Proactive Versus Reactive Control Strategies Differentially Mediate Alcohol Drinking in Male Wistars and P Rats.

Problematic alcohol consumption is associated with deficits in decision-making and alterations in prefrontal cortex neural activity likely contribute. We hypothesized that the differences in cognitive control would be evident between male Wistars and a model of genetic risk: alcohol-preferring P rats. Cognitive control is split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus, whereas reactive control elicits goal-directed behavior at the time of a stimulus. We hypothesized that Wistars would show proactive control over alcohol seeking whereas P rats would show reactive control over alcohol seeking. Neural activity was recorded from the prefrontal cortex during an alcohol seeking task with two session types. On congruent sessions, the conditioned stimulus (CS+) was on the same side as alcohol access. Incongruent sessions presented alcohol opposite the CS+. Wistars, but not P rats, made more incorrect approaches during incongruent sessions, suggesting that Wistars utilized the previously learned rule. This motivated the hypothesis that neural activity reflecting proactive control would be observable in Wistars but not P rats. While P rats showed differences in neural activity at times of alcohol access, Wistars showed differences prior to approaching the sipper. These results support our hypothesis that Wistars are more likely to engage in proactive cognitive control strategies whereas P rats are more likely to engage in reactive cognitive control strategies. Although P rats were bred to prefer alcohol, the differences in cognitive control may reflect a sequela of behaviors that mirror those in humans at risk for an AUD.

Proactive Versus Reactive Control Strategies Differentially Mediate Alcohol Drinking in Wistar and P rats.

Problematic alcohol consumption is associated with deficits in decision-making, and alterations in prefrontal cortex neural activity likely contributes. We hypothesized that differences in cognitive control would be evident between male Wistar rats and a model for genetic risk for alcohol use disorder (alcohol-preferring P rats). Cognitive control can be split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus whereas reactive control elicits goal-directed behavior at the time of a stimulus. We hypothesized that Wistars would show proactive control over alcohol-seeking whereas P rats would show reactive control over alcohol-seeking. Neural ensembles were recorded from prefrontal cortex during an alcohol seeking task that utilized two session types. On congruent sessions the CS+ was on the same side as alcohol access. Incongruent sessions presented alcohol opposite the CS+. Wistars, but not P rats, exhibited an increase in incorrect approaches during incongruent sessions, suggesting that Wistars utilized the previously learned task-rule. This motivated the hypothesis that ensemble activity reflecting proactive control would be observable in Wistars but not P rats. While P rats showed differences in neural activity at times relevant for alcohol delivery, Wistars showed differences prior to approaching the sipper. These results support our hypothesis that Wistars are more likely to engage proactive cognitive-control strategies whereas P rats are more likely to engage reactive cognitive control strategies. Although P rats were bred to prefer alcohol, differences in cognitive control may reflect a sequela of behaviors that mirror those in humans at risk for an AUD.

COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat.

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.

Oscillatory power and synchrony in the rat forebrain are altered by a sensitizing regime of D-amphetamine.

Repeated injections of psychostimulants, such as D-amphetamine (D-AMPH), provide a well-validated model of progressive cellular and systems-level alterations in brain function and behavior associated with addiction. The present study employed quantitative measures of both power spectral density and synchrony from local field potentials (LFPs) recorded simultaneously from the prefrontal cortex (PFC), parietal cortex (PAR), and hippocampus (HPC) in awake, behaving rats to assess changes in oscillations during different stages of D-AMPH-induced sensitization. The induction and development of sensitization altered the power of multiple frequency bands in a brain region-specific manner, whereas no changes were observed in animals treated with chronic saline. Specifically, the induction of sensitization to D-AMPH was accompanied by alterations in delta (2-5 Hz) and theta (5-11 Hz) oscillations similar to those observed in EEG recordings from addicted individuals describing craving and hedonic experience of the drug. Sensitization was also related to increased theta coherence between the PFC and HPC, along with suppression of cross-frequency correlations between theta and fast-gamma (65-100 Hz) in both the HPC and the PFC. Collectively, the present findings indicated the induction of a state in which the timing and synchronizing effects of oscillations are altered by sensitization to D-AMPH and are especially pronounced in the PFC. Furthermore, numerous LFP-derived measures were characterized that may serve as objective physiological correlates of pathological states observed in addiction.

Tolcapone enhances food-evoked dopamine efflux and executive memory processes mediated by the rat prefrontal cortex.

BACKGROUND AND RATIONALE: Genetic variations in catechol-O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly important role in the prefrontal cortex (PFC) where DA transporters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC. OBJECTIVES: The current study characterized the ability of tolcapone to increase DA release in response to behaviorally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task. RESULTS AND CONCLUSIONS: Tolcapone enhanced PFC DA efflux associated with the anticipation and consumption of food when compared to saline controls. Chronic and acute treatment with tolcapone also reduced the number of errors committed during acquisition of the DSWSh. However, no dissociable effects were observed in experiments designed to selectively assay encoding or recall in well-trained animals, as both experiments showed improvement with tolcapone treatment. Taken together, these data suggest a generalized positive influence on cognition. Furthermore, these data support the conclusion of Apud and Weinberger (CNS Drugs 21:535-557, 2007) that agents which selectively potentiate PFC DA release may confer cognitive enhancement without the unwanted side effects produced by drugs that increase basal DA levels in cortical and subcortical brain regions.