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Keywords:

  • 5-Hydroxytryptamine1A (5-HT1A) receptors;
  • MKC-242;
  • fluoxetine;
  • dopamine release;
  • antidepressant;
  • microdialysis
  • 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-2ylmethyl]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.

  • Subcutaneous injection of MKC-242 (0.3–1.0 mg kg−1) increased extracellular levels of dopamine in the prefrontal cortex.

  • 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.).

  • Local application of WAY100635 (10 μM) 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 μM) increased dopamine release in the prefrontal cortex.

  • MKC-242 increased cortical dopamine release in the rats pretreated with 5,7-dihydroxytryptamine (150 μg, i.c.v.) that caused an almost complete reduction in cortical 5-HT content.

  • The effect of MKC-242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens.

  • 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.

  • The present results indicate that activation of postsynaptic 5-HT1A receptors increases dopamine release in a brain region-specific manner.

British Journal of Pharmacology (2000) 129, 1028–1034; doi:10.1038/sj.bjp.0703139