The role of cocaine-induced changes in OMPFC neurophysiology in cocaine addiction

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Cocaine addicts exhibit decreased metabolic basal activity in the orbitofrontal cortex (OFC), as well as decreased metabolic responses to natural reward associated stimuli, relative to healthy controls. However, in addicts, the OFC also shows increased metabolic activity when the subjects are presented with cocaine-associated stimuli. Based on these and other observations two proposals have been put forth. First, it is hypothesized that cocaine-induced plasticity induces a general basal OFC neuronal hypoactivity. However, and second, cocaine also selectively amplifies the strength of neuronal responses to drug-associated events in OFC afferent brain regions. This amplified activity is sufficient in magnitude to maintain or perhaps even amplify OFC firing associated with drug-predictive events. The goal of the proposed project is to use chronic extracellular recording techniques to test these 2 proposals (collectively referred to as the OMPFC hypothesis). Aims 1-2 will test proposals 1-2 respectively. In Aim 1, we will expose three groups of rats to 7 days of limited access cocaine self-administration (2 hrs per day). Thereafter, animals will be assigned to one of three treatment groups, including: 1) 3 days of long-access (LgA) cocaine (6-h per day), 2) 21 days of LgA cocaine, and 3) 21 days of LgA cocaine and 30 days of abstinence. At the end of each treatment, we will use chronic extracellular recording procedures to record basal firing rates of OFC neurons. We will also record the response of the neurons to drug-predictive cues and drug-directed behavior. Three additional control groups will be similarly treated except that they will self-administer sucrose instead of cocaine. The protocol of Aim 2 will be the same as Aim 1 except that recordings will be made in a primary direct OFC afferent, the basolateral amygdala. Based on the OMPFC hypothesis, it is predicted that extended cocaine exposure and cocaine exposure plus extended abstinence will induce a decrease in average basal firing of OFC neurons but an increase in phasic OFC neural responses to drug-associated cues and operant behavior. The same treatments are also expected to increase the strength of amygdala responses to cocaine-associated cues and behavior. No changes in neural activity will be observed in any of the sucrose control groups. The findings would be consistent with the OMPFC hypothesis and reflect an important advance in our understanding of mechanisms that underlie drug addiction.