Discriminative Stimulus Properties Of Amphetamine Research Articles

Dopamine and serotonin antagonists fail to alter the discriminative stimulus properties of ±methylenedioxymethamphetamine

Most studies on discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) have been conducted using a relatively low dose (1.5 mg/kg), and those studies have invariably implicated serotonergic mechanisms. In contrast, dopaminergic mechanisms mediate the discriminative stimulus effects of amphetamine (AMPH). Some studies have suggested that the discriminative stimulus effects of a higher (3.0 mg/kg) dose of MDMA might rely on both serotonergic and dopaminergic mechanisms. This study aimed to determine effects of selective dopamine (DA) and serotonin (5HT) antagonists on the discriminative stimulus properties of AMPH (0.5 mg/kg) and MDMA (3.0 mg/kg). Separate groups of rats were trained to discriminate AMPH (0.5 mg/kg) or MDMA (3.0 mg/kg) from saline using a food-reinforced drug-discrimination procedure. Effects of DA (SCH 23390: 0.003-0.03 mg/kg and eticlopride: 0.03-0.3 mg/kg) or 5HT (ritanserin: 1.0-10.0 mg/kg, WAY-100635: 0.3-1.0 mg/kg and GR129375: 1.0-3.0 mg/kg) antagonists on the discriminative stimulus effects of both drugs were determined. Both DA antagonists dose-dependently decreased the AMPH but not the MDMA discrimination. None of the 5HT antagonists altered the discriminative stimulus effects of either drug. The MDMA (3.0 mg/kg) stimulus comprises both a DAergic and 5HTergic response, and the results suggest that either one is sufficient, but not required, to maintain the stimulus effects.

Interaction of lobeline and nicotinic receptor ligands with the discriminative stimulus properties of cocaine and amphetamine

Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular and plasmalemmal monoamine transporters. Moreover, lobeline has been shown to alter the neurochemical and behavioral effects of psychostimulants. The present study determined the effect of lobeline and drugs selective for nicotinic receptors on the discriminative stimulus properties of low doses of cocaine (1.6 or 5.0 mg/kg) or d-amphetamine (0.3 mg/kg) in rats, using a standard two-lever drug discrimination procedure with food reinforcement. Nicotine substituted for both amphetamine and cocaine. The nicotinic receptor antagonists mecamylamine and hexamethonium did not substitute for or block the cocaine or amphetamine stimulus. In contrast, lobeline substituted for cocaine, but did not substitute for amphetamine. In antagonism tests, lobeline doses that did not substitute for cocaine decreased responding on the cocaine-paired levers. Surprisingly, lobeline did not alter the discriminative stimulus properties of amphetamine. This research further supports the supposition that nicotine, cocaine and amphetamine produce similar, but distinct subjective states. Furthermore, the present findings suggest that lobeline has a complex mechanism of action to disrupt the behavioral effects of drugs of abuse.

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.

Discriminative stimulus properties of amphetamine in a conditioned taste aversion paradigm

It has been proposed that the conditioned taste aversion paradigm may be used to achieve rapid training of subjects in drug discrimination studies. We report here that amphetamine (1.0 mg/kg) may acquire discriminative control over the preference of rats for a distinctive flavour when its administration precedes access to a saccharin solution (0.15% w/v), versus the occasions when the injection of saline precedes no toxicosis after access to the same flavour. Other doses of amphetamine (0.18-1.0 mg/kg) or apomorphine (0.1-1.0 mg/kg) produced a dose-dependent generalization to the stimulus cue of amphetamine (1.0 mg/kg), and haloperidol (0.01-0.1 mg/kg) was able to prevent the stimulus control exerted by amphetamine. No stimulus control was seen in a control group where no distinctive outcomes followed the administration of either amphetamine or saline before the subjects had access to the saccharin-flavoured solution. In the experimental group only, changes in the preference for saccharin were observed, with no changes in the total amount of water and saccharin ingested. Taken together, the present results suggest the usefulness of the conditioned taste aversion procedure to train subjects in drug discrimination.

Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT 2 A antagonist

MDL 100,907 is a potent and selective antagonist of the 5-HT 2 A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT 2 C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT 2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT 2 receptor antagonists as a novel therapeutic strategy for schizophrenia.

Influence of some drugs of abuse on the discriminative stimulus properties of amphetamine

The present study assessed the utility of a drug interaction paradigm for measuring the effects of various psychoactive drugs on the stimulus properties of d-amphetamine. In the first experiment, rats trained to discriminate 1.0mg/kg d-amphetamine from saline were tested for generalization to a range of d-amphetamine doses (0.25, 0.50 and 1.0mg/kg) injected alone or with cocaine, apomorphine or haloperidol. When given alone d-amphetamine yielded an orderly dose-response function and this was altered by the test drugs in a manner consistent with the dopamine agonist or antagonist actions of each compound. In the second experiment, the cueing effects of d-amphetamine were potentiated by nicotine and attenuated by morphine and midazolam. Ethanol enhanced the cueing effects of the lower d-amphetamine doses but produced no drug-lever responding when given alone. These findings confirm the results of previous studies which have assessed the effects of these classes of drugs on the stimulus properties of amphetamine. However, the results are inconsistent with the hypothesis that all drugs of abuse possess psychomotor stimulant properties.

Discriminative stimulus properties of amphetamine, cathinone, and related agents.

Although the AMPH and CATH cues have been studied extensively, inconsistent findings remain that need to be investigated. It is not known to what extent, if at all, AMPH and CATH cues differ and how they differ from the cocaine cue. The extent to which D1 and D2 receptor systems are coupled in AMPH DD assays requires further investigation. The inconsistent findings in substitution studies with nisoxetine need to be addressed in parametric studies in various species. Finally, the possibility that the AMPH cue may generate false positives in screening for drug abuse potential needs to be evaluated.

Discriminative stimulus properties of amphetamine and other stimulants in lead-exposed and normal rats

The present study examined the discriminative stimulus properties of amphetamine (AMP) at progressively lower doses in lead-exposed and normal rats. In addition, generalization gradients of AMP, apomorphine, methylphenidate, and caffeine to both high and low training doses of AMP were determined in these rats. Under the high AMP training dose condition (1.0 mg/kg, IP) generalization gradients of AMP were similar for lead-exposed and control rats. When the training doses were progressively lowered, the lead-exposed rats tended to require a higher range of AMP doses (0.24–0.49 mg/kg) than did control rats (0.18–0.32 mg/kg) to maintain discriminative control. In parallel with this, the minimal discriminable doses tended to be higher for lead-exposed rats than for control rats. Methylphenidate generalization gradients were different for lead-exposed and control rats under the high AMP training condition but became similar under the low AMP training condition. No differences attributable to training dose or lead exposure were evident for apomorphine or caffeine.

Drug discrimination in rats: Evidence for amphetamine-like cue state following chronic haloperidol

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1,2,4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.

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.