Adolescent Intermittent Ethanol-Induced Changes in Pain-Related Plasticity Associated with Pain Sensitivity in Adulthood

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PROJECT SUMMARY Adolescent alcohol abuse is a significant risk factor for alcohol misuse in adulthood. Of particular concern are the potential long-term effects on the ability of an individual to appropriately process and respond to pain. Emerging evidence indicates that adolescent alcohol abuse enhances pain sensitivity and anxiety in adulthood, and increased pain sensitivity and heightened anxiety may enhance the potential for alcohol misuse later in life. Recently, a role for a circuit involving the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and ventrolateral periaqueductal gray (vlPAG) in pain processing has been described. Within this circuit, enhanced activity of BLA inputs to the mPFC results in inactivation of mPFC outputs to the vlPAG whereas inhibition of these inputs results in analgesia. Activity within this circuit is further modulated by dopamine inputs to the mPFC, which originate in the ventral tegmental area (VTA), leading to a reduction in BLA-driven feedforward inhibition of vlPAG projecting mPFC neurons. Adolescence is a critical period for development. Environmental insults occurring during adolescence, such as those caused by repeated episodes of binge-like alcohol consumption, may disrupt normal development of this circuitry resulting in persistent changes in pain processing. Interestingly, we have previously demonstrated that adolescent intermittent ethanol (AIE) disrupts dopamine 1 (D1) receptor function and reduces fast-spiking interneuron excitability in the mPFC of adult animals, highlighting the susceptibility of the mPFC to AIE-induced changes. The overarching hypothesis of this proposal is that hyperalgesia in adult rats subjected to AIE-exposure is associated with selective strengthening of BLA synapses onto parvalbumin positive fast-spiking interneurons (PVINs) in the prelimbic cortex (PrL). It is further hypothesized that decreased dopamine modulation of PVINs following AIE will contribute reduced activation of PrL PVINs in response to an inflammatory pain challenge. The proposed studies will use a combination of projection and cell-type specific labelling, optogenetics, and patch-clamp slice electrophysiology to assess the effects of AIE-induced changes on pain-related plasticity in BLA-PrL-vlPAG circuitry as well as AIE-induced alterations in dopamine modulation of mPFC FSINs following a pain challenge. These experiments will provide novel insight into how alcohol consumption during adolescence contributes to increased pain sensitivity and anxiety in adulthood. These insights could prove valuable in informing the development of new treatments designed to target neurocircuitry involved in aberrant pain processing in adults who consumed alcohol during adolescence.