Decreased Sensitivity of NMDA Receptors on Dopaminergic Neurons from the Posterior Ventral Tegmental Area Following Chronic Nondependent Alcohol Consumption

摘要

Background: The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally applied N-methyl-d-aspartic acid (NMDA; glutamate receptor subtype agonist) were evaluated. Methods: P rats were assigned to alcohol na?ve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from na?ve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC 50 (effective current producing a half maximal excitatory response), E max (maximal excitatory effect), and C DB (the current at which depolarization block-marked decrease in neuronal activity-occurred). Results: Drinking P rats steadily consumed alcohol over the 8-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher C DB values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC 50 values), consistent with decreased receptor affinity. Maximal excitatory responses (E max) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation. Conclusions: NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.