Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol-Reinforced Responding in Rhesus Monkeys

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66264/1/j.1530-0277.1999.tb04173.x.pd

Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.National Institutes of Health (U.S.) (Javits Merit Grant R01 NS025529)United States. Office of Naval Research (N000140710903)National Parkinson Foundation (U.S.) (Lynn Diamond Fellowship

Reinforcing effects of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys

Benzodiazepines are prescribed widely but their utility is limited by unwanted side effects, including abuse potential. The mechanisms underlying the abuse-related effects of benzodiazepines are not well understood, although α1 subunit-containing GABAA receptors have been proposed to have a critical role. Here, we examine the reinforcing effects of several compounds that vary with respect to intrinsic efficacy at α2, α3, and α5 subunit-containing GABAA receptors but lack efficacy at α1 subunit-containing GABAA receptors ('α1-sparing compounds'): MRK-623 (functional selectivity for α2/α3 subunit-containing receptors), TPA023B (functional selectivity for α2/α3/α5 subunit-containing receptors), and TP003 (functional selectivity for α3 subunit-containing receptors). The reinforcing effects of the α1-sparing compounds were compared with those of the non-selective benzodiazepine receptor partial agonist MRK-696, and non-selective benzodiazepine receptor full agonists, midazolam and lorazepam, in rhesus monkeys trained to self-administer midazolam or cocaine, under a progressive-ratio schedule of intravenous (i.v.) drug injection. The α1-sparing compounds were self-administered significantly above vehicle levels in monkeys maintained under a midazolam baseline, but not under a cocaine baseline over the dose ranges tested. Importantly, TP003 had significant reinforcing effects, albeit at lower levels of self-administration than non-selective benzodiazepine receptor agonists. Together, these results suggest that α1 subunit-containing GABAA receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas α3 subunit-containing GABAA receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration

Spectroscopic and electrochemical studies of cocaine–opioid interactions

Abstract The drugs of abuse cocaine (C), heroin (H), and morphine (M) have been studied to enable understanding of the occurrence of cocaine–opioid interactions at a molecular level. Electrochemical, Raman, and NMR studies of the free drugs and their mixtures were used to study drug–drug interactions. The results were analyzed using data obtained from quantum-mechanical calculations. For the cocaine–morphine mixture (C–MH), formation of a binary complex was detected; this involved the 3-phenolic group and the heterocyclic oxygen of morphine and the carbonyl oxygen and the methyl protons of cocaine’s methyl ester group. NMR studies conducted simultaneously also revealed C–MH binding geometry consistent with theoretical predictions and with electrochemical and vibrational spectroscopy results. These results provide evidence for the occurrence of a cocaine–morphine interaction, both in the solid state and in solution, particularly for the hydrochloride form. A slight interaction, in solution, was also detected by NMR for the cocaine–heroin mixture. Figure "Schematic representation of the proposed model for cocaine:morphine salt interaction