Molecular Neurobiology and Alcohol Actions

Alcohol Abuse And Alcoholism

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Abstract

The basolateral amygdala (BLA) is a critical component of the amygdaloid circuit, which is thought to be involved in conditioned responses, and it has been suggested that conditiond responses may be involved in the alcohol abuse and alcoholism. Using whole-cell patch-clamp recording, we found that activation of nicotinic acetylcholine receptors (nAChRs) leads to an action potential-dependent increase in the frequency of spontaneous GABAergic currents in principal neurons in the BLA. These spontaneous GABAergic currents were abolished by a low Ca2+/high Mg2+ bathing solution, suggesting that they are spontaneous inhibitory postsynaptic currents (sIPSCs). Blockade of ionotropic glutamate receptors did not prevent this increased frequency of sIPSCs, nor did blockade of alpha7-nAChRs. Among the nAChR agonists tested, cystisine was more effective at increasing the frequency of the sIPSCs than nicotine or 1,1-dimethyl-4-phenyl piperazinium iodide (DMPP), consistent with a major contribution of beta4-nAChR subunits. The nicotinic antagonist, dihydro-beta-erythroidine, was less effective than d-tubocurarine in blocking the increased sIPSC frequency induced by ACh, suggesting that alpha4-containing nAChR subunits do not play a major role in the ACh-induced increased sIPSC frequency. Although alpha2/3/4/7- and beta2/4-nAChR subunits were found in the BLA by RT-PCR, the agonist and antagonist profiles suggest that the ACh-induced increase in sIPSC frequency involves predominantly alpha3/beta4-containing nAChR subunits. Consistent with this, alpha-conotoxin-AuIB, a nAChR antagonist selective for the alpha3/beta4 subunit combination, inhibited the ACh-induced increase in the frequency of sIPSCs. The observations suggest that nicotinic activation increases the frequency of sIPSCs in the BLA by acting mainly on alpha3/beta4-containing nicotinic receptors on GABAergic neurons and may play an important role in the modulation of synaptic transmission in the amygdala. Experiments are also in progress to elucidate the cellular and molecular mechanisms involved in the function and the alcohol & neuroactive substance sensitivity of other neurotransmitter-gated membrane ion channels, such as N-methyl-D-aspartate (NMDA) receptors, glycine receptors and ATP receptors. These studies hold the promise that such cellular and molecular approaches will advance our knowledge of the cellular and molecular basis of alcohol abuse and alcoholism.