Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

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PROJECT SUMMARY Substance use disorder (SUD) is a major epidemic, and its impact may be particularly severe for women. One of the most striking examples is “the telescoping effect” wherein women meet criteria for SUD and/or seek treatment after fewer years of drug use as compared to men. This effect has been reported for multiple drug classes, including psychostimulants and opioids. Our data obtained from the previous funding period establish that a similar phenomenon occurs in a rat model of cocaine use disorder (CUD) with females developing an addiction-like phenotype sooner during abstinence than males. We have defined an addiction-like phenotype as an enhanced motivation for cocaine. This feature develops over abstinence following extended-access (ExA, >6-hr/day) but not short-access (ShA) self-administration, and like SUD in humans, it represents a lasting shift toward a higher motivational state. Our data show that 7 days of abstinence is sufficient for inducing this phenotype in females, whereas males require 14 days. Females tested after 7 days of abstinence also display greater compulsive cocaine use, as measured using a punishment procedure, but by 14 days of abstinence, males reach the female-level. Our goals with this competitive R01 renewal application are to characterize molecular shifts that underlie the telescoping effect, and to determine whether, similar to humans, the telescoping effect also occurs with opioids. Our primary hypothesis is that a shift from nucleus accumbens (NAc) dopamine D1 receptors (D1R) to glutamate AMPA receptors (AMPAR) occurs sooner during abstinence in females than males and underlies the telescoping effect. This hypothesis is based on our findings showing that following the development of an addiction-like phenotype, the mechanisms motivating cocaine use shift in both males and females from NAc D1R to AMPAR, and that in females, estradiol is necessary for the development of this phenotype and the shift to a diminished role of NAc D1R. In Aim 1, using site-specific antagonism of NAc D1R and AMPAR, we will determine mechanistic shifts that occur with the development of an enhanced motivation for cocaine and compulsive cocaine use. Effects will be examined following ExA self-administration and 1-day of abstinence, which will not induce an addiction-like phenotype or molecular shift in either sex, or 7- days of abstinence, which will induce this phenotype and molecular shift in females with estradiol, but not males or females without estradiol. In Aim 2, we will use RNA- and ChIP-sequencing to test the hypothesis that estrogen receptors regulate the transcriptional events that accompany the development of an addiction-like phenotype. Finally, in Aim 3, we will use an ExA fentanyl self-administration procedure optimized for studying sex differences to test the hypothesis that, similar to humans, female rats develop an opioid addiction-like phenotype sooner during abstinence than males. These studies will provide entirely novel information of the mechanism underlying the telescoping effect and identify possible targets to prevent its occurrence in women. They will also establish the biological basis for the telescoping effect with opioids.