Neurotensin (NT) is a peptide neuromodulator that regulates and is regulated by dopamine (DA). Behavioral effects of psychostimulant drugs, such as cocaine and amphetamine, and injections of NT into the mesencephalic ventral tegmental area (VTA) are similar, and both undergo sensitization - i.e., repetitions produce long-lasting augmentations of neurochemical and behavioral responses to subsequent challenges. Psychostimulant sensitization is blocked by VTA injections of several receptor antagonists, including the NT antagonist, SR-48692, which may attenuate the development of psychostimulant sensitization by blocking an observed stimulatory action of NT on VTA DA neurons. A neuroanatomical study recently carried out in this laboratory revealed that the neurons of origin of a dense NT immunoreactive fiber plexus in the VTA are located largely in the lateral preoptic region and rostral lateral hypothalamus (LPH region). These LPH neurons are not in the striatopallidal circuitry and don?t exhibit the robust regulatory effects that DA exerts on striatal neurons, so it is likely that they are regulated separately. The objectives of the proposed research are 1: to determine if stimulation of the pathway from LPH NT-expressing neurons to the VTA [a] alters extracellular NT levels in the VTA and, if so, [b] the effect is associated with a change in locomotor activation state; 2: to determine if extracellular levels of NT in the VTA are altered by acute or repeated administrations of cocaine or by a cocaine challenge in rats that have developed sensitization to cocaine and whether any changes observed are reversed by lesions of the LPH-VTA pathway; and 3: to determine if responses to cocaine challenge are altered by bilateral lesions of the LPH-VTA NT pathway in a manner that is reversed by delivering NT bilaterally to the VTA. The results of these studies will contribute to a more circuitry-based appreciation of how NT influences normal motivated behavior and behavior modified by psychostimulant drug administration. The data may lead to better, more selective therapeutic approaches to prevention of psychostimulant sensitization, which is thought play a significant role in destructive drug seeking behaviors.
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