ABSTRACT
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.
Subject(s)
Cocaine-Related Disorders/physiopathology , Reflex, Acoustic , Reflex, Startle , Animals , Male , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Anesthetics, Local/administration & dosage , Brain-Derived Neurotrophic Factor/metabolism , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Prefrontal Cortex/drug effects , Animals , Brain-Derived Neurotrophic Factor/genetics , Drug Administration Schedule , Food Deprivation , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Prefrontal Cortex/metabolism , Reinforcement ScheduleABSTRACT
Septal infusions of the gamma-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.
