist-antagonists) and pure antagonists to block the discriminative stimulus effects of spiradoline, a kappa-opioid agonist. Rats were trained to discriminate between 3.0 mg/kg spiradoline and saline (SC) in a two-choice discrete-trial procedure. Graded doses of test drugs were administered in combination with 3.0 mg/kg spiradoline and the dose that reduced selection of the spiradoline-appropriate choice lever by 50% (AD₅₀) was calculated. Ten drugs blocked the discriminative effects of spiradoline in an orderly dose-dependent manner. They spanned a 150-fold potency range, from diprenorphine (5 times as potent as naloxone) to nalbuphine (0.03 times as potent as naloxone). Antagonism was stereoselective: 0.1–1.0 mg/kg (–)-N-allylnormetazocine (NANM) reduced spiradoline-appropriate responding by 50% whereas 3.0 mg/kg (+)-NANM did not. (–)-Pentazocine (0.1–10 mg/kg) and butorphanol (0.1–3.0 mg/kg) also did not block the discriminative effects of spiradoline. Antagonism was surmountable when graded doses of spiradoline were tested with a fixed dose of diprenorphine, naloxone, or levallorphan. Apparent pK_B values derived from the interactions between those three drugs and spiradoline were in accord with relative antagonist potencies based upon the AD₅₀s. Because the potency of a competitive antagonist is determined by its receptor affinity, the relative potencies of mixed-action opioids and pure antagonists in blocking the discriminative stimulus effects of spiradoline can provide an estimate of the relative in vivo affinities of these drugs for the kappa-opioid receptor. Present address: Weinberg Consulting Group, 1220 19th Street, Suite 300, Washington, DC 20036-2400, USA     

Memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects in rats

It has recently been reported that the amantadine derivative, memantine, which is used in the treatment of Parkinsonism, has N-methyl-D-aspartate (NMDA) antagonist properties. In order to investigate whether the behavioural effects of memantine could also be mediated through this mechanism the drug was administered to rats trained to discriminate phencyclidine (3mg/kg) from saline. Memantine produced a dose-related (2.5-10mg/kg) substitution for phencyclidine. Neither amantadine nor cocaine substituted for phencyclidine. In rats trained to discriminate cocaine (10mg/kg) memantine did not substitute. These results show that memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects indicating that the behavioural actions of memantine, like those of phencyclidine, are probably produced by a non-competitive inhibition of NMDA receptors.     

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.     

Overlapping, but not identical, discriminative stimulus effects of the neuroactive steroid pregnanolone and ethanol

Many behavioral effects of neuroactive steroids are mediated by GABA(A) receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced >80% pregnanolone-lever responding. In contrast, neither morphine nor the negative GABA(A) modulator beta-CCE substituted for pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced <20% pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABA(A) modulators, and not morphine or beta-CCE, for pregnanolone in all rats suggests that positive modulation of GABA(A) receptors is important in the discriminative stimulus effects of pregnanolone. Although pregnanolone might have actions at other receptors, in addition to actions at GABA(A) receptors, substitution of ethanol for pregnanolone only in some rats suggests that the mechanisms of action of pregnanolone and ethanol overlap, but are not identical.     

Reinforcement frequency, but not gender, determines sensitivity to discriminative stimulus effects of morphine

We demonstrated previously that several parameters of a morphine discrimination were significantly different in female versus male rats, using a fixed ratio (FR)-10 schedule of food reinforcement; however, this schedule produced a significant bias in reinforcement frequency between saline and morphine sessions in males but not in females. To determine whether this schedule-drug-sex interaction caused the sex difference in discriminability of morphine, female and male rats were trained to discriminate 3.0 mg/kg morphine from saline using a variable interval (VI) 15-s/VI 15-s (Phase I), a VI 7.5-s/VI 15-s (Phase II), and a VI 15-s/VI 15-s (Phase III) schedule of food reinforcement on morphine/saline levers, respectively. After a minimum of 40 training sessions in each phase, mean reinforcement rates in morphine sessions were highest, and the ED50 values for morphine discrimination were lowest, in Phase II. Thus, as predicted, the morphine dose-effect curves shifted to the left from Phase I to Phase II, and back to the right from Phase II to III, presumably due to the bias in reinforcement rate between saline and morphine sessions that was induced by manipulating the VI schedule on the morphine lever. However, there were no sex differences in the morphine versus saline reinforcement rate or in discrimination ED50 in any phase, suggesting that the sex difference observed in our initial study was probably due to the bias in reinforcement frequency (towards the saline condition) that occurred only in males under the FR-10 schedule. This study demonstrates the importance of considering group differences in schedule-drug interactions when comparing discriminative stimulus properties of drugs between groups.     

Nitrous oxide generalizes to a discriminative stimulus produced by ethylketocyclazocine but not morphine

The discriminative stimulus properties of nitrous oxide, an analgesic and anesthetic gas, were evaluated in rats trained to discriminate the effects of morphine or ethylketocyclazocine. Administration of nitrous oxide in concentrations as high as 80 percent did not produce generalization to the discriminative cue produced by morphine. Nitrous oxide did, however, generalize in a concentration-dependent manner in rats trained to discriminate ethylketocyclazocine, a psychotomimetic opioid. Naltrexone, a potent narcotic antagonist, did not block the generalization of nitrous oxide to ethylketocyclazocine. These results suggest that the subjective effects of nitrous oxide are similar to those produced by psychotomimetic drugs rather than those produced by morphine. These findings are in close agreement with those generated in man. Thus, nitrous oxide exhibits some pharmacological properties similar to those of morphine, for example, naloxone reversible analgesia. Yet, it has other properties such as subjective effects that are dissimilar from morphine.     

Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms.

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.     

Dopaminergic activity and the discriminative stimulus effects of mu opioids in pigeons: importance of training dose and attenuation by the D3 agonist (±)-7-OH-DPAT

 The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors, releasers, a D₁ agonist, a D₂ agonist and a D₃ agonist engendered partial substitution (50–79% butorphanol responding) for the butorphanol stimulus in the low-dose group. In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group, the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D₁ antagonist (+)-SCH 23390 and the D₂ antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol. Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin [(±)-7-OH-DPAT] attenuated butorphanol’s stimulus effects in a dose-dependent manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol, and in the high-training dose group, activation of the D₃ receptor by (±)-7-OH-DPAT results in the attenuation of the discriminative stimulus effects of mu opioids. Received: 19 May 1997 / Final version: 30 September 1997     

Tolerance to the analgesic,but not discriminative stimulus effects of morphine after brief social defeat in rats

One of the most prominent consequences of defeat in a social confrontation is a long-lasting tolerance-like insensitivity to the analgesic effects of opiates, even when only small short-lived changes in nociception are detectable during the acute social stress. The present experiments examined (1) which kinds of social experiences lead to morphine tolerance, (2) whether or not the morphine tolerance in defeat-experienced rats extends from the analgesic effects to the discriminative stimulus and rate-decreasing effects of morphine, and (3) how long morphine tolerance lasts after a defeat experience. After five brief social confrontations including attack and threat by a resident rat leading to submission or defeat of the intruder, the latter exhibits marked tolerance to the analgesic effects of morphine, but not to the discriminative stimulus or behaviorally suppressive effects. Changes in social housing did not alter morphine's behavioral effects. Tolerance to the analgesic morphine effects was detected for 2 months after the defeat experience, whereas the discriminative stimulus and rate-decreasing effects were closely similar to those before defeat. This pattern was seen in animals for whom discriminative stimulus training with morphine was suspended after defeat as well as in those for whom it continued. In additional defeated and non-defeated animals, morphine's effects on the acoustic startle reflex was assessed. In contrast to the tail flick reflex to a noxious heat stimulus, the acoustic startle response remained unaffected by defeat experience or by morphine (up to 30 mg/kg). The long-lasting and large degree of tolerance after brief social defeat experiences appears to be limited to the analgesic effects of morphine. Whether or not endogenous opioid peptide activity during the actual defeat may substitute for the morphine stimulus remains to be established.     

Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine

This study utilized drug discrimination procedures to assess the functional consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin depletion, and to determine whether concomitant injections of fluoxetine averted these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)-MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant procedure. After dose generalization tests were completed, training was suspended, and subjects were administered saline injections twice daily for four days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline, to ascertain that discriminative stimulus control was maintained in the absence of training over a two-week period. All subjects received two additional weeks of training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline (SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections, S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA generalization tests, and rose from 2.78% to 22.14% during SAL generalization tests. This disruption did not occur, however, in rats administered the combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated rats. Postmortem neurochemical assays indicated that 5-HT levels were significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL, compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5-HIAA levels were significantly lower in the prefrontal cortices of both (+/-)-MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control. These results support previous findings that fluoxetine protects against (+/-)-MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug discrimination is a sensitive assay in which to examine behavioral correlates of (+/-)-MDMA-induced serotonergic deficits, and the protection against these deficits by fluoxetine.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Nicotine does not interact with the discriminative stimulus effects of clozapine in rats

The purpose of the present study was to assess the potential interaction between clozapine, an atypical antipsychotic recently approved for clinical use in the United States and nicotine. Male Sprague-Dawley rats were trained to discriminate nicotine or clozapine in a standard two-lever operant drug discrimination procedure. Rats were tested for generalization to nicotine and clozapine, and the interactions produced by combining various doses of nicotine and clozapine were evaluated. Results suggest that nicotine does not interact with the discriminative stimulus effects of clozapine. Thus, patients who smoke while receiving clozapine therapy may not experience the decreased antipsychotic effectiveness which is common in patients who smoke while receiving treatment with typical antipsychotic compounds. © 1992 Wiley-Liss, Inc.     

Tolerance to the discriminative stimulus effects of ethanol

These experiments tested (1) the specificity of the discriminative stimulus produced by ethanol (EtOH), (2) the ability of Ro 15-4513 to block the EtOH stimulus, and (3) whether tolerance would develop to the discriminative effects of EtOH following high-dose EtOH administration. Rats were trained to use EtOH, 1 g/kg, i.p., as a discriminative stimulus in a two-choice, food-reward task. Following establishment of stimulus control, EtOH and pentobarbital substituted for EtOH in a dose-related manner; in contrast, pentylene-tetrazole and cocaine produced responding on the vehicle lever. Ro 15-4513, a partial inverse agonist at benzodiazepine receptors, failed to block the EtOH stimulus. Following these experiments, subjects were withheld from training and given EtOH in a nutritionally complete liquid diet, in two feedings per day for 6 days. Subjects consumed approximately 10 g of EtOH per day from this diet. On days 4 to 6 of this regimen, 12-h after a previous EtOH feeding, subjects were retested with EtOH. After recovery from this procedure and re-establishment of baseline performance, subjects were again given the high-dose EtOH treatment and tested for pentobarbital substitution. High-dose EtOH produced tolerance to EtOH and some degree of cross-tolerance to pentobarbital. These results are consistent with the hypothesis that chronic EtOH administration produces tolerance to the stimulus effects of EtOH.     

D-Ala2,D-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine

Male Sprague-Dawley rats were trained to discriminate between the effects of saline and either fentanyl (0.04 mg/kg) or ethylketocyclazocine (0.32 mg/kg) by responding on a FR 10 schedule of food reinforcement with a lever on one side of a food cup following a subcutaneous saline injection and responding with a lever on the alternate side following the subcutaneous injection of one of those drugs. The effects of an intracerebroventricular injection of either fentanyl (2.89-14.45 nmol) or D-Ala2,D-Leu5-enkephalin (0.172-1.72 nmol) dose-dependently generalized to the discriminative stimulus produced by fentanyl injected subcutaneously. Intracerebroventricular injection of ethylketocyclazocine (15.7-125.8 nmol) but not D-Ala2,D-Leu5-enkephalin (1.72-13.76 nmol) dose-dependently generalized to the discriminative stimulus produced by ethylketocyclazocine injected subcutaneously. These data demonstrate similarities in the discriminative stimulus properties of proposed micron and delta but not kappa and delta opiate receptor agonists.     

Antagonism of diazepam's anticonflict effects in rats by nicotine,but not by arecoline

The purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague-Dawley rats were tested with a modified Geller-Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed-interval 60-sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed-ratio 1 schedule. In Experiment 1 (?)-nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (?)-nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley-Liss, Inc.