Interaction of the anxiogenic agent, RS-30199, with 5-HT1A receptors: modulation of sexual activity in the male rat.

RS-30199 has been shown previously to have atypical interactions at 5-HT1A receptors. RS-30199 and RS-64459, an analogue of buspirone with a buspirone side chain, were compared with the classic, partial agonist at 5-HT1A receptors, 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) and buspirone. At human (h) 5-HT1A receptors in CHO cells, RS-30199-193 (racemate) and its enantiomers (-197, -198) inhibited [3H]-8-OH-DPAT binding (RS-30199-198, ki, 29.7 +/- 11.7 nM; RS-30199-197, ki, 74.1 +/- 11.7 nM) as did RS-64459 (ki, 24.9 +/- 6.0 nM), but RS-30199-197 and -198 were almost full agonists in a [35S]-GTPgammaS binding assay, whereas RS-64459 was a partial agonist, resembling buspirone and 8-OH-DPAT. RS-64459 and the enantiomers of RS-30199 had weaker affinity for 5-HT2C and 5-HT7 receptors. These compounds did not induce the 5-HT behavioural syndrome in male rats. However, in a model where naive male rats were introduced to estrogen-progesterone primed, sexually receptive female rats, RS-30199-197 (0.1, 1, 10 mg/kg, s.c.) had a profound inhibitory effect on sexual behaviour score. Neither buspirone nor 8-OH-DPAT reduced the sexual behaviour score. Unlike 8-OH-DPAT, which shortens intromission latency, RS-30199 prolonged intromission latency. RS-30199 (10 mg/kg s.c.) fully inhibited the facilitation of sexual behaviour caused by the alpha2-adrenoceptor antagonist, delequamine (0.1 mg/kg, p.o.). In contrast, RS-64459 (100, 250, 1000 and 4000 microg/kg, s.c.) failed to modify the sexual behaviour score and did not modify intromission latency. The differences between the effects of RS-30199 and RS-64459 in binding and functional experiments are supported by molecular models of the receptor-ligand interaction, where the compounds interact in different ways with the receptor; a model is proposed for the allosteric interaction of different agents with the receptor, resulting in different functional profiles. RS-30199 can be considered an atypical agonist at 5-HT1A receptors.

Modulation of sexual behaviour in the rat by a potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197).

1. The contributions of alpha 2-adrenoceptors and 5-HT1A receptors to sexual behaviour in the rat have been re-evaluated by use of a highly potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197), yohimbine, idazoxan and the partial agonist at 5-HT1A receptors, 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT). 2. In a model where naive male rats were introduced to oestrogen-progesterone primed, sexually receptive female rats, delequamine (0.4-6.4 mg kg-1, p.o.) dose-relatedly increased the sexual behaviour score over the entire dose-range whereas yohimbine was effective at only one dose, 2 mg kg-1, p.o.. Idazoxan was active only at 2.5 and 5 mg kg-1, p.o. Yohimbine, but neither delequamine nor idazoxan, decreased ejaculation latency. 8-OH-DPAT (0.1 and 0.25 mg kg-1, s.c.) reduced the time, and the number of intromissions to ejaculation without affecting other parameters. A combination of delequamine (0.4 mg kg-1, p.o.) and 8-OH-DPAT (0.1 mg kg-1 s.c.) increased the percentage of rats mounting, intromitting and ejaculating, and reduced ejaculation latency and the number of intromissions. 3. In orchidectomized, sexually experienced rats exposed to sexually receptive females, delequamine, idazoxan and yohimbine increased the number of rats mounting, and there was a tendency to increase the number of animals intromitting, but no effect on ejaculatory behaviour. 4. In ovariectomized female rats brought to low level receptivity by priming with low dose injections of oestradiol benzoate and progesterone, delequamine, at 1.6 and 6.4 mg kg-1 p.o., increased lordosis, while yohimbine, at 2, 4 and 8 mg kg-1 p.o., reduced lordotic responses to sexually experienced males in a dose-dependent manner. 8-OH-DPAT at 0.1, 0.25 mg kg-1, s.c. reduced lordosis in a dose-dependent manner. 5. These findings may be explained on the basis that yohimbine is an alpha 2-adrenoceptor antagonist with affinity for 5-HT1A receptors and that the effects of 5-HT1A receptors may modulate the sexual behaviour responses to alpha 2-receptor antagonism in some models. Thus, in contrast to yohimbine, the highly-selective alpha 2-adrenoceptor antagonist, delequamine, was very effective in increasing the behavioural score in male and female rats over a wide dose-range.

Serum copper levels in elderly patients with femoral-neck fractures.

The serum copper levels of 46 elderly patients with fractures of the femoral neck were assayed and found to be significantly lower than those of a group of controls matched for age and sex. These findings are consistent with nutritional copper deficiency which may contribute to the development of fractures by reducing bone strength.

Effects of lesions in various structures of the suprachiasmatic-preoptic region on LH regulation and sexual behavior in female rats.

Lesions of the suprachiasmatic nuclei (SCN) completely eliminated phasic LH release in ovariectomized rats as measured by the positive feedback response to estradiol benzoate (EB)/progesterone or the response to mating. Basal LH levels and the negative feedback response to EB were not affected. Lesions of the medial preoptic area (MPOA) or bed nucleus-dorsal MPOA also inhibited phasic LH release in ovariectomized rats as measured by positive feedback. However, the inhibition was not complete if there was no damage to the SCN, and the degree of inhibition was correlated with the size ofthe lesion. Basal LH levels and negative feedback were not significant affected. It is suggested that both the SCN and MPOA are involved in phasic LH release, the former in its role as a neural regulator of circadian rhythms and the latter as part of a diffuse system possibly including estrogen-sensitive and/or LH-RH neurons. Sexual behavior (lordosis) in hormone-primed, ovariectomized rats was not significantly affected by lesions of any structure in the suprachiasmatic-preoptic region.