Cocaine Self-Administration Selectively Decreases Noradrenergic Regulation of Metabotropic Glutamate Receptor-Mediated Inhibition in Dopamine Neurons

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Abstract
Stimulant drugs of abuse have several effects on neural activity, including altering the excitability of dopamine neurons via the noradrenergic and glutamatergic systems. Thus, an interaction between noradrenergic and glutamatergic systems may play a role in drug-seeking behavior. Although many of the direct pharmacological effects of psychostimulants on dopamine neuron physiology are well established, the neurophysiological bases of drug-seeking behavior have yet to be fully elucidated. The present study measured short-term (3 d) and long-term (14 d) access to cocaine, by self-administration or passive exposure, and the regulation of metabotropic glutamate receptor (mGluR)-mediated inhibition of dopamine cells in rat midbrain slices. The results indicated that α-adrenoreceptor modulation of the mGluR-mediated inhibition is selectively reduced in animals that self-administered cocaine for 3 d. This effect was not observed in slices from either yoked cocaine animals, which were given cocaine in an amount and pattern equal to that used for the self-administering animals, or saline control animals. However, after 14 d of cocaine, α-adrenoreceptor regulation of the mGluR-mediated inhibition was equally reduced in both self-administering and yoked cocaine animals relative to saline controls. The results suggest that α-adrenoreceptor regulation of the mGluR-mediated inhibition is an adaptive cellular mechanism involved in early cocaine self-administration that is distinct from a direct pharmacological effect of cocaine on dopamine neurons. The noradrenergic system could therefore serve to alter the reward value of stimuli that have significant effects on dopamine neuron firing pattern through mGluRs.