ABSTRACT
Alcoholism is often associated with other forms of drug abuse, suggesting that innate predisposing factors may confer vulnerability to addiction to diverse substances. However, the neurobiological bases of these factors remain unknown. Here, we have used a combination of imaging, neurochemistry and behavioral techniques to investigate responses to the psychostimulant amphetamine in Marchigian Sardinian (msP) alcohol-preferring rats, a model of vulnerability to alcoholism. Specifically, we employed pharmacological magnetic resonance imaging to investigate the neural circuits engaged by amphetamine challenge, and to relate functional reactivity to neurochemical and behavioral responses. Moreover, we studied self-administration of cocaine in the msP rats. We found stronger functional responses in the extended amygdala, alongside with increased release of dopamine in the nucleus accumbens shell and augmented vertical locomotor activity compared with controls. Wistar and msP rats did not differ in operant cocaine self-administration under short access (2 hours) conditions, but msP rats exhibited a higher propensity to escalate drug intake following long access (6 hours). Our findings suggest that neurobiological and genetic mechanisms that convey vulnerability to excessive alcohol drinking also facilitate the transition from psychostimulants use to abuse.
Subject(s)
Alcoholism/diagnostic imaging , Amphetamine/pharmacology , Brain/drug effects , Central Nervous System Stimulants/pharmacology , Cocaine/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Alcoholism/metabolism , Amygdala/diagnostic imaging , Amygdala/drug effects , Amygdala/metabolism , Animals , Brain/diagnostic imaging , Brain/metabolism , Conditioning, Operant , Disease Models, Animal , Dopamine/metabolism , Functional Neuroimaging , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Locomotion , Magnetic Resonance Imaging , Microdialysis , Nucleus Accumbens/diagnostic imaging , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Rats , Self Administration , gamma-Aminobutyric Acid/drug effects , gamma-Aminobutyric Acid/metabolismABSTRACT
Originally studied for its role in energy homeostasis, the paraventricular nucleus of the thalamus (PVT) has recently gained attention because of its involvement in the modulation of drug-directed behavior. The posterior part of the PVT (pPVT) is connected with brain structures that modulate motivated behavior, and we tested whether the pPVT plays a pivotal role in cocaine seeking. The aim of the present study was to investigate whether transient inactivation of the pPVT prevents cue-induced reinstatement of cocaine seeking but not natural reward seeking. Male Wistar rats were trained to associate a discriminative stimulus (S(+)) with the availability of cocaine or a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Following extinction, the cocaine S(+) and SCM S(+) elicited comparable levels of reinstatement. Intra-pPVT administration of the γ-aminobutyric acid-A (GABAA) and GABAB receptor agonists muscimol and baclofen (0.06 and 0.6mM, respectively) prior to the presentation of the cocaine or SCM S(+) completely prevented the reinstatement of cocaine seeking, with no statistically significant effects on SCM seeking. These data show that the pPVT plays an important role in neuronal mechanisms that drive cocaine-seeking behavior.
