The addictive and psychogenic effects of stimulants in humans are most commonly associated with a pattern of repeated """"""""binge"""""""" exposures preceded by progressively escalating loses (ED) of the drug. To simulate these conditions, we exposed rats to multiple stimulant binges, preceded by relatively long-term, intermittent or ED. Rats treated with amphetamine (AMPH), methamphetamine, or cocaine, gradually developed a unique behavioral profile which consisted of a decrease in the continuous stereotypy component, a pronounced increase in the magnitude of locomotion, and a qualitative change in the ambulation. Furthermore, with multiple high dose AMPH binges, the caudate-putamen extracellular dopamine (DA) response, but not the nucleus accumbens DA response, developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. Similar results were obtained with serotonin, whereas the hippocampus and frontal cortex norepinephrine responses were increased. Our proposed research is designed to further examine the neurochemical and behavioral processes associated with ED/Binges. We will use microdialysis to further characterize the relationship between the regional DA response shift and the expression of the emergent behavioral profile (EBP). Lower AMPH doses as well as other stimulants will be used to determine the generality of this relationship and the persistence of the behavioral and neurochemical changes. Possible molecular mechanisms underlying the regional DA response shift, and the role of other DA systems in the behavioral response will also be examined. Behavioral (startle and noise paradigms) and neuroendocrine measures (CRF, corticosterone, ACTH, prolactin) will be used to test our hypothesis that the EBP reflects a highly aroused or stressed state. Additional studies are aimed at further assessing the roles of noradrenergic, serotonergic, and glutamatergic systems in the EBP. Elucidation of the neurobiological processes underlying the behavioral changes associated with the ED/Binge treatment may have implications for understanding stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of high dose stimulant abuse.
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