Postsynaptic 5-hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex

1 5-Hydroxytryptamine (5-HT) plays a role in the regulation of 3,4-dihydroxyphenylethylamine (dopamine) neurons in the brain, but the precise mechanism of regulation by 5-HT1A receptors of dopamine release has not been defined. The present study describes the effect of 5-{3-[[(2S)-1,4-benzodioxan-2-ylmethyl]amino]propoxy}-1,3-benzodioxole HCl (MKC-242), a highly potent and selective 5-HT1A receptor agonist, on dopamine release in the prefrontal cortex using microdialysis in the freely moving rat. 2 Subcutaneous injection of MKC-242 (0.3-1.0 mg kg(-1)) increased extracellular levels of dopamine in the prefrontal cortex. 3 The effect of MKC-242 in the prefrontal cortex was antagonized by pretreatment with the selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)- cyclohexanecarboxamide (WAY100635; 1 mg kg(-1), i.p.). 4 Local application of WAY100635 (10 mu M) via a microdialysis probe antagonized the effect of systemic MKC-242 in an increasing dopamine release, and locally infused 8-hydroxy-2-(di-n-propylamino)tetralin (10 mu M) increased dopamine release in the prefrontal cortex. 5 MKC-242 increased cortical dopamine release in the rats pretreated with 5,7-dihydroxytryptamine (150 mu g, i.c.v.) that caused an almost complete reduction in cortical 5-HT content. 6 The effect of MKC-242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens. 7 Fluoxetine, a selective serotonin reuptake inhibitor, increased dopamine release in the prefrontal cortex, but not in the nucleus accumbens, while buspirone, a 5-HT1A receptor agonist, increased dopamine release in both brain regions. 8 The present results indicate that activation of postsynaptic 5-HT1A receptors increases dopamine release in a brain region-specific manner.