Effects of protein kinase C inhibitor on 5-HT1A and 5-HT2A/2C receptor interaction in the mediobasal hypothalamus

Activation of 5-HT1A receptors within the mediobasal hypothalamus (MBH) inhibits female rat lordosis behavior and coinfusion with 5-HT 2A/2C receptor agonists attenuates this inhibition. The mechanism by which 5-HT2 receptors mediate the attenuation of 5-HT1A mediated inhibition of lordosis behavior is unknown. 5-HT1A and 5-HT2 receptors are coupled to Gi/o/z and Gq/11 proteins, respectively. It has been suggested that 5-HT2 receptors can induce heterologous desensitization via a protein kinase C (PKC)-induced phosphorylation of 5-HT 1A receptors. This investigation tests the hypothesis that PKC inhibitors can attenuate the ability of 5-HT2 receptor agonists to reduce the lordosis-inhibiting effects of 5-HT1A receptor agonists. In the first experiment, ovariectomized Fischer rats, hormonally primed with 10 μM estradiol benzoate and 500 μM progesterone, received bilateral MBH infusion with the 5-HT1A receptor agonist, 200 ng (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), or 200 ng 8-OH-DPAT, plus 2000 ng (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A/2C receptor agonist. DOI was able to attenuate the lordosis inhibiting effects of 8-OH-OH-DPAT. In the second experiment, following hormonal priming, rats were preinfused with either water or 1.0 x 10-1 nmol of the PKC inhibitor, bisindolylmaleimide I HCl (BIM), 30 min or 90 min before infusion with 8-OH-DPAT or with 8-OH-DPAT plus DOI. BIM prevented the DOI mediated attenuation of 8-OH-DPAT mediated inhibition. Varying doses of BIM (1.0 x 10-1 to 1.0 x 10-7 nmol) were used 90 min prior to infusion with 8-OH-DPAT plus DOI in order to see if BIM had a dose-dependent effect on DOI mediated attenuation. The data suggest that BIM dose dependently attenuated DOI's effect. The results of the present study suggest that PKC might play a role in DOI mediated attenuation of lordosis behavior.