Discriminative Stimulus Properties Of D-amphetamine Research Articles

FACILITATORY AND INHIBITORY ACTIONS OF MORPHINE ON THE DISCRIMINATIVE STIMULUS PROPERTIES OFD-AMPHETAMINE

Facilitatory and inhibitory actions of morphine on the discriminative stimulus properties ofD-amphetamine were examined in rats trained to discriminateD-amphetamine (1 mg kg−1) from saline in a two–lever food reinforced operant task. Morphine (0.625–2.5 mg kg−1) did not itself generalize to amphetamine. When the percentages of rats selecting the drug–appropriate lever were plotted as a function of the individual lowest generalized dose (LGD), a log–linear model fitted to cell frequency indicated a ‘morphine×amphetamine×lever selection’ interaction. Subsequent comparisons indicated that morphine significantly increased or decreased drug lever selection in rats receiving one–half LGD or LGD, respectively. In both cases no difference was found among morphine doses. The present study confirms that the discriminative stimulus properties of amphetamine can be both potentiated and attenuated by morphine. The direction to which morphine modulates the interoceptive effects of 1 mg kg−1amphetamine seems to be dependent on the individual sensitivity of animals to amphetamine rather than on the overall effect of the test dose of amphetamine alone.

Sertindole and several antipsychotic drugs differentially inhibit the discriminative stimulus effects of amphetamine, LSD and St 587 in rats.

The effects of sertindole, clozapine, Cis(Z)-flupentixol and haloperidol on the discriminative stimulus properties of d-amphetamine (dopamine DA stimulant), d-LSD (5-HT(2) agonist) and St 587 (alpha(1)-adrenoceptor agonist; 2-chloro-5-trifluoromethyl-phenylimino)-imidazolidine) have been studied. Sertindole, a putative antipsychotic compound with limbic selectivity, antagonized the effects of d-LSD and St 587, whereas that of d-amphetamine was unchanged. Clozapine preferentially inhibited St 587, but also antagonized d-LSD and d-amphetamine, together with increases in reaction time. Cis(Z)-flupentixol antagonized d-amphetamine and St 587 effects, whereas haloperidol antagonized d-amphetamine only. Behavioural disruption was induced by haloperidol in St 587 and d-LSD-trained animals. The 5-HT(2) antagonist ketanserin selectively inhibited the effect of d-LSD, and the selective alpha(1)-adrenoceptor antagonist prazosin partially inhibited the effect of St 587, but did not inhibit d-LSD or d-amphetamine. The partial inhibition of St 587 effects by prazosin was not further increased by co-treatment with haloperidol. Prazosin partially substituted for the training dose of St 587. The results indicate that drug discrimination techniques can be used to demonstrate different activity profiles of typical and atypical neuroleptics. The classical neuroleptics have preferential amphetamine antagonistic activity, whereas clozapine has a broad activity profile. Furthermore, the atypical neuroleptic sertindole fails to induce acute DA antagonism in doses much higher than those inhibiting d-LSD and St 587.

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

The discriminative stimulus (DS) properties of d-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.

An experimental paradigm for studying the discriminative stimulus properties of drugs in humans

An experimental paradigm for studying the discriminative stimulus effects of drugs in human subjects is presented. The paradigm was tested by training subjects to discriminate 10 mg d-amphetamine from placebo. Subjects who successfully learned the discrimination were then tested with two lower doses of d-amphetamine and with 10 mg diazepam. The discriminative stimulus properties of d-amphetamine were dose-dependent, and in two of five subjects the d-amphetamine stimulus generalized to diazepam. The simplicity and versatility of the paradigm give it the potential for use in a wide variety of experimental and clinical situations.

The effects of electroconvulsive shock on the discriminative stimulus properties of d-amphetamine and apomorphine: evidence for dopamine receptor alteration subsequent ECS.

Sprague-Dawley male rats responding for sweetened milk on a variable interval 20 s schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with 1.0 mg/kg of d-amphetamine or saline prior to daily training sessions. Following acquisition of the discrimination a dose-response generalization function was determined by testing animals on 0.10, 0.15, 0.25, 0.35, 0.50 and 0.75 mg/kg of amphetamine. Subjects then received either three electroconvulsive shock (ECS) treatments of sham-ECS forty-eight hours after the final treatment all subjects were injected with 0.25 mg/kg of amphetamine and retested. ECS was found to enhance the ability of the animals to discriminate amphetamine. In a second experiment it was found that ECS also facilitated the ability of animals to discriminate the cue properties of apomorphine, a direct dopamine receptor agonist. These results suggest that dopamine receptor sensitivity is altered by electroconvulsive shock.

Discriminative properties of d-amphetamine in gerbils: Tests for drug generalization and antagonism

1. 1. Discriminative stimulus properties of d-amphetamine was studied in the Mongolian gerbil ( Meriones unguiculatus). 2. 2. Both haloperidol and propranolol blocked the stimulus effects of d-amphetamine. 3. 3. A central locus for the amphetamine-discrimination is indicated because para-hydroxyamphetamine did not substitute for the training dose of amphetamine when tested at equimolar doses. 4. 4. Fenfluramine and Δ 9-THC did not substitute for d-amphetamine in thus trained gerbils, suggesting pharmacological drug specificity. 5. 5. Results with apomorphine produced intermediate results and the significance of dopaminergic transmission for the discriminable effects of amphetamine is discussed.

Discriminative stimulus properties of d-amphetamine and related compounds in rats

The discriminative stimulus properties of amphetamine were demonstrated in rats trained to discriminate between 0.8 mg/kg of d-amphetamine sulfate and saline. During the discriminative training, animals were shaped on a DRL 15-second schedule to respond to one of two levers for a food reward when they were given d-amphetamine, and to respond to the other lever when they were treated with saline. Tests for the discriminative stimulus properties consisted of 10-min extinction sessions in which the reinforcement delivery was disconnected. Animals receiving low doses (0.2–0.4 mg/kg) of d-amphetamine exhibited mostly saline-like responses, but at a dose of 0.8 mg/kg they produced more than 80% responses on the amphetamine lever. Doses higher than 2.4 mg/kg caused an initial stereotyped behavior and the animals showed a period of latency before responding on the amphetamine lever. In order to elucidate the structural characteristics of d-amphetamine involved in the production of the discriminative stimulus properties, a number of amphetamine derivatives and related compounds were administered to these animals. 1-Amphetamine, ephedrine, norephedrine, 4-methoxyamphetamine and methylphenidate all produced the discriminative stimulus properties similar to d-amphetamine, but doses of 2–10 times greater than d-amphetamine were necessary. Mescaline, STP and DOET did not produce the d-amphetamine-like responses. These results suggest that most psychomotor stimulants, although having different structures, are likely to produce discriminative stimulus properties similar to d-amphetamine.