Prior exposure either to repeated stress or to stimulants elicits an enhanced behavioral response to an acute amphetamine challenge, suggesting that both stimuli may induce similar neurochemical and/or neuroendocrine changes that lead to this sensitized response. One common action of both amphetamine and stress is to stimulate release of corticotrophin releasing factor (CRF). This neuropeptide is uniquely poise to coordinate the common effects of both stimuli, since CRF acts as both a neurotransmitter within the brain and a regulator of endocrine responses in the periphery. CRF is almost certainly involved in mediating the increase in hypothalamic-adrenalpituitary (HPA) activity that is a common response to both amphetamine and stress. In addition, CRF may also be important in mediating another common effect of amphetamine and stress: an increase in central dopamine (DA) transmission. However, the Dopaminergic actions of central CRF are relatively unexplored and no data exist on the interaction between CRF, DA and the HPA axis in modulating stimulant-induce behavioral phenomena such as sensitization. The proposed studies will directly examine the role of CRF as a mediator of the neurochemical, endocrine and behavioral effects of amphetamine administration in awake, behaving animals, using in vivo microdialysis in conjunction with repeated blood sampling and behavioral testing. It is hypothesized that CRF may directly influence the activity of catecholaminergic neurons, leading to increases in DA-mediated behaviors such as locomotor activity. At the same time, CRF is like to stimulate secretion of adrenal steroids, which, in turn, have been shown to facilitat DA transmission and drug-seeking behaviors. Concurrent examination of the temporal and quantitative characteristics of the DA and HPA responses to amphetamine and CRF should provide valuable information on how these systems are regulated and how this regulation may subsequently be altered by chronic exposure to amphetamine. An increase understanding of the neurochemical and neuroendocrine consequences of stimulant administration will provide valuable insight into how coordinate changes in these pathways may influence drug-related behaviors and may point to novel pharmacological targets for drug abuse therapy.
