A critical issue for the understanding of drug addiction is what neurobiological mechanisms are responsible for the transition from non-dependent drug use to addiction. This is a competing renewal application to continue to study the neural mechanisms of cocaine reinforcement that lead to compulsive drug seeking behavior. Work during the previous funding period has established that neurochemical mechanisms within specific subregions of a basal forebrain circuit termed the extended amygdala may be involved in the acute reinforcing effects of cocaine and reward system dysfunction associated with chronic administration of cocaine. Within this neural circuitry, evidence was generated for a role in cocaine dependence of specific dopaminergic and serotonergic receptors subtypes as well as interactions with the glutamate system and the brain stress neurotransmitter corticotrophin releasing factor. In addition, during the previous funding period, a model of the transition to compulsive drug seeking was developed where rats allowed more prolonged daily access to cocaine (6 hours) escalate their cocaine intake over time whereas rats that were allowed more limited exposure (1 hour) showed stable, non escalating cocaine intake. This escalation in drug intake was accompanied by a shift of the cocaine dose effect function upwards such that the animals were taking more cocaine at each dose. In addition, animals with a history of drug escalation more readily escalated drug intake upon re-exposure to cocaine. It is hypothesized that this escalation in cocaine intake results from a change in reward set point that reflects changes in neural activity within the extended amygdala and its connections. The purpose of the proposed studies is to further characterize escalation of cocaine intake with more prolonged access (Specific Aim 1), and to explore the neuroanatomical substrates for escalation of cocaine intake (Specific Aim 2). In addition, the proposed studies are designed to explore the neuropharmacological mechanisms involved in escalation of cocaine intake (Specific Aim 3). Finally, drawing on the results of Specific Aims 2 and 3, the role of specific neuropharmacological mechanisms within the extended amgydala in escalation of cocaine intake will be explored (Specific Aim 4). These experiments will provide critical information on the brain changes that accompany the transition from the stable drug intake of limited access to the escalated intake of more prolonged access. Such information is essential for the development of new treatments for drug addiction as well as for the development of strategies to identify vulnerability to the development of addiction.
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