Some people are capable of experimenting recreationally with drugs, like cocaine, while others escalate their drug intake and seek drugs compulsively to the point of addiction. Like addicts, animals self- administering cocaine adjust their intake to maintain optimal brain cocaine and dopamine levels that ultimately determine the pattern of neural activity in circuits that regulate the behavior. Identifying the specific neuronal mechanisms responsible for the plasticity that controls the feedback on drug intake and drug- seeking is fundamental to understanding addiction. A very useful cocaine self-administration animal model that reproduces this high, escalating level of drug intake and drug-seeking has been recently developed. This model induces rats to progressively escalate their cocaine intake to high levels over several days to weeks by allowing them 6 hour daily access to cocaine. After extinction training their relapse responding increases linearly over the course of several weeks. To date, no in vitro studies have measured the neurophysiological adaptations associated with prolonged access volitional cocaine administration, nor have any studies examined the potential for extinction learning to reverse the neurophysiological adaptations. Self and colleagues (2003) have demonstrated extinction learning to reverse several molecular changes induced by cocaine self- administration and have proposed a role for extinction in addiction therapy. Unfortunately, almost all studies examining synaptic or intrinsic plasticity have used noncontingent, experimenter delivered drug, which does not allow extinction learning to occur. While effective at inducing behavioral plasticity, like sensitization, noncontingent drug delivery lacks the volitional and motivational components as well as the intermittent temporal activation of brain regions in the reward circuitry important for synaptic plasticity. Ideally, a candidate brain region worth investigating for a role in the plasticity associated with escalation or incubation of cocaine craving would have the following criteria;1) Substantial innervation within the brain reward circuitry;2) Neural responses to rewarding stimuli and conditioned stimuli or contexts associated with them;3) Modulation of neuronal activity by dopamine and cocaine;3) A role in the formation or storage of reward-related memory;4) Regulation of dopamine neuronal activity or levels in the reward circuit;5) Bidirectional regulation of reinstatement of extinguished responding (i.e. neuronal activation triggers and inhibition decreases reinstatement). Few brain regions meet all of these criteria, however, the ventral subiculum is one such structure that does. Our past in vitro experiments have shown the ventral subiculum, the major hippocampal output structure and interface to the dopamine system to be susceptible to repeated psychostimulant-induced plasticity. This study proposes to study synaptic and intrinsic excitability and dopamine modulation of subicular excitability using a combination of 64 channel planar multielectrode array field potential recording and whole?cell patch clamp recording in rats that have been trained for high/escalating cocaine intake and incubation of cocaine-seeking at prolonged withdrawal times. Extinction will be used to reverse the cocaine-induced neuroplasticity. Two hallmark features of addiction are the loss of controlled drug intake and the associated high relapse risk. Identifying the brain regions and specific neuronal mechanisms that control the feedback on drug intake and drug-seeking is fundamental to understanding addition. Our goal is to use the cocaine self-administration behavioral model of contingent volitional drug intake to allow us to correlate cocaine intake (low, high or escalating) and extinction of drug taking with detailed measures of neurophysiological excitability for the purposes of better understanding the neural plasticity associated with memory is linked to addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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University of Colorado at Boulder
Other Domestic Higher Education
United States
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