Briand, L. A. | bioRxiv Science

bioRxiv2018

PKMζ in the nucleus accumbens acts to dampen cocaine seeking

The constitutively active, atypical protein kinase C, protein kinase M-{zeta} (PKM{zeta}), is exclusively expressed in the brain and its expression increases following exposure to drugs of abuse. However, the limitations of currently available tools have made it difficult to examine the role of PKM{zeta} in cocaine addiction. The current study demonstrates that constitutive deletion of PKM{zeta} potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine taking, without affecting cue-driven food seeking in both male and female mice. Conditional deletion of PKM{zeta} within the nucleus accumbens recapitulated the increase in cocaine taking and seeking seen in the constitutive knockout mice, but only in male animals. Site-specific knockdown of PKM{zeta} in the nucleus accumbens had no effect on cocaine or natural reward behaviors in female mice. Taken together these results indicate that PKM{zeta} may act to dampen addictive phenotypes. Furthermore, these results indicate that PKM{zeta} is playing divergent roles in reward seeking in males and females.

neuroscience↗

bioRxiv2018

Adolescent Social Isolation Increases Vulnerability to Cocaine.

Childhood and adolescent adversity is associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the molecular mechanisms underlying how chronic stress during adolescence alters reward signaling remains largely unexplored. Understanding how adolescent stress increases addiction-like phenotypes could inform the development of targeted interventions both before and after drug use. The current study examined how adolescent-onset isolation stress affected behavioral, molecular, and physiological responses to cocaine in male and female mice. Adolescent-onset social isolation did not alter the ability of mice to learn an operant response for food, nor influence food self-administration or motivation for food on a progressive ratio schedule. However, male and female socially stressed mice exhibited an increase in motivation for cocaine and cocaine seeking during a cue-induced reinstatement session. Additionally, we demonstrated that adolescent-onset social isolation increased cocaine-induced neuronal activation, as assessed by Fos expression, within the nucleus accumbens core and shell, ventral pallidum, dorsal bed nucleus of the stria terminalis, lateral septum and basolateral amygdala. Taken together, the present studies demonstrate that social stress during adolescence augments the behavioral responses to cocaine during adulthood and alters the responsiveness of reward-related brain circuitry.

neuroscience↗