Search PubMed⌕ Search

Biomedical subjects

K M Coen

Publications and source records attributed to K M Coen.

13 recordsLinked to original sources
PubMed1992

The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.

Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.

Animals↗
PubMed1992

The reinforcing and discriminative stimulus properties of para-ethoxy- and para-methoxyamphetamine.

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.

Amphetamines↗
PubMed1992

Discriminative stimulus properties of substituted amphetamine derivatives.

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.

Amphetamines↗
PubMed1991

Opiate antagonists reduce cocaine but not nicotine self-administration.

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.

Animals↗
PubMed1991

Selective dopamine antagonists reduce nicotine self-administration.

The effects of selective D1 (SCH23390) and D2 (spiperone) dopamine antagonists, as well as of haloperidol, were examined on nicotine self-administration, food-maintained responding, and locomotor activity in rats. Antagonists reduced both operant responding and locomotor activity. Response patterns indicated that motor impairment was not the cause of the decreases, since responding was attenuated only in the latter half of operant sessions. Locomotor activity scores were significantly reduced by SCH23390, but not by spiperone. The effects of dopamine antagonists on nicotine self-administration are different from the effects of these antagonists on cocaine self-administration. Results are discussed in terms of the role of dopamine in drug reinforcement versus its role in sensorimotor integration.

Animals↗
PubMed1991

Cocaine self-administration is increased by both D1 and D2 dopamine antagonists.

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↗
PubMed1990

Selective D1 and D2 dopamine antagonists decrease response rates of food-maintained behavior and reduce the discriminative stimulus produced by heroin.

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.

Animals↗
PubMed1989

Nicotine maintains robust self-administration in rats on a limited-access schedule.

Intravenous nicotine maintained substantial responding on the drug-reinforced lever with a limited-access, fixed-ratio 5 schedule of self-administration. Responding demonstrated the expected pharmacological sensitivity; it was dose-dependently reduced by pre-session treatment with either nicotine or mecamylamine but not with hexamethonium. In addition, responding was dependent on the size of the unit dose, with maximum values occurring at 0.01 and 0.03 mg/kg/infusion. Self-administration behavior decreased at doses both above and below these, and extinction followed the substitution of saline for nicotine. Total session drug intake increased with unit dose up to a maximal value of approximately 0.5 mg/kg at 0.03 mg/kg/infusion, but did not increase further at the 0.06 mg/kg/infusion dose. A decrease in the time-out duration at the dose of 0.03 mg/kg/infusion also did not change the total session intake of nicotine. It is suggested that nicotine intake is controlled both by the total amount of drug obtained and by the magnitude of the unit dose. These results demonstrate that intravenous nicotine can maintain substantial self-administration behavior in rodents.

Animals↗
PubMed1989

Fixed-interval schedules for drug self-administration in the rat.

The practicality of using second-order fixed-interval schedules in studies of heroin reinforcement with rats was examined. Optimum rates of responding were obtained with a dose of 0.03 mg/kg/infusion and an interval duration of 3 min. In addition, schedules consisting of a only a single interval were shown to be practical, leading to response rates comparable to those obtained with cocaine or food as reinforcer.

Animals↗
PubMed1989

Heroin self-administration by rats: influence of dose and physical dependence.

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.

Animals↗
PubMed1989

Evidence for a behavioral deficit during withdrawal from chronic nicotine treatment.

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.

Animals↗
PubMed1988

Evidence for opioid mechanisms in the behavioral effects of nicotine.

The effects of nicotine, heroin, mecamylamine, and naltrexone were studied in rats trained to respond under a fixed-interval 3-min schedule of food presentation. Nicotine (0.1-3.0 mg/kg) first increased, then decreased response rates; heroin (0.03-0.6 mg/kg) produced only dose-related response rate decreases. Mecamylamine (0.1-3.0 mg/kg) and naltrexone (0.3-10.0 mg/kg), administered alone, each had little effect on response rates. However, when administered in combination with increasing doses of nicotine, mecamylamine (1.0 mg/kg) blocked the increases in response rate caused by 0.3 and 1.0 mg/kg nicotine and partially reversed the decreases in rate caused by 3.0 mg/kg nicotine. In contrast, the combination of naltrexone and nicotine, at doses of each that alone either had no effect or increased response rates, markedly decreased responding. This phenomenon was not evident during the first pairing of naltrexone and nicotine, but appeared in the second and subsequent pairings. After drug combinations had been tested, the nicotine dose-response curve was unchanged from its previous values, and naltrexone alone produced no tendency to decrease response rate. These observations may be related to previous results that have suggested a role for endogenous opioids in mediating certain of the behavioral effects of nicotine.

Animals↗