MCLEAN HOSPITAL CORPORATION, THE
Grant: $222,790 - National Institutes of Health - Jun. 19, 2009
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Award Description: Nicotine Modulation of Methamphetamine's Behavioral and Neurochemical Effects
Project Description: The overall purpose of this project is to examine the utility of developing novel nicotinic agonists-based medication strategies, and to reveal other innovative treatment approaches for psychostimulant addiction. To this end, the present research is designed to examine how alterations in acetylcholine nicotinic activity may modulate abuse-related behavioral and neurochemical effects of monoaminergic stimulants in nonhuman primates. The goals of this project for Q1 are to: a) acquire and train subjects to discriminate injections of a methamphetamine (MA) from saline using the drug discrimination assay; and b) to establish observational experiments to evaluate how nicotine modifies the effects of dopaminergic compounds on overt behaviors such as visual scanning/checking, eye blinking, and scratching. Both groups of subjects will later be used in studies to determine how the effects of dopaminergic and nicotine-related drugs are altered by chronic treatment with nicotine. Drug Discrimination studies: Four squirrel monkeys have successfully been trained to discriminate 0.1 mg/kg MA from saline. Dose-response curves for MA, cocaine, citalopram, nicotine, and varenicline have been established. Results thus far indicate that MA and cocaine fully substitute for the 0.1 mg/kg MA in a dose-dependent manner. In contrast, the selective serotonin reuptake inhibitor, citalopram, failed to engender MA-like discriminative stimulus effects. The full nicotinic cholinergic agonist, nicotine, also fully substituted for MA in a dose-related manner, whereas the partial nicotinic cholinergic agonist, varenicline, only partially substituted for MA. Observational studies: Four squirrel monkeys have successfully been set up to conduct all observation studies. Thus far, the effects of vehicle, MA, and cocaine on visual scanning/checking have been established. Results thus far indicate that, as anticipated, MA and cocaine produce dose-related increases in visual scanning/checking.
Jobs Summary: This project is designed to provide a greater understanding of the underlying neurobiological and behavioral mechanisms in the addictive effects of methamphetamine (MA) and cocaine. The use and abuse of MA and cocaine is a major public health concern world-wide; despite significant effort to identify indirectly and directly acting dopamine (DA)-based candidate medications as potential agonist-based treatments, no effective pharmacotherapies are yet available for the management of addiction to MA and cocaine. As non-dopaminergic mechanisms, including nicotinic systems, also may contribute importantly to the addictive effects of these psychomotor stimulant drugs, the study of non-dopaminergic ligands, including nicotinic drugs, may lead to novel ‘agonist-based’ candidate medications. Based on reports in the scientific literature and our own preliminary results, nicotinic agonists can interfere with the expression of behavioral and neurochemical effects of MA, and therefore, may be suitable ‘agonist-based’ candidate medications for stimulant abuse and addiction. To evaluate this medication strategy, we propose to determine whether the prototypic agonist nicotine (NIC) attenuates the abuse-related behavioral and neurochemical effects of MA in a primate species. Using established methods to study the discriminative-stimulus and observable effects of dopaminergic drugs, we plan to directly analyze how acute or chronic (15-day) treatment with nicotine may alter behavioral effects of MA. Drug discrimination studies will be conducted in monkeys prepared with dialysis cannulae targeting either the striatum or prefrontal cortex. During drug testing, dialysate samples will be removed and analyzed for DA level. These coordinated studies will allow a comprehensive assessment within the same test session of how the behavioral and neurochemical effects of MA may be modified by nicotinic agonist treatment. The results of these studies will provide important information regarding the potential therapeutic value of nicotinic-based medication strategies for the management of abuse and addiction to MA and related stimulants. The proposed research also should lead to further studies to identify novel nicotinic targets to help combat MA addiction. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
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