Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 320, Issue 1, Pages 376-385Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.111690
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Funding
- NIAAA NIH HHS [AA 12435] Funding Source: Medline
- NIMH NIH HHS [MH 62394] Funding Source: Medline
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The dorsal raphe (DR) receives a prominent dopamine (DA) input that has been suggested to play a key role in the regulation of central serotoninergic transmission. DA is known to directly depolarize DR serotonin neurons, but the underlying mechanisms are not well understood. Here, we show that activation of D-2- like dopamine receptors on DR 5- HT neurons elicits a membrane depolarization and an inward current associated with an increase in membrane conductance. The DA-induced inward current (I-DA) exhibits a linear I-V relationship and reverses polarity at around -15 mV, suggesting the involvement of a mixed cationic conductance. Consistent with this notion, lowering the extracellular concentration of sodium reduces the amplitude of I DA and induces a negative shift of its reversal potential to approximately -45 mV. This current is abolished by inhibiting G- protein function with GDP beta S. Examination of the downstream signaling mechanisms reveals that activation of the nonselective cation current requires the stimulation of phospholipase C but not an increase in intracellular calcium. Thus, pharmacological inhibition of phospholipase C reduces the amplitude of I DA. In contrast, buffering intracellular calcium has no effect on the amplitude of I-DA. Bath application of transient receptor potential ( TRP) channels blockers, 2- aminoethoxydiphenyl borate and SKF96365 [1-(beta-[3-(4- methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H- imidazole], strongly inhibits I DA amplitude, suggesting the involvement of TRP- like conductance. These results reveal previously unsuspected mechanism by which D 2- like DA receptors induce membrane depolarization and enhance the excitability of DR 5- HT neurons.
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