NOT-DA-21-033 Investigation of the neurobiological mechanisms that mediate fentanyl-induced elevations in risk taking in rats

About This Grant

Project Summary Despite available pharmacotherapies, relapse rates of opioid use disorder continue to rise, suggesting targets of these treatments, such as mechanisms mediating drug craving, may not be the only factors driving relapse. A potential cognitive target that has remained underexamined, but holds significant promise, is the impaired deci- sion making and elevated risk taking observed during abstinence from opioid use. A larger concern is that indi- viduals who intentionally use fentanyl, a potent synthetic opioid, underestimate their risk of overdose. This sug- gests these individuals are impaired in their ability to evaluate options associated with rewards and risks of adverse outcomes. The neural mechanisms by which synthetic opioids impact these processes to increase risk taking, however, are unknown. This knowledge gap poses a critical barrier to understanding the factors that promote recurrent relapse. The long-term goal of our research is to identify neural mechanisms responsible for fentanyl-induced elevations in risk taking after prolonged abstinence so as to develop strategies to mitigate ef- fects of opioids on risk taking. To meet this goal, we use a rat model of risk taking that recapitulates real-life decision making in that it incorporates both reward and risk of punishment. Using this model, we have established a role for basolateral amygdala (BLA) projections to the nucleus accumbens shell (NAcS), as well as specific cell populations within the NAcS, in this form of decision making. We have also shown fentanyl self-administration causes enduring increases in risk taking after protracted abstinence from fentanyl. Our central hypothesis is that dysfunction in these neural mechanisms that subserve risk taking under drug-naïve conditions is responsible for fentanyl-induced increases in risk taking. We will test this hypothesis using a combination of optogenetics, ex vivo electrophysiology and fiber photometry in rats with a history of fentanyl self-administra- tion. Aim 1 will use optogenetics to determine if activation of BLA projections to the NAcS rescues effects of fentanyl on risk taking. We will also use ex vivo electrophysiology to identify if fentanyl-induced elevations in risk taking during abstinence are associated with altered glutamatergic transmission between BLA and NAcS cells that express either dopamine D2 receptors (NAcSD2Rs) or dopamine D1 receptors (NAcSD1Rs). Aim 2 will deter- mine the impact of fentanyl on encoding of risk- and reward-related information in NAcS during risk taking as well as on NAcSD2R long-range projections and their association with elevated risk taking. We will use fiber pho- tometry and optogenetics to record from and manipulate, respectively, NAcSD2Rs and NAcSD1Rs during risk taking in fentanyl-exposed rats. We will use ex vivo electrophysiology to assess if fentanyl-induced elevations in risk taking are associated with changes in inhibitory transmission between NAcSD2Rs and the ventral pallidum, a region heavily innervated by NAcSD2Rs and necessary for risk taking. Together, these findings will identify the neural substrates by which fentanyl increases risk taking after prolonged abstinence and thus reveal novel ther- apeutic strategies to reduce opioid-induced elevations in risk taking and, consequently, potential relapse.