Early life trauma is a risk factor for a number of neuropsychiatric disorders, including schizophrenia (SZ). The current study assessed how an early life traumatic event, maternal deprivation (MD), alters cognition and brain function in rodents. Rats were maternally deprived in the early postnatal period and then recognition memory (RM) was tested in adulthood using the novel object recognition task. The expression of catechol-o-methyl transferase (COMT) and glutamic acid decarboxylase (GAD67) were quantified in the medial prefrontal cortex (mPFC), ventral striatum, and temporal cortex (TC). In addition, depth EEG recordings were obtained from the mPFC, vertex, and TC during a paired-click paradigm to assess the effects of MD on sensory gating. MD animals exhibited impaired RM, lower expression of COMT in the mPFC and TC, and lower expression of GAD67 in the TC. Increased bioelectric noise was observed at each recording site of MD animals. MD animals also exhibited altered information theoretic measures of stimulus encoding. These data indicate that a neurodevelopmental perturbation yields persistent alterations in cognition and brain function, and are consistent with human studies that identified relationships between allelic differences in COMT and GAD67 and bioelectric noise. These changes evoked by MD also lead to alterations in shared information between cognitive and primary sensory processing areas, which provides insight into how early life trauma confers a risk for neurodevelopmental disorders, such as SZ, later in life.

Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the θ band (5–11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations.

Polymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may be a critical component of the neuropathology of alcoholism. In the current experiments, the COMT inhibitor tolcapone was utilized in an operant behavioral model of reinforcer-seeking and drinking to determine if this compound was capable of remediating the excessive seeking and drinking phenotype of the alcohol-preferring P rat. Tolcapone was administered to male and female alcohol-reinforced P and Wistar rats. Additionally, tolcapone was administered to male sucrose-reinforced P and Wistar rats to determine if its effects also extended to a natural reinforcer. Animals were trained to make an operant response that resulted in 20 min uninterrupted access to the reinforcer solutions. Tolcapone had no effect in female rats on either seeking or consumption of ethanol. However, reductions of both reinforcer seeking and consumption were observed in male P rats, but only of seeking in Wistars. In separate experiments, using reinforcer naïve male and female animals, COMT expression was assessed via Western Blot analysis. Sex differences in COMT expression were also observed, where male P rats exhibited a marked reduction in protein expression relative to females in the PFC. Sex differences were not observed for Wistars or in the striatum and hippocampus. These data complement our previous findings in which tolcapone reduced cue-evoked responses in P rats and further suggest clinical utility of COMT inhibitors in the treatment of addiction disorders, specifically in male high drinkers.