Discriminative Stimulus In Rats Research Articles

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

The discriminative stimulus properties of the typical antipsychotic chlorpromazine were examined in a two-lever drug discrimination procedure for food reward. Six of nine rats readily acquired the discrimination between 1.0 mg/kg chlorpromazine (i.p.) and vehicle in a mean of 29.7 training sessions. The chlorpromazine generalization curve was dose-dependent and yielded an ED 50 of 0.305 mg/kg (95% confidence interval (CI) = 0.201-0.463 mg/kg). The chlorpromazine cue generalized to the atypical antipsychotics clozapine (ED 50 for the clozapine curve was 0.258 mg/kg [95% Cl = 0.047-1.420 mg/kg]) and olanzapine (ED 50 for the olanzapine curve was 0.199 mg/kg [95% Cl = 0.076-0.522 mg/kg]) and to the typical antipsychotic thioridazine (ED 50 for the thioridazine curve was 3.103 mg/kg [95% Cl = 1.993-4.832 mg/kg]). Haloperidol (a typical antipsychotic) and raclopride (an atypical antipsychotic) did not substitute for chlorpromazine. It is clear from the present results that the discriminative stimulus properties of chlorpromazine share similarities both with the atypical antipsychotics clozapine and olanzapine and with the typical antipsychotic thioridazine. The extent to which the discriminative stimulus properties of antipsychotic drugs reflect or are predictive of their therapeutic effects in schizophrenic patients remains unclear.

Mechanism of Stimulus Classes Formation in Concurrent Discriminations in Rats

The two present experiments examined a premise of stimulus classes formation between discriminative stimuli in rats. Rats were concurrently trained on two discriminations and received occasional compound test trials on which both positive and negative sti muli were simultaneously presented. In Experiment 1, performance on tests was initially very poor, but it gradually improved as rats continued to receive overtraining on two discriminations. Overtraining on one discrimination alone was not sufficient to improve test performance. In Experiment 2, after receiving overtraining on two discriminations, rats were given extinction train ing either on both discriminations or only one before a final test. Extinction on both discriminations did not cause any loss on test performance, but extinction on only one discrimination did. Rats of the group that was extinguished on both discrimination tasks, evinced perfect discrimination performance on the test when food reinforcement was introduced again. These results show that each member of the stimulus class has both the unlearned representation of itself and the learned representation of the other stimulus during overtraining in two concurrent discriminations in rats.

Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline

Citalopram (2.5 mg/kg, i.p.) increased (+145–+180%) extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) in the frontal cortex, nucleus accumbens and striatum of freely-moving rats, whereas dopamine and noradrenaline were unaffected. At this dose, employing a two-lever, food-reinforced, drug discrimination procedure, citalopram generated reliable recognition and fully (>80%) generalized to itself with an Effective Dose 50 (ED 50) of 0.1 mg/kg, s.c. Two further selective 5-HT reuptake inhibitors, sertraline and paroxetine, fully generalized with ED 50s of 0.01 and 0.04 mg/kg, s.c., respectively. In contrast, the anxiolytic, diazepam (0.63), and the antipsychotic, clozapine (2.5), did not (≤20%) generalize. In conclusion, the selective 5-HT reuptake inhibitor, citalopram, elicits a pharmacologically-specific discriminative stimulus in rats at a dose selectively elevating extracellular concentrations of 5-HT.

Discriminative stimulus properties of the putative dopamine D 3 receptor agonist, (+)-PD 128907: role of presynaptic dopamine D 2 autoreceptors

The putative D 3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D 3 receptors in vivo. Given that non-selective D 2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 μg kg −1, s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D 3 receptor mediated response, the non-selective D 2/3 receptor agonist apomorphine and the D 3 preferring agonists 7-OH-DPAT and (−) quinpirole generalised to the cue whilst the D 2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D 1 selective agonist (±)-SKF 81297 and D 1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent α-methyl- p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D 3 receptor. Thus the 10-fold selective D 2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists >40 and >100-fold selective for D 3 receptors, failed to modify the response. These results suggest that presynaptic D 2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D 3 receptors in vivo.

A Review of the Preclinical Development of Zaleplon, a Novel Non‐Benzodiazepine Hypnotic for the Treatment of Insomnia

SUMMARYZaleplon (N‐[3‐(3‐cyanopyrazolo[l,5‐a]pyrimidin‐7‐y l)phenyl)]‐N‐ethylacetamide) is a non‐benzodiazepine sedative‐hypnotic with benzodiazepine‐like sedative effects, but with less apparent liability for accompanying undesirable side effects. Zaleplon displaces [3H]flunitrazepam from rat cortical membranes with an IC50 value of 200 nM and enhances t‐butylbicyclophosphorothionate [35S]TBPS binding by 73%, suggesting pharmacological activity mediated by the GABAA benzodiazepine receptor complex. In various preclinical procedures such as motor activity, muscle relaxation, EEG, anticonvulsant activity, and vigilance, zaleplon produced effects similar to those of other sedative‐hypnotic compounds such as triazolam and flurazepam; furthermore, these effects, when evaluated, were reversed by the benzodiazepine receptor antagonist flumazenil. Zaleplon increased punished (conflict) responding in squirrel monkeys and rats and these effects were also antagonized by flumazenil. When established as a discriminative stimulus in rats at 3.0mg/kg i.p., zaleplon showed a dose‐related increase in drug‐appropriate responding up to the training dose and a correlated decrease in response rate. Triazolam (0.1 to 1.0 mg/kg), the benzodiazepine partial agonist Ro 17‐1812 (0.3 to 3.0mg/kg), and the triazolopyridine CL 218,872 (1.0 to 3.0 mg/kg) substituted consistently for zaleplon in all rats, whereas the imidazo‐pyridines zolpidem (3.0 to 10 mg/kg) and alpidem (10 to 30 mg/kg), the benzodiazepine partial agonist bretazenil (0.03 to 10 mg/kg) and the novel putative anxio‐lytic CL 273,547 (10 to 56 mg/kg) did not result in consistent drug‐appropriate responding in all rats. These results suggest that the effects of zaleplon are similar in many respects to other compounds acting at the benzodiazepine receptor complex but differ as well from both benzodiazepine and non‐ benzodiazepine drugs. This profile of activity, coupled with additional information in ancillary procedures, yields a pre‐clinical profile of a short‐acting sedative‐hypnotic non‐benzodiazepine that is currently in Phase III development for the treatment of sleep disturbances.

Assessment of relative efficacies of 5-HT 1A receptor ligands by means of in vivo animal models

We have evaluated the effects of ligands with varying efficacies at β-adrenoceptors and 5-HT 1A receptors in three in vivo models reflecting pre- and/or postsynaptic 5-HT 1A receptor activation. Forepaw treading in rats is mediated by postsynaptic 5-HT 1A receptors, 8-OH-DPAT (8-hydroxy-2-(di- n-propylamin)tetralin)-induced discriminative stimulus is predominantly mediated by postsynaptic, but presynaptic 5-HT 1A receptors might also be involved, and footshock-induced ultrasonic vocalization involves predominantly presynaptic 5-HT 1A receptors. In vitro receptor binding studies demonstrated high β-adrenoceptor and 5-HT 1A receptor affinity of (−)-penbutolol, high β-adrenoceptor and 60 times lower 5-HT 1A receptor affinity of (+)-penbutolol, high β-adrenoceptor affinity and about 100 times lower 5-HT 1A receptor affinity of pindolol and (−)-tertatolol, only affinity for β-adrenoceptors of metoprolol and ICI 118,551 ( erythro- d,l-1-(7-methylindan-4-yloxy)-3-isopropylamine-butan-2-ol, and only affinity for 5-HT 1A receptors of WAY 100.635 (( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclo-hexane-carboxamide). (−)-Penbutolol, (−)-tertatolol, pindolol and WAY 100.635 antagonized 5-MeODMT-induced (5-methoxy- N,N-dimethyltryptamine) forepaw treading in rats, and (+)-penbutolol, ICI 118,551 and metoprolol were inactive. (−)-Penbutolol, WAY 100.635 and (−)-tertatolol antagonized 8-OH-DPAT-induced discriminative stimulus in rats, pindolol and metoprolol showed a mixed antagonistic and agonistic profile. Pindolol antagonized footshock-induced ultrasonic vocalization in rats, tertatolol inhibited maximum 36% and WAY 100.635, (−)-penbutolol, (+)-penbutolol, metoprolol and ICI 118,551 were inactive. (−)-Penbutolol and WAY 100.635 reversed 8-OH-DPAT-induced inhibition of ultrasonic vocalization completely, (−)-tertatolol reversed maximum 52% and (+)-penbutolol and pindolol were inactive. It is concluded, that efficacies at 5-HT 1A receptors can be estimated by applying a battery of in vivo test models that involve post- and presynaptic receptors to a variable degree. The in vivo ranking order of efficacy at 5-HT 1A receptors was: WAY 100.635 = (−)-penbutolol < (−)-tertatolol < pindolol.

S-8-3 - D2 receptor activation in distinct striatal neurons in comparison with D3 receptors

The putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 μg kg−1, s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (−) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (±)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent α-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists >40 and >100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.

Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine.

The present study was conducted to determine if the tetracyclic antidepressant mianserin could be established as a discriminative stimulus in rats. One group of rats was trained to discriminate mianserin (4.0 mg/kg, IP) from saline in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (0.25 mg/kg, IP) from saline. Generalization testing with the training drugs yielded an ED50 of 0.502 mg/kg for the mianserin-trained rats and an ED50 of 0.048 mg/kg for the scopolamine-trained rats. Asymmetrical cross-generalization between mianserin and scopolamine was observed, because scopolamine produced mianserin-appropriate responding, but mianserin did not produce scopolamine-appropriate responding. This study is the first demonstration that rats can be trained to discriminate mianserin from saline and that antagonism of muscarinic cholinergic receptors is sufficient to produce mianserin-appropriate responding.

Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists

Two novel quinoxalinedione glutamatergic antagonists, with in vitro selectivity for the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primarily designed to compare their effects to those of the noncompetitive NMDA antagonist phencyclidine (PCP). The compounds evaluated were 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminative stimulus effects, although behavioral activity, in the form of response rate suppression, was seen at the higher doses tested (6-25mg/kg, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhesus monkeys trained to discriminate PCP from sham injection, although in the monkeys minimal effects were observed on rates of responding even at the highest dose tested (10.2mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial levels of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 produced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3mg/kg, i.p.). ACEA-1021 was ineffective as an antagonist of NMDA discrimination. Unlike results reported for PCP-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted prepulse inhibition of the acoustic startle reflex in rats. It was not possible to establish ACEA-1021 (10 or 15.6mg/kg) as a discriminative stimulus in rats. In conclusion, the novel glutamate antagonists ACEA-1011 and ACEA-1021 did not produce a profile of behavioral effects similar to that of PCP-like noncompetitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonists.

Insulin, 2-deoxy- D-glucose, and food deprivation as discriminative stimuli in rats

Using a two-lever drug discrimination procedure, two groups of four rats each were trained to discriminate the stimulus effects of 1.0 U/kg insulin or 125 mg/kg 2-deoxy- D-glucose (2-DG) from saline. A third group was trained to discriminate food deprivation produced by feeding 23 h prior to sessions from satiation produced by feeding 2 h prior to sessions. Differential responding was a direct function of dose or deprivation level in each group. Rats trained to discriminate insulin responded as if they had received insulin when they received 2-DG and vice versa. Insulin and 2-DG produced deprivation-appropriate responding in two of four rats trained to discriminate food deprivation. Low insulin and 2-DG doses produced drug-appropriate responding in rats deprived 47 h, but not in rats deprived 23 h. Blood glucose level was altered by the training doses of insulin and 2-DG, but not by 23-h deprivation. These results indicate that operations that induced feeding produce discriminable stimuli, and that these effects overlap or interact. Thus, drug discrimination procedures can be useful in the analysis of ingestive behavior.

Discriminative stimulus effects of the optical isomers of 3,4-methylenedioxyamphetamine (MDA)

The isomers of 3,4-methylenedioxyamphetamine (MDA) functioned as discriminative stimuli in rats trained to discriminate either (-) MDA (1.25mg/kg) or (+) MDA (1.25mg/kg) from saline. Dose- and time-response curves indicated that drug lever selection occurred at doses of at least 1.00mg/kg of (-) MDA and 0.75mg/kg of (+) MDA and that drug-appropriate responding for both isomers was maintained for at least 90min. Cross-substitution was observed between the MDA isomers; both (+) and (-) 3,4-methylenedioxymethamphetamine (MDMA) also substituted completely for (+) and (-) MDA. The hallucinogens (+)-lysergic acid diethylamide (LSD) and (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), substituted for (-) MDA; neither mescaline nor (+) amphetamine or cocaine had (-) MDA-like effects. LSD also substituted for (+) MDA; DOM, mescaline, (+) amphetamine and cocaine failed to have (+) MDA-like effects. The (-) but not the (+) MDA cue was blocked by the 5-HT(2) antagonist pirenpirone; the dopamine (DA) antagonists SCH-23390 and (-) sulpiride had no effect on either the (-) or (+) MDA cues. When animals were trained to discriminate LSD (0.16mg/kg) or (+) amphetamine (1.0mg/kg) from saline, neither (-) MDA nor (+) MDA substituted completely. These results indicate that: (1) the stimulus effects of the isomers of MDA and MDMA are similar; (2) (-) MDA may be more hallucinogenic (or more accurately, LSD- or DOM-like) than (+) MDA; (3) neither (+) nor (-) MDA has potent amphetamine-like effects; and (4) the effects of (-) MDA may be more serotonergic than those of (+) MDA.

Testosterone as appetitive and discriminative stimulus in rats: Sex- and dose-dependent effects

Stimulus properties of subcutaneously injected testosterone were studied in male and female rats. In a conditioned place preference procedure, dose-dependent effects (doses: 0, 0.5, and 1 mg/kg) were observed in males. In females, no place preference could be established (doses: 0, 1, and 3 mg/kg). In addition, 1 mg/kg testosterone acquired discriminative stimulus control in male rats in a taste aversion procedure. Animals injected with this hormone prior to saccharin-LiCl pairings and with its vehicle prior to saccharin-NaCl pairings suppressed fluid intake following the administration of testosterone and not following the administration of the vehicle. Subsequent generalization tests revealed dose-dependent stimulus control of this hormone (range of substitution doses: 0.125–2 mg/kg). It is concluded from the results that at least pharmacological (supraphysiological) doses of testosterone may act as appetitive stimuli in male rats, but not in female rats. Furthermore, in male rats (pharmacological doses of) testosterone also possess discriminative stimulus properties.

5-HT 3 agonist 2-methylserotonin as a training drug in drug discrimination studies

Using a standard two-lever operant procedure, rats were trained to discriminate 5 mg/kg of the 5-HT 3 agonist 2-methylserotonin (2-Me 5-HT;ED 50 = 2.6 mg/kg) from saline using a VI 15-s schedule of reinforcement. The 2-Me 5-HT stimulus dinot generalize to the 5-HT 1/5-HT 2 agonist 5-methox- N, N-dimethyltryptamine, but did generalize to the new 5-HT 3 agonist 1-( m-chlorophenyl)biguanide (ED 50 = 1.6 mg kg). The 5-HT 3 antagonist ICS 205–930 potently antagonized the 2-Me 5-HT stimulus ( ID 50 = 0.001 mg/kg), whereas its quaternary amine analog, which does not readily penetrate the blood-brain barrier, failed to completely antagonize the 2-Me 5-HT stimulus at a 10, 000-fold higher dose. The results of the present investigation show that 2-Me 5-HT serves as a discriminative stimulus in rats when paired when saline and suggest that its properties are likely mediated via a central 5-HT 3 mechanism. As such, this is the first demonstration that a 5-HT 3 agonist can be used as a training drug in drug discrimination studies.

Pharmacological specificity of the phencyclidine discriminative stimulus in rats

The discriminative stimulus effects of phencyclidine (PCP), pentobarbital and the competitive N-methyl-D-aspartate antagonist 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) were examined in rats trained to discriminate PCP from saline under a 2-lever, food-maintained operant schedule. Dose-response curves were obtained for all three drugs at a PCP training dose of 1.25 mg/kg; subsequently, rats were retrained to discriminate either 0.56 or 3.0 mg/kg PCP. The dose-response to PCP was not substantially changed by raising or lowering the training dose. However, doses of pentobarbital and CPP produced augmented levels of substitution when the training dose was lowered and decreased substitution when it was raised. The changes in PCP training dose were, therefore, effective in either diminishing or amplifying the pharmacological specificity of the PCP stimulus. Under conditions where specificity was high (high training dose), neither pentobarbital (0.1-17 mg/kg) nor CPP (1-17 mg/kg) produced appreciable PCP-like stimulus effects, supporting evidence that competitive NMDA antagonists may be no more PCP-like than are barbiturates. These data provide additional evidence for differences in the behavioral effects of noncompetitive and competitive NMDA antagonists.

Terguride, a dopamine D2 partial agonist, as a discriminative stimulus in rats

Drug discrimination training with terguride, a 9, 10-transdihydrogenated derivative of lisuride, was carried out using a two-lever food-reinforced procedure (FR 10) in rats, to investigate its influence on central dopaminergic (DA) and serotonergic (5-HT) functions. The terguride (0.05mg/kg, i.p.) discrimination was established within 64 +/- 5 training sessions (mean +/- S.E.) and was stably maintained thereafter. Higher doses of terguride could not be used for discriminative training due to response disruption. In generalization tests with terguride, drug-appropriate responding increased dose-dependently and reached levels of 45 and 99% at 0.01 and 0.05mg/kg i.p. The D(2) agonist lisuride at low doses and the DA autoreceptor agonist (-)-3-PPP substituted for terguride. The DA agonist apomorphine and the 5-HT agonist 5-MeO-DMT produced dose-dependent but incomplete substitution. The D(1) agonist SKF38393, the DA antagonist haloperidol, the D(2) antagonist sulpiride, the D(1) antagonist SCH23390, the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized. In antagonism tests, sulpride completely blocked the terguride-appropriate response, but SCH23390 and the 5-HT antagonist methysergide did not. These results indicate that discriminative stimulus properties of terguride in rats are mediated primarily by activation of receptors with characteristics similar to those of presynaptic D(2) autoreceptors.

Discriminative stimulus effects of the novel anxiolytic buspirone

Separate groups of Long-Evans rats were trained to discriminate either 0.56 or 1.0mg/kg buspirone i.p. in a two-lever, drug vs no-drug discrimination procedure. Training took twice as long for the lower versus the higher training-dose group. Generalization tests were conducted with buspirone (0.1-1.8mg/kg, i.p., 0.32-10mg/kg, p.o.), pentylenetetrazole (1-18mg/kg, i.p.), meprobamate (3.2-180mg/kg, p.o.), haloperidol (0.01-0.32mg/kg, i.p.), and 8-OH-DPAT (0.01-0.32mg/kg, i.p.). Buspirone p.o. was 0.5-1.0 log(10) units less potent than buspirone i.p. in producing dose-dependent generalization (i.e. > 80% buspirone-lever responding). Dose-effect functions for the 1.0 training-dose group were to the right of those for the 0.56 group. Partial generalization to meprobamate occurred in both groups, representing the first report of overlap of the buspirone discriminative stimulus with that of another anxiolytic. Complete generalization to 8-OH-DPAT occurred, consistent with buspirone's prominent 5HT(1A)-receptor activity and replicating findings in the pigeon. Partial generalization to haloperidol was concluded: every rat generalized to haloperidol, but the gradients did not increase monotonically and drug-lever responding at a given dose was inconsistent within and across rats. The haloperidol results suggest a stronger influence of the dopaminergic component in the buspirone discriminative stimulus in rats than was found with pigeons. Although a previous study found generalization to buspirone from pentylenetetrazole in baboons, there was no generalization to pentylenetetrazole from buspirone in the present study.

Failure of SCH 23390 to function as a discriminative stimulus in rats

Four rats were studied in a two-lever, food-reinforced drug discrimination paradigm using the D1 dopamine antagonist SCH 23390 (0.03 mg/kg, IP, 30 minutes prior to the session) and saline as the training stimuli. After at least 100 training sessions there was no evidence of stimulus control over responding by SCH 23390 in 3 of the 4 rats, and only briefly in the fourth. On the other hand, food delivery exerted control over behavior indicating that SCH 23390 did not disrupt control of behavior by the reinforcing stimulus. An increase in training dose to 0.06 mg/kg for an additional 12 sessions did not improve discriminative accuracy although this dose reduced rate of responding to an extent that made further training using 0.06 mg/kg untenable. The results provide no evidence of stimulus control of behavior by SCH 23390 and suggest that SCH 23390 does not function as a discriminative stimulus in rats.

Adrenocorticotropic hormone fragment ACTH/MSH(4–10) can act as a discriminative stimulus in rats

Five of eight male albino rats learned to discriminate the effects of ACTH/MSH(4–10) (100 μg/kg, SC) from those of saline vehicle in a food-reinforced T-maze task. Generalization tests showed that the ACTH/MSH(4–10) cue was dose related with an ED 50 of approximately 68.0 μg/kg. These findings indicate that ACTH/MSH(4–10) has interoceptive stimulus properties discriminable to some animals, which might provide a useful model for studying the pharmacology of this neuroactive peptide. Moreover, since ACTH/MSH(4–10) induces effects similar to those of ACTH/MSH in the central nervous system but not hormonally, these data suggest that endogenous ACTH or MSH may also have interoceptive stimulus effects unrelated to peripheral endocrine activity.

Does the pentylenetetrazole (PTZ) cue reflect PTZ‐induced kindling or PTZ‐induced anxiogenesis?

AbstractThe discriminative stimulus induced by a subconvulsive dose of pentylenetetrazole (PTZ) in rats is suggested to be anxiogenic in nature; therefore, antagonism of the discriminative stimulus indicates anxiolytic and not anticonvulsant activity. Repeated administration of subconvulsive doses of PTZ eventually leads to seizures, a process known as kindling. The effects of several anxiolytic and anticonvulsant drugs in antagonizing the discriminative stimulus in rats were compared with the effects of the same substances in preventing seizures in rats treated acutely with a high dose of PTZ or in rats exhibiting kindled seizures following repeated low‐dose PTZ treatment. Irrespective of status as an anxiolytic or an anticonvulsant substance, only compounds that antagonized PTZ‐kindled seizures antagonized the PTZ discriminative stimulus. These results illustrate the difficulty in separating the anxiolytic from the anticonvulsant properties of a substance in this model.

A comparison of PCP-like compounds for NMDA antagonism in two [formula omitted] models

The PCP-like compounds ketamine and dexoxadrol were evaluated in two behavioral test procedures known to be sensitive to competitive N-methyl-D-aspartate (NMDA) receptor antagonists. In the NMDA-induced convulsion test in mice, ketamine and dexoxadrol blocked convulsant activity only at doses that also induced nonspecific effects of PCP-like behaviors, thereby confounding the interpretation of results. These compounds also blocked NMDA-induced discriminative stimuli in rats; however, this effect was produced at doses lower than those which induced the nonspecific behavioral effects. These results provide evidence that in behavioral procedures, PCP-like compounds may block excitatory amino acid receptor stimulation by NMDA. The NMDA discrimination identifies these interactions without the influence of motor deficit or other behavioral motor effects.