An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited-or "habitual"-qualities that are resistant to change. We show that selective knockdown of prelimbic prefrontal cortical Brain-derived neurotrophic factor (Bdnf) increases sensitivity to response -outcome associations, blocking habit-like behavioral inflexibility. A history of adolescent cocaine exposure, however, occludes the "beneficial" effects of Bdnf knockdown. This finding highlights a challenge in treating addiction-that drugs of abuse may bias decision-making toward habit systems even in individuals with putative neurobiological resiliencies.Both humans and rodents can learn to associate specific actions with their outcomes. Such actions are considered "goal-directed," meaning their performance is sensitive to changes in the predictive relationship between the behavior and its outcome. Extended training, certain reinforcement schedules, and drugs of abuse can induce a shift from goal-directed to automated, or "habitual," response strategies that are defined by insensitivity to changes in the contingency between the behavior and the outcome (Yin et al. 2008;Balleine and O'Doherty 2010). Within the prefrontal cortex, the prelimbic subregion is intimately linked with goal-directed decision-making. For example, rodents with prelimbic-selective lesions are insensitive to changes in outcome value or modifications in response-outcome associative contingencies (Balleine and Dickinson 1998;Corbit and Balleine 2003;Killcross and Coutureau 2003).Under some conditions, overexpression of the neurotrophin BDNF within the prelimbic cortex also confers habit-like behavioral inflexibility (Graybeal et al. 2011;Gourley et al. 2012). These findings predict that site-selective Brain-derived neurotrophic factor (Bdnf) knockdown might, conversely, augment goal-directed decision-making. Moreover, site-selective knockdown may protect against habits that result from pathological stimuli such as cocaine. This is critical because stimulus-response habits are considered etiological factors in addiction (Jentsch and Taylor 1999;Everitt and Robbins 2005).An important aspect of goal-directed decision-making is differentiating between actions that are more or less likely to be reinforced. Here we trained BALB/c mice to respond for food pellets on two distinct nose poke apertures using a continuous reinforcement schedule. We then modified the schedule such that 50% of the responses on one aperture were reinforced 1 sec after the response. Responding on the other aperture had no consequences; instead, food pellets were delivered noncontingently, "for free," at a rate matched to that of the prior session (Gourley et al. 2013a,b). In this case, only 2.2% of pellets were delivered within 1 sec after a response (Fig. 1). We used these testing parameters (further elaborated below) to ascertain whether targeted...
Septal infusions of the ␥-aminobutyric acid (GABA) A agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA A receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are involved in the memory-impairing effects of septal GABA A receptor activation. Experiment 1 tested whether combining septal co-infusions of subeffective doses of muscimol with scopolamine, a drug that selectively influences GABA SH projections, would produce memory deficits. Experiment 2 tested whether hippocampal infusions of a GABA A receptor antagonist would block the effects of septal muscimol infusions. Fifteen minutes prior to assessing spontaneous alternation (SA) or training in a multiple trial inhibitory avoidance (CMIA) task, male Sprague-Dawley rats were given septal infusions of vehicle, muscimol, scopolamine, or co-infusions of muscimol with scopolamine, or septal infusions of vehicle or muscimol combined with hippocampal infusions of vehicle or bicuculline. Septal co-infusions of muscimol with scopolamine significantly impaired SA and CMIA. Hippocampal bicuculline infusions blocked deficits produced by septal muscimol infusions in SA and attenuated deficits produced in CMIA. Combined, these findings suggest that GABAergic SH projections are involved in the memory-impairing effects of septal GABA receptor activation.
Cocaine addicted men have low startle magnitude persisting during prolonged abstinence. Low startle rats show greater cocaine self-administration than high startle rats. Low startle may be a marker of a vulnerability to heightened cocaine-related behaviors in rats and similarly may be a marker of vulnerability to cocaine addiction in humans.
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