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PubMed1989

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

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

Amphetamine↗
PubMed1989

Evidence for perceptual masking of the discriminative morphine stimulus.

Morphine-amphetamine and morphine-naltrexone interactions were examined in three groups of White Carneaux pigeons (n = 3), which were trained in a two-choice drug discrimination procedure under a FR-30 schedule of food reinforcement using 3.2 mg/kg morphine and saline as discriminative stimuli. Once stimulus control was acquired by these initial training stimuli, the training doses of morphine were gradually changed to 1.0 mg/kg for group A and to 10 mg/kg for group C. The three groups differed in the minimum dose required for stimulus control and the drugs to which the training stimulus generalized. Stimulus generalization to amphetamine was inversely related to training dose. Amphetamine potentiated the discriminative stimulus properties of morphine. Naltrexone blocked the discriminative stimulus properties of morphine to varying degrees, which appeared to be limited by the training dose and the rate-suppressing effects of naltrexone when administered alone. Challenging the morphine stimulus with amphetamine resulted in a qualitatively similar blockade. This blockade was a direct function of the morphine training dose. It is argued that MS-AMP interactions result in perceptual masking of the MS stimulus, which can be differentiated from pharmacological antagonism by NTX. Two other challenge drugs, ketamine and sodium pentobarbital, did not alter stimulus control by morphine.

Animals↗
PubMed1984

Discriminative stimulus properties of beta-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors.

The discriminative stimulus properties of three beta-carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two beta-carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonists Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third beta-carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three beta-carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93423 and ZK 91296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.

Animals↗
PubMed1984

Effects of drug-induced differences in reinforcement frequency on discriminative stimulus properties of fentanyl.

Rats were trained to discriminate between fentanyl (0.04 mg/kg) and saline in a two-lever procedure. Using a FR 10 schedule of food reinforcement, drug-induced differences between the number of reinforcers obtained under fentanyl and saline conditions were observed. The effect of eliminating these differences on the outcome of generalization tests was investigated by different manipulations. In one group (N = 10), the FR 10 schedule used during saline sessions was changed to FR 6 during drug sessions. In a second group (N = 12), saline sessions ended after the number of reinforcers obtained was equal to the number obtained during the preceding drug session. A control group (N = 10) was trained using a FR 10 schedule under both conditions. Elimination of differences in reinforcement frequency accelerated the acquisition of the discrimination, diminished response bias, flattened the slope and reduced the ED50 value of generalization gradients of fentanyl, morphine and sufentanil and increased the ED50 value of naloxone in antagonizing 0.04 mg/kg fentanyl. It is concluded that the unconditioned effects of 0.04 mg/kg fentanyl on response rate in a FR 10 procedure lead to differences between saline and drug sessions which contribute to the apparent discriminative stimulus properties of fentanyl.

Animals↗
PubMed1988

Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role of D-Ala2-D-Leu5-enkephalin (DADL) and dynorphin A (1-13).

The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001-30 micrograms), depending upon ligand and animal, by morphine, by the mu-selective peptides DAGO[D-Ala2-NMePhe4-Gly(ol)-enkephalin] and FK33824[D-Ala2,NMePhe4-Met(O)5-(ol)-enkephalin], and by the delta-selective peptide, DADL[D-Ala2,D-Leu5)enkephalin]. The order of relative potency of these substances was: FK33824 greater than DAGO greater than morphine greater than DADL. In contrast, DPLPE[D-Pen2,L-Pen5)enkephalin], which has much greater delta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1-10 micrograms), a kappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 micrograms DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 micrograms dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings that mu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.

Animals↗
PubMed1990

Reward dominance and passive avoidance learning in adolescent psychopaths.

This study tests predictions that adolescent psychopaths are hyperresponsive to rewards (Quay, 1988) and deficient in passive avoidance learning (Newman & Kosson, 1986). Forty male adolescent juvenile offenders were divided into psychopaths and nonpsychopaths using cluster analysis. Subjects were administered a passive avoidance learning task which required learning when to respond to cards associated with either reward or punishment. Results showed a greater responsivity to reward in psychopaths, with no group differences in passive avoidance errors. Results lend support to the view that psychopaths tend to focus on the prospect of reward under conditions of mixed incentives and, when sufficiently motivated, are capable of improved performance. Together with findings of recent psychophysiological studies, these results suggest that adolescent psychopaths may have latent abilities which could have treatment implications.

Adolescent↗
PubMed1991

Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine.

Evidence suggests that stimulants such as d-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D1 and D2) exist, we investigated the role of both of these receptor subtypes in mediating the internal "state" produced by these stimulants. Two groups of rats (N = 8/group) were trained to discriminate intraperitoneal (IP) injections of either d-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D1 and D2 agonists and antagonists. The D2 agonist quinpirole (0.0313-0.125 mg/kg) mimicked both stimulant cues while the D1 agonist SKF 38393 (5-20 mg/kg) substituted partially for cocaine but not d-amphetamine. Combination tests with DA antagonists indicated that both the D1 antagonist SCH 23390 (0.0063-0.25 mg/kg) and the D2 antagonist haloperidol (0.125-0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) for d-amphetamine was blocked by both DA antagonists. The ability of both D1 and D2 antagonists to attenuate the stimulus effects of d-amphetamine and cocaine raises the possibility that a synergistic ("enabling") interaction between D1 and D2 receptors may modulate stimulant cues.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Increased sensitivity to rate-altering and discriminative stimulus effects of morphine following continuous exposure to naltrexone.

Two experiments evaluated whether termination of a continuous infusion of naltrexone altered sensitivity to the rate-suppressing or discriminative stimulus effects of morphine in rats. An 8-day infusion of saline or doses of 3, 10, or 18 mg/kg/day naltrexone did not alter rates of lever pressing maintained under fixed-ratio 30 schedules of food delivery. A dose of 10 mg/kg day naltrexone produced insurmountable antagonism of the rate-suppressing and analgesic effects of morphine. The ED50 of morphine for rate suppression decreased by 2-fold 1 day after termination of the 8-day infusion of 10 or 18 mg/kg/day naltrexone. The ED50 of morphine returned to initial values within 8 days. Termination of infusion of either saline or 3 mg/kg/day naltrexone did not alter the ED50 of morphine. Changes in morphine stimulus control were evaluated in rats trained to discriminate saline and 3.2 mg/kg morphine under fixed-ratio 15 schedules of food delivery. The ED50 of morphine for stimulus control or rate suppression decreased by 2-fold 1 day after termination of an 8-day infusion of 18 mg/kg/day naltrexone. The ED50 of morphine for rate suppression returned to initial values within 3 days; that for stimulus control, within 5 days. Thus, termination of exposure to high doses of naltrexone produced brief changes in sensitivity to the rate-altering and discriminative stimulus effects of morphine that parallel reported changes in sensitivity to the analgesic and lethal effects of morphine.

Animals↗
PubMed1990

Chlordiazepoxide reduces discriminability but not rate of forgetting in delayed conditional discrimination.

Benzodiazepine and anticholinergic drugs interfere with septo-hippocampal function in similar but not identical ways. They also share a number of common behavioural effects and, in particular, both classes of drug interfere with spatial memory in the Morris Water Maze--a test which is very sensitive to hippocampal dysfunction. We have previously shown that the anticholinergic drug scopolamine impairs discriminability, but not rate of forgetting, in delayed conditional discrimination. In the present study forgetting was quantified by fitting a negative exponential function to estimates of discriminability derived from a signal detection analysis of data from an auditory delayed conditional discrimination task. Chlordiazepoxide produced a highly significant decrease in discriminability which was monotonically related to the logarithm of dose in the range 0.67-18.0 mg/kg IP. The rate of forgetting was not increased. These data confirm the pharmacological independence of changes in discriminability and rate of forgetting; demonstrate that in this task chlordiazepoxide has similar effects to scopolamine; and suggest that the effects of chlordiazepoxide in other working memory tasks could be more a result of changed stimulus processing than impairment of memorial processes.

Animals↗
PubMed1993

Substitution of the 5-HT1 agonist trifluoromethylphenylpiperazine (TFMPP) for the discriminative stimulus effects of ethanol: effect of training dose.

The role of the ethanol training dose on the ability of the selective 5-HT1 agonist TFMPP (m-trifluoromethylphenylpiperazine) to produce ethanol-like discriminative stimulus effects was evaluated in three groups of rats trained to discriminate 1.0 g/kg (n = 5), 1.5 g/kg (n = 6) or 2.0 g/kg (n = 7) ethanol (IG) from water using a two-lever procedure with food reinforcement available under a fixed ratio 20 (FR 20) schedule. Ethanol generalization gradients were comparable in the three groups, indicating few potency differences in the ethanol stimulus across training dose. However, the ability of TFMPP (0.1-1.7 mg/kg; IP) to substitute for ethanol was dependent on the training dose. TFMPP resulted in partial substitution in the 1.0 g/kg group, complete substitution for 1.5 g/kg group and no substitution in the 2.0 g/kg ethanol training group. The results indicate a serotonergic component to the discriminative stimulus effects of an intermediate dose of ethanol that is not prominent as the dose of ethanol is raised. These data add further support for the hypothesis that ethanol produces a mixed discriminative cue, the components of which are not uniformly amplified when the dose of ethanol is increased.

Animals↗
PubMed1993

Discriminative stimulus effects of omega (BZ) receptor ligands: correlation with in vivo inhibition of [3H]-flumazenil binding in different regions of the rat central nervous system.

Rats can be trained to discriminate benzodiazepines (BZ) from vehicle and there is considerable evidence that the stimulus effects of these drugs are mediated by activity at omega (BZ) modulatory sites of the GABAA receptor complex. A number of recent studies, however, have indicated that differences may exist between the discriminative stimulus effects of benzodiazepines and those of certain non-benzodiazepine ligands for the omega (BZ) receptors (e.g. zolpidem, abecarnil). As it is known that several subtypes of omega (BZ) sites are found in the central nervous system, and that drugs such as zolpidem have selectivity for certain subtypes, it is possible that differential stimulus effects may be associated with receptor selectivity. In the present study, correlations were calculated between the potencies of nine compounds with affinity for omega receptors (diazepam, lorazepam, triazolam, clonazepam, alprazolam, zopiclone, suriclone, CL 218, 872 and zolpidem) to substitute for chlordiazepoxide in rats trained to discriminate a dose (5 mg/kg) of this benzodiazepine and the ability of the same compounds to inhibit the binding of [3H]-flumazenil from different structures in the rat central nervous system in vivo. The correlations obtained were: cerebellum 0.46, cortex 0.39, striatum 0.78 (P < 0.05), hippocampus 0.79 (P < 0.05) and spinal cord 0.95 (P < 0.001). These different structures are known to contain different relative concentrations of omega 1 (BZ1) and omega 2 (BZ2) sites with the spinal cord containing the greatest (80%) and cerebellum the lowest (5%) concentration of omega 2 (BZ2) sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Discriminative stimulus effects of melatonin in the rat.

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

Animals↗
PubMed1994

Drug discrimination is a continuous rather than a quantal process following training on a VI-TO schedule of reinforcement.

Debate continues as to whether drug discrimination in animals is an inherently quantal or continuous process. This issue is important in determining the appropriate interpretation of results from drug discrimination studies designed to assess the nature of drug-induced interoceptive cues. The quantal approach holds that subjects perceive a drug cue in an all-or-none manner, while the continuous view proposes that when appropriate training and testing procedures are used, subjects can discriminate along a continuum of interoceptive cues. Data consistent with the quantal view have consistently been generated by animals trained to respond on schedules of reinforcement having an FR component. Since quantal responding is a characteristic of these schedules, results from drug discrimination studies using training schedules with FR components are of little value in empirically determining whether drug discrimination reflects a quantal or continuous process. Use of variable schedules of reinforcement might be more appropriate because the pattern of responding generated does not preclude results consistent with either of the competing views. Data from the following studies that trained subjects using VI schedules with a concurrent TO for incorrect lever responding were analyzed: Barrett et al. (1982): L-5-hydroxytryptophan versus saline; Smith (1990): diazepam versus pentylenetetrazol; Barrett et al. (1992): amphetamine versus haloperidol; Barrett and Steranka (1983): amphetamine versus haloperidol. In every case, when experimental conditions produced a group mean intermediate to that for the training drugs, the distribution of scores for individual animals was normally rather than bimodally distributed.

5-Hydroxytryptophan↗
PubMed1992

Discriminative stimulus properties of 8-OH-DPAT: relationship to affinity for 5HT1A receptors.

Previous studies have shown that discriminative stimulus control established with the 5HT1A receptor agonist, 8-OH-DPAT, generalizes to other 5HT1A agonists and partial agonists but also to the alpha 2-adrenoceptor antagonist, yohimbine. On the basis of these results it has been proposed that the 8-OH-DPAT cue may be produced by activity at more than one receptor. In the present study rats were trained to discriminate a dose of 8-OH-DPAT (0.05 mg/kg, SC) from saline. Substitution tests showed dose-dependent generalisation with the 5HT1A compounds, buspirone, ipsapirone, MDL 72832 and MDL 73005EF, the alpha 2-adrenoceptor antagonists, yohimbine and idazoxan, and BMY 14802, which is usually described as a sigma ligand. The buspirone metabolite 1-pyrimidinyl piperazine (1-PP) which possesses mainly alpha 2-adrenoceptor antagonist properties produced only partial generalisation which was not dose related. Receptor binding studies showed that all the compounds which substituted for 8-OH-DPAT displaced [3H]-8-OH-DPAT binding to rat hippocampal membranes. Furthermore, there were statistically significant positive correlations between drug affinity for 5HT1A sites and their ED50 values for both substitution for 8-OH-DPAT and potency to decrease response rates. These results are consistent with the view that the 8-OH-DPAT cue, like the ability of the compounds tested to decrease rates of responding, is largely mediated by activity at 5HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Facilitated acquisition of a temporal discrimination following destruction of the ascending 5-hydroxytryptaminergic pathways.

This experiment examined the effect of destroying the 5-hydroxytryptaminergic (5HTergic) pathways on the acquisition and performance of discrimination between two brief time intervals. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats were trained in a series of discrete trials to press lever A following a 200-ms presentation of a light stimulus and lever B following an 800-ms presentation of the same stimulus. Both groups gradually acquired accurate performance, attaining 80%-85% accuracy by the end of 40 sessions. The lesioned group learnt the task significantly faster than the control group. When stable performance had been attained, "probe" trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) did not differ significantly between the two groups; however, the Weber fraction was significantly smaller in the lesioned group than in the control group. The levels of 5HT and 5-hydroxy-indole-acetic acid were markedly reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. The results indicate that destruction of the 5HTergic pathways facilitates acquisition of a temporal discrimination. The lack of an effect of the lesion on the bisection point contrasts with our previous finding using longer stimulus durations; it is suggested that different behavioural processes may underlie millisecond-range and second-range temporal discrimination, and that these may be differently affected by 5HT depletion.

5,7-Dihydroxytryptamine↗