Circulating ovarian hormones interact with protein interacting with C kinase (PICK1) within the medial prefrontal cortex to influence cocaine seeking in female mice.

Protein interacting with C kinase 1 (PICK1) is an AMPA receptor binding protein that works in conjunction with glutamate receptor interacting protein (GRIP) to balance the number of GluA2-containing AMPARs in the synapse. In male mice, disrupting PICK1 in the medial prefrontal cortex (mPFC) leads to a decrease in cue-induced cocaine seeking and disrupting GRIP in the mPFC has the opposing effect, consistent with other evidence that removal of GluA2-containing AMPARs potentiates reinstatement. However, PICK1 does not seem to play the same role in female mice, as knockdown of either PICK1 or GRIP in the mPFC leads to similar increases in cue-induced cocaine seeking. These previous findings indicate that the role of PICK1 in the prefrontal cortex is sex specific. The goal of the current study was to examine whether ovarian hormones contribute to the effect of prefrontal PICK1 knockdown on reinstatement of cocaine seeking. While we replicated the increased cue-induced cocaine seeking in prefrontal PICK1 knockdown sham mice, we did not see any difference between the GFP control mice and PICK1 knockdowns following ovariectomy. However, this effect was driven primarily by an increase in cocaine seeking in ovariectomized GFP control mice while there was no effect ovariectomy in PICK1 knockdown mice. Taken together, these findings suggest that circulating ovarian hormones interact with the effects of PICK1 on cue-induced reinstatement.

Sex-specific role for prefrontal cortical protein interacting with C kinase 1 in cue-induced cocaine seeking.

Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2-containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue-induced cocaine seeking in both males and females. Protein interacting with C kinase 1 (PICK1) plays an opposing role to that of GRIP, removing AMPARs from the synapse. Consistent with our hypothesis that disruption of PICK1 in the mPFC would lead to a decrease in addiction-like behaviour, we found that conditional deletion of PICK1 in the mPFC attenuates cue-induced cocaine seeking in male mice. However, prefrontal PICK1 deletion had the opposite effect in females, leading to an increase in cue-induced reinstatement of cocaine seeking. We did not see any effects of PICK1 knockdown on sucrose taking or seeking, suggesting the sex-specific effects do not generalise to natural reinforcers. These findings suggest the role of PICK1 in the prefrontal cortex of females may not be consistent with its accepted role in males. To determine whether these sex differences were influenced by gonadal hormones, we gonadectomised a cohort of males and found that removal of circulating androgens eliminated the effect of prefrontal PICK1 knockdown. As there was no effect of gonadectomy on its own on any of the behavioural measures collected, our results suggest that androgens may be involved in compensatory downstream effects of PICK1 knockdown. Taken together, these results highlight the need for consideration of sex as a biological variable when examining mechanisms underlying all behaviours, as convergent sex differences can reveal different mechanisms where behavioural sex differences do not exist.

Glutamate receptor interacting protein acts within the prefrontal cortex to blunt cocaine seeking.

Glutamate receptor interacting protein (GRIP) is a neuronal scaffolding protein that anchors GluA2-containing AMPA receptors to the cell membrane. GRIP plays a critical role in activity-dependent synaptic plasticity, including that which occurs after drug exposure. Given that cocaine administration alters glutamate receptor trafficking within the prefrontal cortex (PFC), a better understanding of the role of receptor trafficking proteins could lead to a more complete understanding of addictive phenotypes. AMPA receptor trafficking in general, and GRIP specifically, is known to play a role in cocaine seeking and conditioned reward in the nucleus accumbens, but its role in the PFC has not been characterized. The current study demonstrates that conditional deletion of GRIP1 in the medial prefrontal cortex increases the motivation for cocaine and potentiates cue-induced reinstatement of cocaine seeking in male and female mice. As no effects of PFC GRIP1 deletion were seen in reinstatement of food seeking, strategy set-shifting, or reversal learning the effects on cocaine seeking are not related to generalized alterations in cognitive function. While disrupting GRIP1 might be expected to lead to decreased AMPA transmission, our electrophysiological data indicate an increase in sEPSC amplitude in the prefrontal cortex and a corresponding decrease in paired pulse facilitation in the nucleus accumbens. Taken together this suggests a strengthening of the PFC to NAc input following prefrontal GRIP1 deletion that may mediate the enhanced drug seeking behavior.

Sex Differences in Psychiatric Disease: A Focus on the Glutamate System.

Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states. This review describes the clinical and preclinical evidence for these sex differences with a focus on two conditions that are more prevalent in women: Alzheimer's disease and major depressive disorder, and three conditions that are more prevalent in men: schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. These studies reveal sex differences at multiple levels in the glutamate system including metabolic markers, receptor levels, genetic interactions, and therapeutic responses to glutamatergic drugs. Our survey of the current literature revealed a considerable need for more evaluations of sex differences in future studies examining the role of the glutamate system in psychiatric disease. Gaining a more thorough understanding of how sex differences in the glutamate system contribute to psychiatric disease could provide novel avenues for the development of sex-specific pharmacotherapies.