heroin and vanoxerine

In previous studies, heroin was shown to engender cocaine-like discriminative stimulus (DS) effects; however, the mechanisms underlying the cocaine-like effects of heroin are unknown. The present study evaluated the extent to which the shared DS effects of heroin and cocaine involve common monoaminergic mechanisms of action. In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, heroin engendered full or partial substitution for cocaine in three of four monkeys. Pretreatment with the selective dopamine transport inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909) dose dependently enhanced the cocaine-like DS effects of heroin in these three monkeys as well as the DS effects of cocaine in all subjects. Neither talsupram, a noradrenergic transport inhibitor, nor prazosin, a noradrenergic antagonist selective for alpha-1 receptors, systematically altered the cocaine-like DS effects of heroin at doses that enhanced (talsupram) or attenuated (prazosin) the DS effects of cocaine. Pretreatment with the serotonin uptake inhibitor citalopram similarly failed to alter the cocaine-like DS effects of heroin at doses that attenuated the DS effects of cocaine. Altogether, these findings suggest that heroin shares DS effects with cocaine in a subset of monkeys, and these cocaine-like effects are mediated at least in part by enhanced dopaminergic activity. Unlike the DS effects of cocaine itself, however, the cocaine-like DS effects of heroin do not appear to involve either noradrenergic or serotonergic mechanisms.

Topics: Animals; Carrier Proteins; Citalopram; Cocaine; Discrimination, Psychological; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Interactions; Heroin; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neuropeptides; Norepinephrine Plasma Membrane Transport Proteins; Piperazines; Prazosin; Receptors, Adrenergic, alpha-1; Saimiri; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Symporters; Thiophenes; Vesicular Biogenic Amine Transport Proteins

Heroin previously was shown to engender partial cocaine-like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909.. In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine-lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects.. These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin.

Topics: Animals; Cocaine; Discrimination, Psychological; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Heroin; Male; Narcotics; Piperazines; Saimiri

The neurobiological mechanisms underlying the persistence of drug craving in detoxified addicts are still poorly understood.. The present study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour following long-term (>3 weeks) extinction of IV drug self-administration in rats.. To that end, we studied the effects of direct and indirect dopamine (DA) agonists on reinstatement of previously extinguished responding for heroin (50 microg/kg per injection; 14-15 daily 3-h sessions) and cocaine (500 microg/kg per injection; 10-11 daily 2-h sessions).. In animals with a cocaine history, priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2 receptor agonist quinpirole resulted in robust and selective reinstatement of non-reinforced nose poking behaviour in the previously drug-paired hole. In contrast, the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA agonist apomorphine even suppressed responding in these animals. In heroin-trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists were ineffective. Again, the two highest doses of apomorphine decreased responding in these animals. In a parallel study, the ability of DA ligands to express behavioural sensitization in animals pretreated with amphetamine or morphine was evaluated. Interestingly, all agonists that reinstated responding in the present study caused expression of locomotor sensitization and vice versa.. The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats.

Topics: Animals; Behavior, Addictive; Benzazepines; Cocaine; Dopamine Agonists; Dopamine Uptake Inhibitors; Heroin; Male; Narcotics; Piperazines; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine; Substance Withdrawal Syndrome