Stimulation of beta-adrenoceptors inhibits lordosis behavior in the female rat

Existing reports on the effects of beta-adrenergic antagonists on lordosis behavior appear contradictory, with (+/-) propranolol being reported to inhibit, and (+/-) pindolol to facilitate this behavior. In the present study, both the (-) and (+) optical isomers of propranolol were effective in inhibiting lordosis behavior in ovariectomized rats treated with estrogen and progesterone. This finding suggests that the lordosis-inhibiting effects of propranolol were not due to blockade of beta-adrenergic activity, but rather to the membrane stabilizing effect of the drug. An observed inhibition of lordosis following the peripheral administration of the local anesthetic lidocaine is consistent with this possibility. (+/-) Propranolol had no effect 30 min after peripheral administration in estrogen-treated, ovariectomized rats with low baseline levels of lordosis behavior. (+/-) and (-) pindolol, but not (+) pindolol also inhibited lordosis 30 min after administration. However, in addition to its antagonist effects, pindolol acts as a partial agonist in some tissues. Centrally active doses of the pure beta-antagonist (+/-) metoprolol produced no inhibitory effects. Indeed, metoprolol reversed the inhibitory effect of the beta-agonist (+/-) salbutamol. This suggests that the lordosis-inhibiting effects of pindolol were due to its partial agonist effects. Taken together, the present data indicate that activity at central beta-adrenoceptors inhibits rather than facilitates lordosis behavior.     

Evidence for the involvement of central 5-HT1A receptors in the mediation of lordosis behavior in the female rat

5-Hydroxy-L-tryptophan (5-HTP), 25 mg kg^-1 IP, in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg kg^-1 IP, and the selective inhibitor of neuronal 5-hydroxytryptamine (5-HT) re-uptake, zimeldine, 10 mg kg^-1 IP, suppressed lordosis in ovariectomized female rats, treated with estradiol benzoate (EB) or with EB plus progesterone (P). The suppression of lordosis produced by 5-HTP was antagonized by the -receptor blocker (-)pindolol, which also is a selective 5-HT₁ receptor antagonist, but not by the 5-HT₂ receptor antagonists metitepine or pirenperone, nor by the -receptor blocker betaxolol. The EB-or EB plus P-activated lordosis was also suppressed by administration of the selective 5-HT_1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Together, these observations indicate an important role of central 5-HT_1a receptors in the mediation of lordosis behavior in the female rat.     

Methysergide inhibits and facilitates lordosis behavior in the female rat in a time-dependent manner

Reports in the literature have indicated a facilitatory effect of the serotonin antagonist methysergide on lordosis behavior, suggesting an inhibitory role for serotonergic activity. In the present series of experiments, methysergide (7 mg/kg) was found to inhibit lordosis behavior 30 min after intraperitoneal administration to females, treated chronically with estradiol benzoate, or acutely with estradiol benzoate and progesterone. However, methysergide was found to facilitate lordosis behavior 200 and 300 min after administration to female rats treated acutely with estradiol benzoate. These data suggest a time-dependent inhibitory effect of methysergide, and are consistent with the hypothesis that the activity of serotonin type 2 receptors facilitates lordosis behavior in the female rat.     

Cholecystokinin-octapeptide produces inhibition of lordosis in the female rat

The peripheral administration of 3 micrograms/kg CCK-8 produced inhibition of lordosis behavior in ovariectomized female rats primed with estradiol benzoate (EB) and progesterone (P). In Experiment 2, an interaction between CCK-8 and P was evident, with the inhibitory effects of CCK-8 being observed with P doses of 100 and 150 micrograms, but not 250 micrograms. No interaction between CCK-8 and EB was evident, as CCK-8 had no effect on lordosis behavior induced by chronic administration of EB alone. The ineffectiveness of CCK-8 in animals treated with high doses of P, or EB administered chronically, suggests that CCK-8 does not inhibit lordosis via a toxic or non-specific mechanism.     

The influence of alpha-receptors on lordosis in the female rat.

The alpha-adrenergic agonist clonidine suppressed lordotic responding in spayed female rats brought into heat by estrogen and progesterone. The suppression was blocked by the alpha-antagonist yohimbine, but not by phenoxybenzamine or pimozide. The suppression was blocked by the alpha-antagonist yohimbine, but not by phenoxybenzamine or pimozide. Phenoxybenzamine itself had no suppressive effect on lordosis, though yohimbine did under some conditions. These results argue against an important facilitatory influence of norepinephrine on lordosis in the rat. Further, in comparison with the quite different findings recently reported from the guinea pig, they offer support for the presence of two different kinds of alpha-adrenergic receptors in the brain with different physiological functions.     

Facilitation of lordosis behavior by clonidine in female guinea pigs

Lordosis behavior was induced in previously unreceptive, ovariectomized estrogen-primed female guinea pigs by administration of the noradrenergic agonist clonidine. Clonidine also enhanced lordosis responding in females that were weakly receptive after estrogen priming. Unlike progesterone, the lordosis-facilitating effect of clonidine was not accompanied by a subsequent refractory period. Clonidine had a weak lordosis facilitatory effect when administered during the decline in receptivity to estrogen plus progesterone-primed animals and failed to induce lordosis when administered during the refractory period.     

Suppression of lordosis behavior by the putative 5-HT receptor agonist 8-OH-DPAT in the rat

The administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibited the lordosis induced by estradiol benzoate or estradiol benzoate plus progesterone in ovariectomized rats. There was no facilitation of lordosis by 8-OH-DPAT in animals pretreated with a threshold dose of estradiol benzoate. The results are consistent with the view that 8-OH-DPAT is an agonist at 5-HT receptors and provide further support for an inhibition role of central 5-HT in the mediation of lordosis behavior.     

Delta9-Tetrahydrocannabinol enhancement of lordosis behavior in estrogen treated female rats

Rats with self-stimulation electrodes in the medial part of lateral hypothalamus (LH) or in the lateral part of LH were trained to bar press, to run in a continuous, square-shaped runway, and to move their tails from side to side while otherwise restrained, all using LH stimulation on an FI 2 sec schedule as the reinforcement. At low doses of pimozide (a dopaminergic blocker) or of FLA-57 (a dopamine beta- hydroxylase inhibitor) different effects on rates of responding were observed on each of the three tasks at the two electrode placements, indicating that the rate reductions were not the results of specific performance effects of the drugs. The patterns of rate changes suggested that the effects of LH stimulation on behavior in the runway were primarily, but not exclusively mediated by a dopaminergic system; that the effects of LH stimulation on tail movement were primarily, but not exclusively mediated by a noradrenergic system; and that the effect of LH stimulation on bar pressing was mediated by both, or either of these substrates. These results suggest that the reinforcement of behavior by LH stimulation is flexibly mediated by at least two different neural systems.     

Stimulation of mounting behavior but not lordosis behavior in ovariectomized female rats by p-chlorophenylalanine.

Treatment with 126 mg/kg of the 5-hydroxytryptamine synthesis inhibitor p-chlorophenylalanine (PCPA) for 3 days or daily treatment with 40 mg/kg of PCPA stimulated the display of mounting behavior, including ejaculatory patterns, by ovariactomized hormonally untreated female rats. PCPA treatment failed to induce lordosis behavior and did not affect the induction of lordosis behavior by daily injections of 2.0 mug/kg estradiol benzoate. These results show that mounting and lordosis behavior can be dissociated and it is suggested that these two sexual behavior patterns may be regulated by different neurotransmission mechanisms.     

Intraventricular administration of l-kynurenine and kynuramine facilitates lordosis in the female rat

Intraventricular administration of the tryptophan metabolites l-kynurenine (2-32 micrograms) and kynuramine (0.064-8 micrograms) facilitated lordosis behavior in estrogen-primed ovariectomized rats. The facilitatory effects of these drugs were not attenuated by pretreatment with the progesterone antagonist RU 38486, indicating that the effects were not mediated by release of adrenal progesterone. It is suggested that l-kynurenine and kynuramine may serve a physiological role in the modulation of female sexual behavior.     

Restraint accentuates the effects of 5-HT2 receptor antagonists and a 5-HT1A receptor agonist on lordosis behavior

The effect of restraint on lordosis behavior was examined in proestrous and ovariectomized, hormone-primed rats. Restraint durations from 5 to 60 min had no effect on lordosis behavior of proestrous rats. There was also no effect of 5 min restraint on lordosis behavior of ovariectomized rats hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. However, after intraperitoneal treatment with 1.0 mg/kg ketanserin tartrate (ketanserin), 5 min of restraint significantly reduced lordosis behavior of both groups of rats. The 5-min restraint combined with 0.50 or 0.75 mg/kg ketanserin reduced lordosis to mount (L/M) ratios of ovariectomized rats, while L/M ratios of proestrous rats were inhibited only by the 1.0 mg/kg dose. Increasing the restraint duration (10 or 15 min) reduced the dose of ketanserin necessary to reduce the L/M ratios of proestrous rats. Treatment with the selective serotonin (5-HT)(2C) receptor antagonist, SB206553 (2.5 or 5.0 mg/kg), in combination with 5 min of restraint, also reduced L/M ratios of hormonally primed, ovariectomized rats. The neural sites responsible for ketanserin's additivity with restraint are unknown, but infusion of the drug into the ventromedial nucleus of the hypothalamus (VMN) did not mimic the systemic treatment. However, 5 min of restraint did enhance the effects of VMN infusion with the 5-HT(1A) receptor agonist, 8-OH-DPAT. In contrast, 8-OH-DPAT's systemic potency was not enhanced by restraint. These findings support the hypothesis that a mild stressor increases the lordosis-inhibiting effects of 5-HT(1A) receptor agonists and that 5-HT(2) receptors may protect against such disruption of lordosis behavior.     

Potentiative action of alpha- and beta-adrenergic receptor stimulation in inducing lordosis behavior

Ovariectomized (OVX) and ovariectomized-adrenalectomized (OVX-ADX) rats were injected with estradiol benzoate (EB, 4.0 micrograms/rat) and received 44 hr by infusion into the ventromedial hypothalamic area one of the following treatments: norepinephrine (NE), clonidine (an alpha-agonist), isoproterenol (a beta-agonist) or a combination of clonidine and isoproterenol. Infusion of NE (200 ng/rat) induced lordosis in both OVX and OVX-ADX rats 15 minutes after its administration. NE-induced lordosis was blocked by systemic treatment with either the alpha-antagonist, prazosin (1.0 mg/kg), or the beta-antagonist, propranolol (4.0 mg/kg). Intrahypothalamic infusion of clonidine (200 ng/rat) or isoproterenol (200 ng/rat) induced lordosis behavior in OVX, but not in OVX-ADX rats, suggesting the involvement of adrenal secretions in this response. Combined administration of clonidine (100 ng/rat) and isoproterenol (100 ng/rat) induced lordosis behavior 15 minutes after its intrahypothalamic infusion in OVX-ADX animals. Results are discussed in relation to a model proposed for the induction of lordosis behavior involving steroid-NE interactions.     

Factors elevating cAMP attenuate the effects of 8-OH-DPAT on lordosis behavior

The effects of a soluble derivative of forskolin and of two membrane-permeable analogs of cAMP, dibutyryl cAMP, and 8-bromo-cAMP, on the ability of a serotonin (5-HT)(1A) receptor agonist to inhibit lordosis behavior were examined. Sexually receptive, proestrous rats received a bilateral infusion into the ventromedial nucleus of the hypothalamus (VMN) with 68 ng of the forskolin derivative 1, 1.5, 2, or 2.5 h prior to infusion with 200 ng of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Proestrous rats and ovariectomized rats, hormonally primed with 25 microg estradiol benzoate and 500 microg progesterone, were coinfused with 200 ng 8-OH-DPAT and either 50 microg dibutyryl cAMP or 5 microg 8-bromo-cAMP. In proestrous rats, prior infusion with the forskolin derivative reduced the effects of the 5-HT(1A) receptor agonist on lordosis behavior. The best protection occurred at 2 h; by 2.5 h after the preinfusion, any protective effect had disappeared. Coinfusion with either dibutyryl-cAMP or 8-bromo-cAMP reduced the effects of 8-OH-DPAT in proestrous rats. In hormone-primed, ovariectomized rats, dibutyryl cAMP offered significant protection against the effects of 8-OH-DPAT, but there was no protection with 8-bromo-cAMP. These findings are consistent with the speculation that 8-OH-DPAT's inhibition of lordosis behavior results, in part, from an inhibition of adenylyl cyclase, resulting from agonist activation of 5-HT(1A) receptors in the VMN. The findings are also consistent with our earlier observations for differences between proestrous rats and hormone-primed, ovariectomized rats in their response to 5-HT receptor-active compounds.     

Perinatal maternal exposure to picrotoxin: effects on sexual behavior in female rat offspring

A previous study in our laboratory showed that perinatal maternal picrotoxin exposure (0.75 mg/kg) in rats improved heterosexual behavior in male offspring. In the present study, we examined the effects of this maternal treatment on sexual behavior in the female offspring. The dams received 0.75 mg/kg picrotoxin treatment (PT) once a day on the 18th and 21st day of pregnancy, 2 h after parturition and once a day during the first 4 days of lactation. The results showed that (1) at birth, the body weight and anogenital distance were not modified by treatment; (2) female sexual behavior was improved in experimental animals. These results demonstrate that perinatal picrotoxin exposure improves adult sexual behavior in female rat offspring as suggested by increase in the lordosis quotient.     

Dispensability of spinal monoaminergic systems in mediating the lordosis reflex of the female rat

The possibility that bulbospinal monoaminergic systems are essential for expression of the estrogen-induced lordosis reflex in female rats was tested by studying the effects of reserpine and monoamine antagonists on the lordosis responses to mating and manual stimulation. Lordosis performance of five groups of ovariectomized rats, either treated (groups II through V) or not treated (group I) with estrogen, were measured before and after pharmacological treatments. Immediately after post-treatment measurements, females (except group V) were decapitated and the lumbosacral cord quickly removed, frozen, and later assayed for norepinephrine, dopamine and serotonin. Group I females (n=7) did not show any lordosis before or after a control saline injection, and their spinal monoamine contents were not different from those of group II (n=8), who showed near maximal levels of lordosis both before and after a saline injection. Reserpine at low (2 mg/kg; group III, n=6) or high (10 mg/kg, group IV, n=10) doses depleted spinal monoamines severely but had no significant effect on lordosis, except for a slight decline of lordosis intensity after the high dose treatment. A combination treatment of reserpine (10 mg/kg) and a serotonin receptor blocker, methiothepin (10 mg/kg), did not affect lordosis performance (group V, n=6). Further injection of an α-adrenergic antagonist, phenoxybenzamine (20 mg/kg), in addition to this combination, had no effect on the lordosis reflex in response to manual stimulation, although the response to mating stimulation was reduced. The reduction was probably a result of a drug-induced abnormal posture, which made most of the reflexogenic skin area of the female inaccessible to mating stimuli. These results showed that estrogen treatment sufficient to induce a near maximal level of lordosis performance did not alter spinal monoamine contents, and that the monoamines in the spinal cord are not necessary for mediating the estrogen-stimulated lordosis reflex.     

Serotonin receptor blockade potentiates behavioural effects of beta-phenylethylamine

The 5-hydroxytryptamine (5HT) receptor blocker, methysergide (10 mg/kg), was found to potentiate the behavioural effects of β-phenylethylamine (PEA) (at doses between 20 and 60 mg/kg) on food reinforced schedule-maintained behaviour in two separate experiments involving a fixed interval 2 min schedule and a fixed ratio 20 schedule. Potentiation caused a parallel shift to the left in the log dose/response curve for suppression of responding induced by phenylethylamine, and was observed in both male and female rats. These data contrast with recent reports indicating that inhibition of functioning of 5HT systems blocks the effects of phenylethylamine in inducing the “Serotonin behavioural syndrome” (Sloviter et al., 1980a; Dourish, 1981). However, the potentiation reported here is compatible with frequent reports indicating that behavioural effects of amphetamine (-methyl-PEA) can be potentiated by reduction in 5HT functioning and are thus compatible with the hypothesis that phenylethylamine is a potential “endogenous amphetamine”.     

Examination of some factors that control the effects of septal lesions on lordosis behavior

Various experimental parameters related to the effects of septal lesions on the lordosis behavior of rats have been examined. First, the failure of septal lesions to facilitate lordosis behavior in male rats appears to be related to the degree of exposure to androgens neonatally. The normal facilitation in lordosis behavior associated with septal destruction in adult female rats does not occur if these female rats are treated with 1.0 mg of testosterone propionate (TP) on Day 1 of life. Yet female rats given 270 μg of TP on Day 3 of life respond the same as do normal females to septal lesions. Second, these sexually dimorphic effects of septal lesions can be modified in adult rats by chronic treatment with gonadal hormones following septal destruction. Whereas previous studies indicated that chronic estrogen injections permit a facilitation in lordosis behavior to occur in septal lesioned male rats, the present results showed that chronic injections of TP following a septal lesion attenuates the facilitation in lordosis behavior typically observed in adult female rats following a septal lesion. Third, examination of the time course for the facilitation in lordosis behavior following a septal lesion revealed a four to six day delay before the appearance of heightened female sexual behavior. Fourth, in support of the possibility that modifications in lordosis behavior by septal lesions may be mediated by a depletion or imbalance in brain amines, amphetamine was found to reduce the high levels of lordosis behavior of septal lesioned female rats to control levels. Finally, further evidence of a potential role for brain amines in the effects of septal lesions was provided by the observation of significantly lower content and turnover of dopamine in the amygdala of septal lesioned female rats, relative to sham operated controls.     

Dual effect of morphiceptin on lordosis behavior: possible mediation by different opioid receptor subtypes

Intracerebroventricular (ICV) infusions of the selective mu receptor agonist morphiceptin produce a dual effect on lordosis behavior in ovariectomized, steroid-primed rats. Low doses of morphiceptin (20 ng) inhibit lordosis whereas higher doses (2000 ng) facilitate this behavior. The present experiment tested whether naloxone, an antagonist of both high- and low-affinity mu receptors, or the long-acting high-affinity mu receptor antagonist naloxazone could block the dual effect of morphiceptin on lordosis. Ovariectomized rats primed with estrogen and progesterone received naloxone, naloxazone, or a control solution prior to ICV infusions of either 0, 20, or 2000 ng of morphiceptin. Naloxone reversed both the inhibition and facilitation of lordosis produced by morphiceptin, but had no effect on lordosis when administered before control infusions. In contrast, naloxazone reversed the inhibition but not the facilitation of lordosis. These results indicate that the inhibitory effect of morphiceptin on lordosis reflects the activation of high-affinity mu receptors whereas the facilitatory effect reflects either the activation of low-affinity mu receptors or other opioid receptor subtypes. The failure of naloxone or naloxazone to affect lordosis in rats receiving control infusions of saline further suggests that endogenous opioid systems do not exert a tonic inhibitory or facilitatory action on lordosis behavior.     

Progesterone reduces the inhibitory effect of a serotonin 1B receptor agonist on lordosis behavior

Ovariectomized Fischer inbred rats were hormonally primed with 10 μg estradiol benzoate and sesame seed oil (EO rats) or with estradiol benzoate and 500 μg progesterone (EP rats). Four to six hours after progesterone or oil, rats were pretested for sexual behavior and then infused bilaterally into the ventromedial nucleus of the hypothalamus with 0, 50, 100 or 200 ng of the 5-HT_1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrol[3,2-bi]pyridin-5-one-dihydrochloride (CP 93129). Sexual receptivity was monitored by the lordosis to mount (L/M) ratio. EO rats showed a transient decline in lordosis behavior following infusion with the saline vehicle and this was amplified by CP 93129. There were no effects of any infusion in EP rats. These findings are discussed in terms of the possible stress effect of the intracranial infusion in EO rats and their implications for a role of 5-HT_1B receptors in the response to a mild stress.