Differential roles of serotonin receptor subtypes in the modulation of lordosis behaviour in the female rat
Creators: name: Mendelson, Scott Douglas
Publisher: name: University of British Columbia
Year: 2010

description: In 1985, Mendelson and Gorzalka proposed the dual role hypothesis of serotonergic modulation of lordosis behaviour. In this hypothesis it was proposed that serotonergic activity can either inhibit or facilitate lordosis behaviour. Specifically it was suggested that the lordosis-inhibiting effects of serotonin are mediated by activity at 5-HT₁ receptors, whereas lordosis-facilitating effects of serotonin are mediated by activity at 5-HT₂ receptors. The purpose of the following series of studies was both to confirm and to extend the dual role hypothesis. The intraperitoneal administration of the 5-HT2 antagonists pizotefin (1 mg/kg), cyproheptadine (1 mg/kg), metitepine (1 mg/kg), and ketanserin (1 mg/kg) were found to inhibit lordosis behavior in ovariectomized rats that had been primed with estradiol benzoate (EB) and progesterone (P). Pipamperone was ineffective. The 5-HT₂ agonist guipazine (3 mg/kg) was ineffective alone, but it reversed the inhibitory effects of pizotefin, cyproheptadine, and ketanserin. It did not reverse the effects of metitepine. The highly selective 5-HT₂ antagonist LY53857 (0.3 mg/kg) was also found to inhibit lordosis behaviour in female rats that had been primed with EB and P. The lordosis-inhibiting effect of LY53857 (1 mg/kg) in females primed with EB and P was reversed by quipazine (3 mg/kg). The nonselective 5-HT antagonist methysergide (7 mg/kg) was found to inhibit lordosis behavior 30 min after intraperitoneal administration to females treated chronically with EB, or with EB and P. However, methysergide was found to facilitate lordosis behavior 200 and 300 min after administration to female rats treated acutely with EB. In an analysis of dose response it was found that methysergide (0.02 - 7 mg/kg) administered 30 min prior to behavioural testing produced no facilitation of lordosis in females primed with EB. However, when administered 200 min prior to testing, methysergide (1 mg/kg) produced a significant facilitation of lordosis. The administration of the 5-HT₁ A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) inhibited lordosis behavior in ovariectomized rats primed with EB. 8-OH DPAT was ineffective at 0.01 mg/kg, whereas inhibition occurred at the 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg doses. In an evaluation of the effects of 8-OH DPAT on the expression of male sexual behaviour by females treated chronically with testosterone, 8-OH DPAT ( 1 mg/kg) increased the number of females mounting and significantly increased mount frequency. The 5-HT₁ A agonists ipsapirone (0.1 mg/kg) and gepirone (0.3 mg/kg) facilitated lordosis in females treated with EB. When administered at higher doses, ipsapirone (3.0 mg/kg) and buspirone (3.0 mg/kg) inhibited lordosis in rats treated with EB. In females treated with EB and P, ipsapirone (&gt; 1.0 mg/kg), gepirone (&gt; 0.3), and buspirone (&gt; 0.3) inhibited lordosis behaviour. The newly developed 5-HT₁ A antagonist BMY 7378 (0.2 mg/kg) facilitated lordosis behaviour in females treated with EB. However, this facilitation was no longer apparent at the 5 mg/kg dose. BMY 7378 (0.04 - 5 mg/kg) was ineffective in females primed with EB and P. The 5-HTTB agonist 1 -(3-trifluoromethylphenyl)piperazine (TFMPP, 0.2 -5 mg/kg) was found to facilitate lordosis in females treated with EB. In females primed with EB and P, TFMPP (5 mg/kg) produced a significant inhibition of lordosis. The 5-HT₁ B agonist m-chlorophenylpiperazine (MCPP, 0.04 - 5 mg/kg) was ineffective in females primed either with EB or with EB and P. The 5-HT₃ Antagonist ICS 205-930 (5 mg/kg) was found to facilitate lordosis behaviour, whereas the 5-HT₃ Antagonist MDL 72222 (0.05 - 5 mg/kg ) was found to be ineffective in females primed with EB. The results of these studies tend to confirm that serotonergic activity can either inhibit or facilitate lordosis behaviour. It is suggested that the lordosis-inhibiting effects of serotonin are mediated by activity at postsynaptic 5-HTTA and possibly 5-HT₃ Receptors. The lordosis-facilitating effects of serotonin are mediated by activity at 5-HT₂ and possibly presynaptic 5-HT₁ B receptors. Finally, it is suggested that activity at somato-dendritic 5-HT₁ A autoreceptors may mediate facilitatory effects of low doses of 5-HT₁ A agonists. In closing, there is a discussion of the implications these results might hold for the understanding of the effects of serotonergic drugs on human behaviour.