Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors

Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A-/-). Inhibition of mIPSCs frequency by low (10 mu M) and high (100 mu M) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A-/- mice. In WT mice, only 100 mu M 5-HT significantly reduced mIPSCs frequency. In 5HT(2A)-/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 mu M 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 mu M 5-HT were enhanced in cocaine binge-treated 5-HT2A-/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine.