Specificity of serotoninergic involvement in the decrease of food intake induced by quipazine in the rat.

The effect of quipazine on brain monoamines and the significance of this interaction in its anorectic activity was studied in rats. At doses ranging from 2.5 to 10 mg/kg quipazine markedly reduced brain 5-hydroxyindolacetic acid concentrations without significant effects on steady-state levels of serotonin, noradrenaline and dopamine. Striatal levels of homovanillic acid were significantly reduced by 10 mg/kg of quipazine but not modified by a dose of 5 mg/kg. Quipazine counteracted the decrease of brain serotonin induced by fenfluramine but did not significantly modify the effect of 6-hydroxydopamine on brain nonadrenaline and dopamine. The decrease of food intake induced by 5 mg/kg of quipazine was completely prevented by pretreatment with methergoline but was not affected by an intraventricular injection of 6-hydroxydopamine or pretreatment with penfluridol, propranolol or phentolamine. The results indicate that at doses between 2.5 and 5 mg/kg quipazine specifically acts on brain serotonin and this interaction may be important for its anorectic activity.     

Effect of quipazine on rat plasma prolactin levels

Quipazine (2-(1-piperazinyl) quinoline maleate), a serotonin agonist which also has other effects on serotonin metabolism, in doses from 2.5 – 20 mg/kg, i.p., was found to markedly increase plasma prolactin levels in male rats. This increase was blocked by the serotonin antagonists methysergide and brom-lysergic acid diethylamide and potentiated by para-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings suggest that the increase in plasma prolactin levels is due to the serotonin agonist properties of quipazine. Apomorphine and 2-Br-α-ergocryptine pretreatment blocked the effect on plasma prolactin of quipazine, while apomorphine given 15 min after quipazine brought about a rapid decline in the elevated plasma prolactin levels produced by quipazine.     

Effects of the antiestrogens,MER-25 and CI 628, on rat and hamster lordosis

Antiestrogens were used to test the hypothesis that estrogen exerts a “maintenance,” as well as a “priming,” effect on rat and hamster sexual receptivity as it apparently does for guinea pigs. MER-25 (75 or 150 mg/kg) significantly reduced rat LQ when given ?2 hr or 8 hr after EB injection. MER-25 given at 34 hr (2 hr prior to P) failed to diminish rat LQ. With hamsters, MER-25 in large doses (750 mg/kg) given either at ?2 hr or 34 hr reduced lordosis duration to 40% of controls, but this effect was confounded by severe illness among the MER-25 injected animals. Lower doses failed to block behavior, but still produced some toxicity. CI 628 (50 mg/kg) greatly reduced hamster lordosis duration and increased lordosis latency when given 0 hr, but not 34 hr, after EB. The results are consistent with similar previous work on rats and do not support the concept of estrogen “maintenance” in either rats or hamsters.     

Role of serotonin2 receptors in regulating aggressive behavior

Quipazine and pirenperone , the drugs interacting with serotonin2 -receptors, more readily displaced 3H-spiroperidol from its binding sites in the frontal cortex than in the striatum. Pirenperone (0,07-0,3 mg/kg), antagonist of serotonin2 -receptors, selectively decreased the intensity of apomorphine aggressiveness. The antiaggressive action of haloperidol (0,01-0,2 mg/kg) was in correlation with its antistereotypic activity. Long-term administration of naloxone (0,5; 15,0 mg/kg), together with apomorphine (0,5 mg/kg) reduced the number of head-twitches caused by quipazine (2,5 mg/kg). The administration of quipazine 48 hours after the last injection of naloxone and apomorphine caused spontaneous aggressiveness that did not differ from apomorphine aggressiveness. Intracerebroventricular injection of cholecystokinin tetrapeptide (CCK-4) markedly enhanced the foot-shock aggression. The same dose of CCK-4 also decreased the intensity of quipazine (2,5 mg/kg) head-twitches. Compared to haloperidol, pirenperone was a more selective antagonist of CCK-4. After long-term apomorphine treatment (0,5 mg/kg during 10 days, twice daily), the effect of CCK-4 on aggressive behaviour was markedly enhanced. It is possible that two subtypes of serotonin2 -receptors exist in the brain and have opposite action on the aggressive behaviour. CCK-4 may play the role of an endogenous modulator of sensitivity of serotonin2 -receptors involved in the control of aggressiveness.     

Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: evidence for serotonin-catecholamine interactions

The present study tested whether administration of the serotonin agonist, quipazine maleate, affects the secretion of luteinizing hormone (LH) and prolactin (PRL) and concomitantly, the activity of central noradrenergic and dopaminergic systems. Quipazine (15 mg/kg, ip) significantly reduced LH and increased PRL when administered to ovariectomized rats. Associated with these changes, the depletion of dopamine seen after synthesis inhibition with alpha-methyl tyrosine was reduced by quipazine in the caudate nucleus and median eminence, suggesting a depression of dopaminergic activity. The depletion of norepinephrine in the median eminence was unaffected. In a second experiment, quipazine (1 microM) diminished the potassium-induced release of both norepinephrine and dopamine from fragments of medial basal hypothalamus, in vitro. Release from preoptic area was unaffected. These results suggest that central serotonergic systems may interact with noradrenergic and dopaminergic systems that regulate LH and PRL secretion, respectively.     

Paced mating behavior in female rats in response to different hormone priming regimens

A female rat will display a repertoire of behaviors during a sexual encounter with a male rat including sexually receptive (the lordosis response) and proceptive (hopping, darting) behaviors. In addition, when given the opportunity, a sexually receptive female rat will approach and withdraw from the male rat, controlling the timing of the receipt of mounts, intromissions, and ejaculations, a behavior known as paced mating behavior. The present experiments tested the hypotheses (1) that progesterone regulates paced mating behavior, and (2) that multiple hormone regimens used previously to induce sexual receptivity have the same effect on paced mating behavior. Paced mating behavior was assessed in sexually receptive ovariectomized female rats after treatment with: (1) estradiol benzoate (EB; 30.0 mg/kg) followed by a range of doses of progesterone (P; 1.0-8.0 mg/kg), (2) two pulses of unesterified estradiol (E2; 2.0 microg/rat) followed by 1.0 mg/rat of P, and (3) EB alone (5.0 microg/rat) for 6 days. No differences in sexual receptivity or in paced mating behavior were observed across doses of P (1.0-8.0 mg/kg). In contrast, the number of hops and darts per min increased with the dose of P administered. E2 + P administration resulted in slightly, but significantly, lower levels of sexual receptivity along with significantly longer contact-return latencies following an intromission in relation to the other treatment conditions. In addition, female rats exhibited fewer hops and darts per min in response to E2 + P than in response to EB + 8.0 mg/kg of P. The administration of EB alone for 6 days induced levels of receptivity and paced mating behavior indistinguishable from EB + P, while eliciting significantly fewer hops and darts per min than the EB + 8.0 mg/kg P treatment condition. Hormone priming regimen had no effect on the percentage of exits displayed during the paced mating tests in any experimental phase. Dose of P had no effect on paced mating behavior in sexually receptive rats. In addition, P does not appear to be necessary for the display of paced mating behavior following long-term treatment with EB. In contrast, the pulsatile administration of E2 + P induced a different pattern of paced mating behavior in sexually receptive rats.     

Facilitation of receptive behavior in estrogen-primed female rats by the anti-progestin, RU 486

The progestin receptor antagonist RU 38486 (henceforth referred to as RU 486) was tested for facilitative effects on female receptive behavior in ovariectomized Long-Evans rats primed with 2 micrograms estradiol benzoate (EB). RU 486 (0, 0.5, 1.6, or 5.0 mg) was administered 48 hr after estrogen priming. The lordosis quotient (LQ) and lordosis score (LS) were assessed 4 hr after RU 486 administration in a standardized test consisting of a 10-mount test by a stimulus male. A significant dose effect was found by both LQ and LS, with those subjects receiving 5 mg of RU 486 being significantly more receptive than vehicle control animals. Thus RU 486 acted as a weak progestin agonist under testing conditions typical for assessment of progestin facilitation of female sexual behavior in rats. Low levels of proceptive behavior (hops and darts) were seen in a minority of the tests, and did not vary systematically as a function of the dose of RU 486 administered. We also examined the effects of RU 486 given before progesterone (P) on receptivity in a blocking paradigm and confirmed previous reports that the antagonist significantly attenuates facilitation of sexual behavior when given in combination with P. A progestin receptor assay of the cytosols of the hypothalamus-preoptic area in estrogen-primed female rats treated with 5 mg RU 486 revealed a significantly greater depletion of available cytosolic P receptors than when rats were treated with a similarly facilitating dose of P (100 micrograms). The results suggest a possible dual mode of action for RU 486--a weak, receptor-mediated agonistic effect on sexual behavior when given alone to estrogen-primed rats, and a competitive blocking effect on receptivity when administered with P.     

Serotonin neuroleptics change patterns of preovulatory secretion of luteinizing hormone in rats

Serotonin receptor agonists or antagonists were used in this study to determine the timing and influence of serotonergic neurotransmission on phasic secretion of luteinizing hormone (LH). Daily injections of cyproheptadine (CP) or methysergide (MS), serotonin antagonists, initiated at 1600h on the day of vaginal proestrus, blocked the LH surge and ovulation. Vaginal smears remained cornified for 2–3 days. The drugs were ineffective when given at 0800h, though they terminated the LH surge prematurely when administered at 1730h. When quipazine, a serotonin receptor agonist was injected at 1400h or 2000h on proestrus, serum LH levels rose. This effect caused the LH surge to begin prematurely or to be sustained unusually long. Quipazine injected on diestrus 2 did not cause LH levels to rise, suggesting that its effect is estrogen dependent. Serotonin turnover in the hypothalamus was greater during onset of the LH surge than during its termination. When the LH surge was prolonged by exposing rats to light on proestrous evening, serotonin turnover remained high. The results of this study indicate that phasic secretion of LH on proestrus is accompanied by and may be dependent upon a period of serotonin neural activity.     

The effects of serotonin agonists on the hypothalamic regulation of sexual receptivity in Syrian hamsters

One brain region that has been implicated in the regulation of lordosis is the medial preoptic-anterior hypothalamic continuum (MPOA-AH). Previous studies have suggested that this zone may be part of the circuit mediating the effects of serotonin (5-HT) on sexual receptivity. In the present experiments, we investigated the role of 5-HT(1a/7) and 5-HT(2) receptor subtypes in the MPOA-AH in the control of lordosis. In two experiments, either 5-HT(1a/7) or 5-HT(2) agonists were injected unilaterally into the MPOA-AH of ovariectomized, hormonally primed female hamsters. In the first experiment, microinjections of the 5-HT(1a/7) agonist 8-hydroxy-2,9-(di-n-propylamino)tetralin resulted in an attenuation of the lordosis posture by causing a decrease in the mean lordosis duration and an increase in the number of lordosis episodes over the entire testing period. In the second experiment, microinjections of the 5-HT(2b/2c) agonist m-chlorophenylpiperazine did not result in any changes in sexual receptivity. However, microinjections of the 5-HT(2) agonist (2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl facilitated lordosis by increasing the mean lordosis duration and decreasing the number of lordosis episodes in the first 5 min of the testing period. These data indicate that serotonin may act in the MPOA-AH via 5-HT(1a/7) receptors to attenuate and 5-HT(2) receptors to facilitate sexual receptivity.     

The effects of progestins,mineralocorticoids, glucocorticoids,and steroid solubility on the induction of sexual receptivity in rats

In the first experiment, progesterone and its 5α-reduced metabolite, 5α-dihydroprogesterone, dissolved in two different vehicles were compared for their effectiveness in facilitating lordosis behavior in ovariectomized estrogen-primed rats. When dissolved in oil vehicle, 5α-dihydroprogesterone was less effective than progesterone. However, when dissolved in Tween 80 solution, the two progestins were equally effective. In the second experiment, adrenal corticoids dissolved in Tween 80 solution were tested for their relative ability to facilitate sexual receptivity. Progesterone, desoxycorticosterone, and desoxycorticosterone acetate were equally effective in facilitating sexual receptivity. Aldosterone, corticosterone, and corticosterone acetate were no more effective than the vehicle in facilitating sexual receptivity.     

Chin marking behavior, sexual receptivity, and pheromone emission in steroid-treated, ovariectomized rabbits

The effect of daily injections of estradiol benzoate (1 or 10 micrograms) and of progesterone (10 mg) on chin marking activity, sexual receptivity, and emission of nipple-search pheromone in ovariectomized rabbits was investigated. Both estradiol treatments resulted in a significant increase in all three measures over baseline and control group levels within 1-3 days, and withdrawal in a return to pretreatment levels within 2 weeks (Experiment I). In contrast, the administration of progesterone to such estradiol-primed does resulted in an almost immediate suppression of chin marking and lordosis, but in marked enhancement of pheromone emission and aggressive behavior (Experiment II). However, progesterone given alone to nonprimed does had no effect on any of these measure (Experiment III). The response profiles resulting from these treatments correspond well to patterns reported for intact does during estrus (= estradiol alone), pregnancy (= estradiol plus progesterone), and at parturition (= progesterone withdrawal).     

Progesterone-Facilitated Lordosis in Medial Preoptic Area-Lesioned, Juvenile Guinea Pigs

Juvenile female guinea pigs rarely display lordosis in response to estradiol and progesterone treatments that elicit sexual receptivity in adults. To test the hypothesis that the medial preoptic area (MPOA) tonically inhibits the display of steroid-induced lordosis in juveniles, 11-day-old guinea pigs were ovariectomized (OVX) and received bilateral, sham, or electrolytic lesions aimed at the MPOA 3–4 days later. At 20–22 days of age, these females were tested for the expression of sexual receptivity following injections of estradiol benzoate (EB, 10 μg sc) and progesterone (0.5 mg sc, 40 h after EB). The lesions damaged portions of the MPOA, the nucleus of the diagonal band of Broca, the lateral aspect of the medial preoptic nucleus, the medial part of the preventricular portion of the periventricular nucleus, and the anterior commissure. The lesions did not alter the display of estradiol-induced lordosis. However, after treatment with EB plus progesterone, 20% of the sham-lesioned females displayed lordosis, as compared to 80% of the MPOA-lesioned animals. These data are consistent with the hypothesis that neurons originating in and/or traversing the MPOA tonically suppress the display of progesterone-facilitated lordosis in juvenile guinea pigs. Removal of this inhibitory input allows prepubertal females to respond behaviorally to estradiol and progesterone in an adult-typical fashion.     

Independence of progesterone-induced facilitation and inhibition of lordosis behavior in ovariectomized guinea pigs

In ovariectomized Hartley guinea pigs, 15 μg progesterone was shown to facilitate lordosis in 48% of animals when administered 36 hr after a 3.3 μg injection of estradiol benzoate. This dose of progesterone also inhibited lordosis behavior in 65% of animals administered an additional 0.6 mg progesterone at 60 hr. Significant inhibition of lordosis response to the 0.6 mg progesterone existed among animals in which lordosis was not facilitated by the initial 15 μg dose of progesterone. These results show that progesterone-induced inhibition can occur without prior facilitation of lordosis as tested by the manual stimulation technique.     

Ovarian hormones,copulatory stimuli,and female sexual behavior in the Mongolian gerbil

The effects of repeated estradiol benzoate (1.0 or 3.3 μg) and progesterone (0.5 mg) injections and mating experiences (10 min or 4 hr) were examined in ovariec-tomized female Mongolian gerbils (Meriones unguiculatus) paired with sexually vigorous but unfamiliar males. Estradiol benzoate alone for 2 days did not elicit female sexual responses. Estradiol benzoate for 2 days followed by progesterone facilitated lordosis in the female. In females injected daily with 1.0 μg estradiol benzoate, progesterone exposure for approximately 1 day produced a significant inhibition in subsequent lordosis, although these females continued to respond to the male with lordosis quotients of approximately 60. A 4-hr mating experience produced a nearly complete elimination of sexual activity in tests observed 24 hr later with a fresh male. Footstomping was positively associated with sexual activity in both sexes, although females footstomped more often in the 1.0 rather than the 3.3-μg estradiol benzoate condition. Fighting was most frequent in tests in which lordosis quotients were low. Interactions among copulatory experiences and inhibitory effects of progesterone summed to terminate female sexual receptivity and alter other social interactions in the gerbil.     

Mu-, delta-, and kappa-opioid receptor agonists selectively modulate sexual behaviors in the female rat: differential dependence on progesterone.

Previous studies suggested that opioid receptor agonists infused into the lateral ventricles can inhibit (through mu receptors) or facilitate (through delta receptors) the lordosis behavior of ovariectomized (OVX) rats treated with estrogen and a low dose of progesterone. The present study investigated the behavioral and hormonal specificity of those effects using more selective opioid receptor agonists. Sexually experienced OVX rats were implanted stereotaxically with guide cannulae aimed at the right lateral ventricle. One group of rats was treated with estradiol benzoate (EB, 10 micrograms) 48 hr and progesterone (P, 250 micrograms) 4 hr before testing, whereas the other group was treated with EB alone. Rats were infused with different doses of the selective mu-receptor agonist DAMGO, the selective delta-receptor agonist DPDPE, or the selective kappa-receptor agonist U50-488. The females were placed with a sexually vigorous male in a bilevel chamber (Mendelson and Gorzalka, 1987) for three tests of sexual behavior, beginning 15, 30, and 60 min after each infusion. DAMGO reduced lordosis quotients and magnitudes significantly in rats treated with EB and P, but not in rats treated with EB alone. In contrast, DPDPE and U50-488H increased lordosis quotients and magnitudes significantly in both steroid-treatment groups. Surprisingly, measures of proceptivity, rejection responses, and level changes were not affected significantly by mu or kappa agonists, although proceptivity and rejection responses were affected by DPDPE treatment. These results suggest that the effects of lateral ventricular infusions of opioid receptor agonists on the sexual behavior of female rats are relatively specific to lordosis behavior. Moreover, the facilitation of lordosis behavior by delta- or kappa-receptor agonists is independent of progesterone treatment, whereas the inhibitory effect of mu-receptor agonists on lordosis behavior may require the presence of progesterone.     

Activation of mu-opioid receptors inhibits lordosis behavior in estrogen and progesterone-primed female rats

The present study investigated the effect of highly selective mu-opioid receptor (OR) agonists on lordosis behavior in ovariectomized rats treated with 3 microg of estradiol benzoate followed 48 h later by 200 microg of progesterone. Ventricular infusion of the endogenous mu-OR agonists endomorphin-1 and -2 suppressed receptive behavior in a time- and dose-dependent fashion. At 6 microg, both endomorphin-1 and -2 inhibited lordosis behavior within 30 min. However, while the effect of endomorphin-1 lasted 60 min, endomorphin-2 inhibition lasted up to 120 min after infusion. Pretreatment with naloxone (5 mg/kg sc) was able to block both endomorphin-1 and endomorphin-2 effects on lordosis. Site-specific infusions of endomorphin-1 or endomorphin-2 into the medial preoptic area (mPOA), the ventromedial nucleus of the hypothalamus (VMH), or into the mesencephalic central gray did not affect receptivity. In contrast, infusion of 1 mug of either compound into the medial septum/horizontal diagonal band of Broca inhibited lordosis in a pattern very similar to that seen after intraventricular infusions. Infusion of the potent synthetic mu-OR agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (0.08 microg) into the VMH and mPOA inhibited lordosis behavior for at least 60 min after infusion. The nonspecific opioid receptor antagonist naloxone was able to facilitate lordosis in partially receptive female rats when infused into the mPOA but not when infused into the VMH. The behavioral effects of the agonists and antagonist used in this study suggest that the endogenous mu-opioid system modulates estrogen and progesterone-induced lordosis behavior.     

The reversible inhibition of steroid-induced sexual behavior by intracranial cycloheximide

Cycloheximide(Cyclo), an inhibitor of protein synthesis by a direct action on protein synthesis at the ribosomal level, was used to reversibly inhibit estrogen-induced sexual receptivity. Cyclo (100 μg per rat) was infused into the preoptic area(POA) of ovariectomized rats at varying times before, simultaneously with, and after 3 μg of subcutaneous estradiol benzoate (EB). All animals received 0.5 mg progesterone (P) 36 hr after EB, and were tested for sexual receptivity 4–6 hr after P. The females were placed with stud males and a lordosis quotient was computed for each female (lordosis quotient = number of lordosis responses/20 mounts by the male × 100). Females receiving Cyclo 6 hr before, simultaneously with, or 12 hr after EB showed significantly lower levels of sexual receptivity when compared to females receiving Cyclo 36 hr before and 18 and 24 hr after EB. When those animals that showed low levels of sexual behavior after Cyclo infusion were reprimed with EB and P 7 days later and presented with a male they showed high levels of sexual receptivity. Thus, the effect of Cyclo was reversible. Only Cyclo infusions into the POA (bilateral) and third ventricle were effective in suppressing sexual behavior. Caudate nucleus, lateral ventricle, and unilateral POA infusions were without effect.The data presented are in agreement with earlier work that utilized actinomycin D to inhibit steroid-induced sexual behavior. Cyclo was found to be less toxic than actinomycin D. All of the available evidence is consistent with the hypothesis that estrogen stimulates RNA and/or protein synthesis in its facilitation of sexual behavior in the female rat.     

Serotonin type 2 antagonists inhibit lordosis behavior in the female rat: reversal with quipazine

The theory that activation of serotonin type 2 (5-HT2) receptors facilitates lordosis behavior in the female rat was tested. The 5-HT2 antagonists pizotefin, cyproheptadine, metitepine, and ketanserin were found to inhibit lordosis behavior in ovariectomized rats that had been primed with estradiol benzoate and progesterone. Pipamperone was ineffective. The 5-HT2 agonist quipazine was ineffective alone, but it reversed the inhibitory effects of pizotefin, cyproheptadine, and ketanserin. It did not reverse the effects of metitepine. The results support the theory of a facilitatory role for 5-HT2 receptors in lordosis behavior.     

GABAergic drugs and lordosis behavior in the female rat

Agents modifying GABAergic neurotransmission were administered to ovariectomized rats treated with different doses of estradiol benzoate (EB) + progesterone (P) or with EB alone. Hormone treatments were designed to induce an intermediate level of receptivity in order to be able to observe both stimulatory and inhibitory effects on lordosis behavior. Both the GABAA receptor agonist THIP and the GABAB receptor agonist baclofen inhibited lordosis behavior at doses from 20 and 5 mg/kg, respectively. The GABA transaminase inhibitor gamma-acetylen GABA (GAG) and the GABA agonist 3-aminopropanesulfonic acid had no effects, even when high doses were administered. The GABAA receptor antagonist bicuculline had no effect by itself nor did it block the effects of THIP. It is therefore suggested that the GABAA receptor is of slight importance in the control of lordosis behavior. No evidence could be found supporting the hypothesis that an interaction between P and GABA is important for hormone-induced receptivity. It does not appear likely that motor disturbances are responsible for the inhibitory effects of baclofen and THIP. The exact mechanism by which these drugs inhibit lordosis behavior is not clear at present.     

Estrogen-progesterone induction of mating in female rats

Ovariectomized female rats were administered 1, 2, 4, and 8 μg of estradiol benzoate and either 10, 25, 50, 100, or 200 μg of progesterone and were tested for sexual receptivity. The probability of lordosis was related directly to the dose of both steroids. Individual differences in hormone response were marked. Ear wiggling and hopping were primarily related to the dose of progesterone.