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<p dir="ltr">Compulsive alcohol drinking is a defining feature of alcohol use disorder and is characterized as drinking alcohol despite knowledge of negative consequences. This behavior is hypothesized to be due to a disruption in the decision-making process. Decision making relies on a balance between goal-directedness and habit systems to efficiently execute behavior. An important distinction between compulsive and non-compulsive individuals is the ability to withhold drinking in the face of a negative consequence. The dorsomedial striatum (DMS) and dorsomedial prefrontal cortex (dmPFC) are brain regions necessary for goal directed behavior where the dmPFC is important for cognitive control and behavioral inhibition while the DMS is important for action selection. Importantly, the dmPFC sends a glutamatergic input to the DMS. We hypothesize this input is a behavioral control which is necessary to withhold action selection. Thus, in order to maintain non-compulsive alcohol use, the dmPFC and DMS need to work together to orchestrate inhibition of action selection in the face of negative consequences. Previous research shows a causal role for both the dmPFC and DMS in preventing compulsive alcohol drinking and a role for the projections from the dmPFC to DMS in behavioral inhibition. However, no research has demonstrated a role for this circuit’s activity in prevention of compulsive alcohol use. The current experiment tested the hypothesis that inhibiting the glutamatergic projection from the dmPFC to the DMS will cause non-compulsive Wistar rats to drink alcohol compulsively.</p>

Dysregulation of glutamatergic signaling mechanisms is a component of many psychiatric diseases. A number of these diseases exhibit a bias toward one sex, yet the ways in which glutamate is affected by or modulates this bias is poorly understood. In cocaine addiction, women progress from initial use of the drug to substance use disorder faster than men, and have more difficulty remaining abstinent. The same is true in female rodents. We used a mouse model of cocaine self-administration to study the role of glutamate receptor trafficking proteins in cocaine addiction-like behavior in males and females. In the first set of experiments, mice received a conditional knockout of glutamate receptor interacting protein 1 (GRIP1) in the medial prefrontal cortex (mPFC). This led to an increase in motivation for cocaine as well as enhanced likelihood of relapse behavior, as measured by a progressive ratio schedule and cue-induced reinstatement, respectively. No sex differences were seen after prefrontal deletion of GRIP1. The next set of experiments used the same behavioral paradigm, but mice received a conditional knockout of protein interacting with C kinase 1 (PICK1) in the mPFC. PICK1 and GRIP1 are both involved in the activity dependent trafficking of the GluA2-containing AMPA receptor, but while GRIP1 maintains these receptors in the synapse, PICK1 internalizes them in response to a stimulus such as drug experience. The prefrontal deletion of PICK1 was predicted to decrease cue-reinstatement responding, and this was observed in the male mice. The female mice displayed an increase in cue-induced reinstatement responding, similar to the effects seen by prefrontal GRIP1 deletion. Sex differences in PICK1 have not previously been described in the literature. Our results suggest that PICK1 is involved in different baseline processes in females, and merit further study. The final set of experiments considered the interaction of gonadal hormones and PICK1 in males. Bilateral gonadectomy or sham surgery was combined with prefrontal PICK1 knockout to determine if circulating gonadal hormones could explain the results in males. After gonadectomy or sham surgery, there was no significant effect of prefrontal PICK1 deletion on cue-induced reinstatement. These results do not fully explain the sex difference observed in intact mice. Together, these studies suggest that baseline sex differences exist in PICK1-mediated mechanisms of cocaine reinstatement and that these differences are not due to the influence of gonadal hormones alone. / Psychology

Yes / Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

Yes / The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity. / Partially supported by a University of Hull Faculty of Science scholarship to MDM and by funding from MIUR and FP7 VPH-DARE to AV.

Executive functioning is a multidimensional concept encompassing higher-order adaptive abilities, such as judgment, decision-making, self-monitoring, planning, and emotional regulation. Disruption in executive functioning often results in devastating impairments in vitally-important areas of life, such as one's ability to hold employment and maintain social relationships. Executive functions have been associated primarily with the prefrontal cortex. However, the nature and degree of the association between frontal lobe damage and performance on executive functioning tests remains controversial. Research suggests that the association may vary based on the specific location of damage within the prefrontal cortex, as well as the used measure of executive functioning. Few investigations have systematically addressed these variables. The current study employed the lesion method to investigate the relationship between performance on a battery of executive functioning tests and damage to specific regions of the prefrontal cortex. Three groups of participants with lesions in one of the locations of interest [ventromedial prefrontal (VMPC, n = 14), dorsolateral prefrontal (DLPC, n = 14), and non-frontal (n = 18)] were administered the Delis-Kaplan Executive Function System (D-KEFS, 2001), a comprehensive battery of executive functioning tests. Results revealed no statistically-significant differences between group performances on the D-KEFS primary measures. However, a qualitative analysis of the results revealed several meaningful group differences. It appears that some relationship exists between frontal lobe damage, particularly in the DLPC, and decreased performance on several executive functioning tests but further research overcoming the methodological limitations of most existing literature on this topic is needed to clearly resolve this issue.