Hypothalamic infusion of the 5-HT21C agonist, DOI, prevents the inhibitory actions of the 5-HT1A agonist, 8-OH-DPAT, on lordosis behavior

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Abstract

Sexually receptive, intact, proestrous rats were infused bilaterally into the ventromedial nucleus of the hypothalamus (VMN) with 200 ng of the 5-HT1A agonist, 8-hydroxy-2-di-n-propylamino)tetraline (8-OH-DPAT), with 2000 ng of the 5-HT21C agonist, (±)-(2,5-dimethoxy--4-iodophenyl)-2-aminopropane HCl (DOI), or with both 8-OH-DPAT and DOI. Alone, VMN infusions of 8-OH-DPAT, but not DOI, inhibited lordosis behavior. When 200 ng DOI was infused simulttneously with 8-OH-DPAT, the inhibitory effects of 8-OH-DPAT were completely abolished. These results suggest that neural sites responsible for the reported facilitatory effects of 5-HT21C agonists on lordosis behavior coexist in the VMN with those sites in which 5-HT1A agonists are effective in reducing lordosis behavior. In contrast to the protective action of the 5-HT21C receptor agonist following VMN infusion, no protection was seen when both DOI and 8-OH-DPAT were administered intraperitoneally. Thus, the interaction of these two receptor subtypes in the control of lordosis behavior may be different in regions outside the VMN.

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    In contrast, agonists that act primarily on 5-HT2 or 5-HT3 receptors facilitate lordosis behavior in female rats with relatively low sexual receptivity (Mendelson and Gorzalka, 1985; Wolf et al., 1999; Wolf et al., 1998). A potentially beneficial effect of 5-HT2 and 5-HT3 receptors is inferred from observations that 5-HT2 and 5-HT3 receptor agonists protect against the lordosis-inhibiting effects of 5-HT1A receptor agonists (Maswood et al., 1998; Uphouse et al., 1994) and that 5-HT2 and 5-HT3 receptor antagonists inhibit lordosis behavior (Gonzalez et al., 1997; Maswood et al., 1997). Therefore, drugs which lead to generalized increases in extracellular 5-HT could disrupt the balance between activation of 5-HT receptors that inhibit and those that facilitate lordosis behavior.

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    Endogenous 5-HT acts upon all available 5-HT receptors so that the net behavioral outcome is a composite of all the information received from receptor activation. For example, while 8-OH-DPAT inhibits lordosis behavior following infusion into the VMN, co-infusion with either 5-HT2 receptor agonists or a 5-HT3 receptor agonist can prevent the lordosis inhibition (Uphouse et al., 1994b; Maswood et al., 1998) Similarly, the 5-HT2A/2C receptor agonist DOI can attenuate the reduction in lordosis behavior initiated by the 5-HT3 receptor antagonist, tropisetron (Maswood et al., 1998). Therefore, composite effects of the individual receptors are likely to provide important clues as to how the endogenous system is actually functioning.

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