Drug addiction is a chronic brain disease characterized by uncontrolled drug taking, craving, and relapse. Addictive drugs invariably induce non-physiological DA signal that likely interferes with ongoing motivational and associative learning behaviors, modify reward circuits via plasticity mechanisms similar to that underlie these behaviors, and alter reactivity of these circuits with DA, perpetuating use of a drug. A particularly important region in the dopaminergic reward circuitry is the prefrontal cortex (PFC), which mediates executive control of motivation and choice and is implicated in directing addictive behaviors. Alterations in glutamatergic plasticity are hypothesized to promote the compulsive character of drug seeking in addicts and hinder extinction of drug use memories, promoting relapse. Unlike primary sensory cortices, PFC circuits are to some degree refractory to experience scalping but are readily modified by drugs, suggesting unique plasticity mechanisms that show increased dependence on DA in this associative cortex. Precise mechanisms by which DA drives synaptic plasticity in PFC are poorly understood. In particular, it is unclear (i) how glutamatergic synaptic modifications can occur in native circuits tightly controlled by GABAergic inhibitory tone, (ii) what precise roles DA might play in enabling synaptic plasticity as suggested by behavioral studies, and (iii) how addictive drugs modify PFC circuits and their reactivity to DA, resulting in an addicted circuitry. Our recent studies indicate that a brief phasic DA is necessary to enable spike-timing dependent long-term potentiation (t-LTP) in native PFC circuits under conditions of intact GABAergic inhibition. This enabling requires a cooperation between D1-class receptors (D1Rs) in excitatory circuits and D2-class receptors (D2Rs) in inhibitory circuits, whereby D2R activation gates t-LTP induction by suppressing local GABAergic inhibition and D1R activation controls the timing window for t-LTP induction, respectively. Our results reveal a previously unrecognized circuit-level mechanism by which DA receptors in separate microcircuits cooperate to drive Hebbian synaptic plasticity. The goals of this R01 application are to define the molecular, synaptic, and signaling details in interconnected PFC excitatory (Aim 1) and inhibitory (Aim 2) circuits that permit DA to empower synaptic modifications in the PFC. We will also investigate how repeated cocaine exposures in vivo alter the t-LTP induction and dopaminergic teaching rules in PFC synapses (Aim 3). A combination of slice electrophysiological, molecular, biochemical, and morphological approaches will be employed. These studies address fundamental issues concerning modifications of PFC inhibitory and excitatory microcircuits, and the roles of DA reward signal in these processes. Our studies will also provide key insights into how addictive drugs may erode intrinsic rules governing associative plasticity and usurp the prefrontal reward circuitry. The information obtained will advance our knowledge of the reward circuitry plasticity mechanisms and facilitate understanding and treatments of addiction.
Drug addiction is a chronic brain disease characterized by compulsive drug seeking, craving, and relapse. Drugs of abuse are thought to modify dopaminergic reward circuits, including the prefrontal cortex (PFC), by acting on synaptic plasticity mechanisms similar to that underlie learning and memory, leading to addiction. The purpose of this application is to delineate the rules and underlying mechanisms that govern associative synaptic plasticity in the PFC, as well as their relevance to addiction, using a rodent model of cocaine addiction. The information obtained will advance our knowledge of the reward circuitry plasticity mechanisms and facilitate understanding and treatments of addiction.
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