Stimulation of alpha1-adrenoceptors in the rat medial prefrontal cortex increases the local in vivo 5-hydroxytryptamine release: reversal by antipsychotic drugs.
Pyramidal neurons of the medial prefrontal cortex (mPFC) project to midbrain serotonergic neurons and control their activity. The stimulation of prefrontal 5-HT2A and AMPA receptors increases pyramidal and serotonergic cell firing, and 5-hydroxytryptamine (5-HT) release in mPFC. As the mPFC contains abundant alpha1-adrenoceptors whose activation increases the excitability of pyramidal neurons, we examined the effects of their stimulation on local 5-HT release, using microdialysis. The application of the alpha1-adrenoceptor agonist cirazoline by reverse dialysis increased the prefrontal 5-HT release in a concentration-dependent manner, an effect antagonized by coperfusion of TTX, prazosin (alpha1-adrenoceptor antagonist), BAY x 3702 (5-HT1A agonist), NBQX (AMPA/KA antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by MK-801 (NMDA antagonist). Cirazoline also enhanced the increase in 5-HT release induced by DOI (5-HT2A/2C agonist) and AMPA. In addition, M100907 (5-HT2A antagonist) but not SB-242084 (5-HT2C antagonist) reversed the cirazoline- and AMPA-induced 5-HT release. These results suggest that the stimulation of prefrontal alpha1-adrenoceptors activates pyramidal afferents to ascending serotonergic neurons. The effect of cirazoline was also reversed by coperfusion of classical (chlorpromazine, haloperidol) and atypical (clozapine, olanzapine) antipsychotics, which suggests that a functional antagonism of the alpha1-adrenoceptor-mediated activation of prefrontal neurons may partly underlie their therapeutic action.
Amargós-Bosch
Mercè
M
Department of Neurochemistry, Institut d' Investigacions Biomèdiques de Barcelona (CSIC), IDIBAPS, Barcelona, Spain.
Adell
Albert
A
Bortolozzi
Analía
A
Artigas
Francesc
F
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018340:Receptors, Adrenergic, alpha-1; D017366:Serotonin Receptor Agonists; D012701:Serotonin