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The subtype-selective serotonin 5-HT3 antagonists MDL 72222 and ICS 205-930 were tested for their ability to modify nicotine self-administration and locomotor activity in rats. In self-administration experiments, MDL 72222 produced no statistically significant changes over a dose range of 1 to 30 micrograms/kg, nor at the considerably higher dose of 1 mg/kg. MDL 72222 was similarly without effect in nicotine-produced locomotor activity, except at the 1 mg/kg dose, which reduced scores. In an initial test on nicotine self-administration, ICS 205-930 produced a small decrease in drug-taking behavior at 1 and 3 micrograms/kg which just reached statistical significance, but had no effects at higher doses. However, these low-dose effects could not be replicated. In addition, ICS 205-930 was without effect on nicotine locomotor activity, even at the two low doses that had reduced self-administration. We conclude that these 5-HT3 antagonists do not modulate nicotine reinforcement or behavioral arousal.

The ability of D1 and D2 dopamine antagonists to reduce the subjective effects of nicotine was examined in rats trained to discriminate nicotine (0.3 mg/kg, base) from saline. Each of SCH 23390 (a D1 antagonist) and spiperone (a D2 antagonist) reduced responding on the drug-appropriate lever, and produced a reduction in overall response rates. The nicotine cue was also tested for generalization to the dopamine reuptake blocker GBR 12909. Doses of GBR 12909 that produced complete responding on the drug-appropriate lever in cocaine-trained animals led to only minimal selection of the nicotine-appropriate lever in nicotine-trained animals; as with the dopamine antagonists, response rates after GBR 12909 were markedly reduced in nicotine-trained, but not in cocaine-trained, rats. These data suggest that dopaminergic mechanisms play, at best, a small role in the discriminative stimulus properties of nicotine.

Animals were trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR 10), food-reinforced paradigm. Amphetamine-appropriate responding was engendered by the training dose, and by 3 mg/kg, while at lower doses there was a progressive decrease in the extent of responding on the drug-appropriate lever. The following three novel amphetamine derivatives were tested for their ability to produce amphetamine-appropriate responding: 2,5-dimethoxy-4-ethoxy-amphetamine (DMEA); 2,5-dimethoxy-4-methylthio-amphetamine (DMMTA), and 2,4,5-trimethoxy-amphetamine (TMA). DMEA produced only minimal (< 20%) amphetamine-appropriate responding over a dose range of 0.1-10 mg/kg. Substantial decreases in response rate limited testing of the other amphetamines to a dose maximum of 3 mg/kg, but over the range of 0.1-3.0 mg/kg there was little evidence for generalization. At 3 mg/kg of either DMMTA or TMA, only 2 of 10 animals completed at least one uninterrupted FR 10 on either lever, and with either compound only 1 of these 2 animals responded more than 50% on the drug-appropriate lever. Of the three compounds tested, DMMTA had the greatest response rate-decreasing effect.

The purpose of this study was two-fold: 1) to assess the degree to which para-methoxyamphetamine and para-ethoxyamphetamine maintain self-administration behavior, and 2) to determine the similarity or difference between these drugs and amphetamine in drug discrimination tests. Animals were trained to self-administer 0.3 mg/kg/infusion cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Substitution of para-ethoxyamphetamine (PEA), para-methoxyamphetamine (PMA), or saline produced similar results; in all cases responding decreased substantially. A separate group of animals was trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR10), food-reinforced paradigm. PEA and PMA produced only limited responding on the amphetamine-appropriate lever (maximum of approximately 30%). Both PMA and PEA had effects on response rate which were similar to those of amphetamine, although PMA had slightly greater rate-decreasing effects than the other two compounds. These data suggest that neither PMA nor PEA are reinforcing in rats, and do not possess amphetamine-like discriminative properties.

Rats were trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement with a 1-min time-out period following each infusion. Cocaine was available at doses of either 0.1, 0.3 or 1.0 mg/kg/infusion. A low dose (3 microgram/kg) of the D1 antagonist SCH23390 caused an increase in cocaine self-administration which was more prominent at higher, as compared to lower, doses of cocaine. Higher doses of SCH23390 generally caused decreases in self-administration which may in part be due to the response-decreasing properties of this agent. The D2 antagonist spiperone generally caused an increase in self-administration of cocaine. These data suggest that cocaine reinforcement depends upon both D1 and D2 receptor subtypes.

Animals were trained to discriminate heroin from saline in a two-lever food-reinforced paradigm. Tests with the heroin metabolites O6-monoacetylmorphine and morphine suggest that the heroin discriminative stimulus was mediated by monoacetylmorphine. The heroin discriminative stimulus was not blocked by pretreatment with low doses of the D1 dopamine antagonist SCH23390 or the D2 antagonist spiperone; higher doses of the antagonists produced decreases both in selection of the drug-appropriate lever after heroin, and in food-maintained responding. The data suggest that dopamine may mediate the heroin discriminative stimulus. When administered in the absence of opioids, the D2 antagonist spiperone did not have rate-decreasing effects, whereas SCH23390 did. Heroin partially reversed the rate-decreasing effects of SCH23390, possibly as a result of the ability of opioids to release dopamine.

Rats that had been trained to respond for food on a fixed-interval 3-minute schedule were treated once daily with nicotine (2 mg/kg) for 50 days. Animals developed marked tolerance to the depressant effect of nicotine as measured by the decreased effect of the treatment dose on response rates over days. Substitution of saline for nicotine during chronic treatment resulted in response rates which were significantly less than pretreatment values. In addition, following cessation of chronic treatment, response rates were initially suppressed below pretreatment rates; by the third day of withdrawal, response rates had returned to baseline levels. It is proposed that the response deficit observed during nicotine absence represents one behavioral component of a nicotine withdrawal syndrome.

Lever-pressing behavior reinforced by intravenous infusion of various concentrations of heroin, and consequent development of physical dependence, were examined in rats. In addition, the influence of opiate dependence, and of its disappearance following withdrawal, on heroin self-administration were investigated. It was found that intravenous self-administration of heroin at 0.03 mg/kg/infusion maintained self-administration behavior without producing physical dependence. Total responses per session decreased with increasing unit dose of heroin, whereas the total amount of drug self-administered was directly related to unit dose. Significantly greater numbers of withdrawal signs and percentage body weight losses in response to naloxone injections were observed following self-administration of heroin at 0.1, 0.3 or 0.6 mg/kg/infusion. Intake of heroin at 0.03 mg/kg/infusion, but not at 0.1, 0.3 or 0.6 mg/kg/infusion, was found to increase significantly in opiate-dependent and postdependent animals. These findings support the previous use of 0.03 mg/kg/infusion as a suitable dose for illustrating the reinforcing effect of heroin without the influence of physical dependence.