The current status of the platelet 5-HT(2A) receptor in depression.

The author reviews the current status of the platelet serotonin (5-HT)(2A) receptor in depression. Considered are studies of receptor binding, and 5-HT-induced platelet activation and aggregation. 5-HT(2A) receptor density tends to increase in depression, although this more clearly relates to suicidality than depression per se. Indeed, data are consistent with the hypothesis that increased density of platelet 5-HT(2A) receptors may be a marker for increased risk of suicide. 5-HT-induced calcium mobilization is enhanced in unipolar depression; however, unlike in bipolar depression, baseline calcium levels are not. Despite inconsistencies, 5-HT-induced aggregation appears inhibited in depression. This may manifest as a relative inhibition, i.e. no change in aggregation response despite a higher density of 5-HT(2A) receptors. The inhibited aggregation response is state dependent, and acute phase proteins or components of the stress response may be factors. It is unclear if differences between depressed and normal subjects in disposition of 5-HT(2A) receptors are generally indicative of traits or states. Nonetheless, there is little evidence that the degree of departure from normal density or activity of platelet of 5-HT(2A) receptors reflects severity of depression.

Effect of 5,7-dihydroxytryptamine, ovariectomy and gonadal steroids on serotonin receptor binding in rat brain.

Quantitative autoradiography was used to assess alterations in serotonin (5-HT) receptor binding in the hypothalamus and hippocampus following denervation with 5,7-dihydroxytryptamine (5,7-DHT), ovariectomy (OVX) and gonadal steroid manipulation. Seven days after 5,7-DHT injection, 5-HT1a receptor density was significantly increased in the ventromedial hypothalamic nucleus (VMN) of intact but not OVX female rats. Under these conditions 5-HT1b receptor density was unchanged in any brain region examined and 5-HT transporter binding was decreased in all 5,7-DHT injected animals. In addition, there was a significant interaction between OVX and 5,7-DHT for both the 5-HT1a receptor and the 5-HT transporter in the VMN, such that OVX inhibited the 5,7-DHT-induced increase in 5-HT1a receptors and attenuated the 5,7-DHT-induced decrease in 5-HT transporter binding. In a separate experiment the effect of gonadal steroid manipulation on 5-HT receptor binding was assessed. In female OVX rats, 5-HT1a receptor density was unchanged by estrogen or estrogen and progesterone administration. In male rats, castration significantly decreased 5-HT1a receptor density in the medial preoptic area. Estrogen and progesterone administration to female OVX rats increased the density of 5-HT1b receptors in the VMN, as compared to estrogen alone. The relationship of these results to the role of 5-HT in mediating lordosis behavior is discussed.

5-HT1A receptor agonists induce anterograde amnesia in mice through a postsynaptic mechanism.

The effect of the 5-HT1A receptor partial agonist tandospirone on memory was investigated in mice using a single trial, step-through passive avoidance task. Tandospirone disrupted performance in a dose-dependent manner when administered before the training trial but not when injected immediately post-training. The pre-training effect was not the result of reduced responsiveness to foot shock because tandospirone did not alter current threshold intensity to elicit flinch, run and vocalization responses. The performance deficit was alleviated by treatment with d-amphetamine prior to the retention test. The memory impairment by tandospirone was mimicked by the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-dipropylaminotetralin HBr) and blocked by the 5-HT1A receptor antagonist BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4]- decane-7,9-dione). BMY7378 alone was ineffective. Treatment with the 5-HT synthesis inhibitor PCPA (parachlorophenylalanine) resulted in apparent enhancement rather than disruption of the avoidance behavior. However, the anterograde amnestic effects of tandospirone and 8-OH-DPAT were not affected by PCPA, and lack of interactions between PCPA and the 5-HT1A agonists revealed in the statistical analyses indicated that the effects of PCPA were not mediated by 5-HT1A receptors. It is concluded that 5-HT1A receptor agonists and partial agonists produce a reversible anterograde amnesia that is mediated by postsynaptic 5-HT1A receptors.

Autoradiographic analyses of the effects of estradiol benzoate on [3H]paroxetine binding in the cerebral cortex and dorsal hippocampus of gonadectomized male and female rats.

Effects of estradiol benzoate (EB) on [3H]paroxetine binding in dorsal hippocampus and cerebral cortex of gonadectomized male and female rats were evaluated by quantitative autoradiography. EB significantly decreased [3H]paroxetine binding in male and female rats in the oriens layers of CA1-CA4, and in the radiata/lacunosum moleculare layers of CA2 and CA3. Sex differences were also noted, with binding of [3H]paroxetine being significantly lower in female rats in the radiata/lacunosum moleculare layers of CA2 and CA4, and in the suprapyramidal dentate. No significant effects of either EB or sex were noted in the cortex.

Alterations of serotonin receptor binding in the hypothalamus following acute denervation.

Quantitative autoradiography was used to determine the effect of acute serotonergic denervation with 5,7-dihydroxytryptamine (5,7-DHT) or serotonin 5HT1a and 5-HT1b receptors in male rats. Seven days after intrahypothalamic 5,7-DHT injection there was a significant increase in the density of 5HT1a receptors in the ventromedial and dorsomedial hypothalamic nuclei (VMN and DMN) of male rats. In adjacent sections. 5-HT1b receptors were significantly increased only in the VMN. No changes in receptor density were observed in the lateral hypothalamic area or hippocampus even though binding of [3H]paroxetine, which labels the presynaptic transporter site, was significantly decreased in all evaluated brain regions in 5,7-DHT-treated animals. In addition to demonstrating that 5-HT1a and 5-HT1b receptors are differentially regulated in different brain areas, these results show that in the brain regions examined both 5-HT1a and 5-HT1b receptors are primarily post-synaptic.

Quantitative autoradiographic analyses of the time course and reversibility of corticosterone-induced decreases in binding at 5-HT1A receptors in rat forebrain.

Quantitative autoradiography was used to evaluate the time course and reversibility of corticosterone (CORT)-induced decreases in binding at 5-HT1A receptors in the dorsal hippocampus, cortex and septum of the male rat. Continuous exposure to high levels of CORT decreased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the dentate gyrus and in the oriens and lacunosum moleculare layers of CA4 after 16 to 48 h. CORT-induced decreases in binding were also observed in the dorsal lateral septum after 2-4 days, and in the intermediate lateral septum after 4-8 days of exposure to high levels of CORT. When CORT pellets that had remained in rats for 8 days were removed 3 weeks prior to sacrifice, binding at 5-HT1A receptors increased in comparison to control values in the oriens and lacunosum moleculare layers of CA2, and in layers 4-6 of the parietal/temporal cortex. These increases in binding were associated with very low serum CORT levels, and resembled increases previously observed in those areas in ADX rats. Although removal of CORT reversed the decreases in binding in the septum, no significant increases above control values were observed. Thus, there appear to be differences in the degree of sensitivity in the various brain regions to low and high levels of circulating adrenal steroids.

Autoradiographic analyses of the effects of adrenalectomy and corticosterone on 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat.

Quantitative autoradiography was used to evaluate the effects of adrenalectomy (ADX) and corticosterone (CORT) on binding at 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat. ADX increased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the oriens and lacunosum moleculare layers of CA2 and CA3, in the lacunosum moleculare layer of CA4 region, and in the dentate gyrus. In restraint-stressed ADX rats, binding was increased only in the oriens and lacunosum moleculare layers of CA2. Restoration of baseline levels of CORT reversed the effects of ADX on 5-HT1A receptors in the hippocampus, while high levels of CORT decreased binding at 5-HT1A receptors in the dentate gyrus. No treatment affected binding at 5-HT1A receptors in the CA1 region of the hippocampus or in the cortex. ADX increased binding of [125I]iodocyanopindolol at 5-HT1B receptors in the infrapyramidal dentate, but this effect was not observed in ADX rats that were restrained. CORT treatment in both ADX and SHAM (adrenally intact) rats resulted in binding at 5-HT1B receptors that was lower than that in untreated ADX and SHAM rats in the infrapyramidal dentate, and lower than that in ADX rats in the suprapyramidal dentate and CA4. In ADX and SHAM rats, CORT also reduced binding at 5-HT1B receptors in area 2 of the cortex. It is suggested that decreases in binding at 5-HT1A and 5-HT1B/1D receptors resulting from chronic exposure to high levels of CORT may also occur in animals that fail to adapt to chronic severe stress. Such changes in binding may play important roles in the etiology of depression.

A review and reevaluation of the role of serotonin in the modulation of lordosis behavior in the female rat.

The role of serotonin (5-HT) in the modulation of sexual receptivity (lordosis) in the female rat is reviewed and reevaluated. The effects on lordosis of drug treatments that decrease or increase the activity and availability of central 5-HT are first discussed, and this is followed by an evaluation of the effects of drugs that act directly at 5-HT receptors. In order to shed light on the physiological significance of effects of serotonergic drugs on lordosis, there is also a review of what is known of changes in levels of serotonergic activity and densities of 5-HT receptors in the female rat brain that take place through the estrous cycle and in response to administration of behaviorally effective doses of gonadal steroids. Serotonin has generally been thought to have a tonic, inhibitory effect on lordosis. However, it is concluded that 5-HT can either inhibit or facilitate lordosis depending on which subtypes of central 5-HT receptors become activated. Because of a lack of consistent or compelling evidence of effects of ovarian hormones on serotonergic activity or 5-HT receptors in critical areas of the brain, it is stated that there is at present no basis to conclude that the effects of pharmacological manipulations of serotonergic activity on lordosis reflect an important, physiological role of 5-HT in the modulation of lordosis behavior in the female rat.

Autoradiographic analyses of the effects of restraint-induced stress on 5-HT1A, 5-HT1C and 5-HT2 receptors in the dorsal hippocampus of male and female rats.

Quantitative autoradiography was used to evaluate the effects of sex and either 1 or 5 daily 2-hour sessions of restraint stress on binding at 5-HT1A, 5-HT1C and 5-HT2 receptors in the rat dorsal hippocampus. Neither sex nor restraint stress were found to have effects on binding at 5-HT1C or 5-HT2 receptors. However, restraint stress increased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the CA4 region and in the infrapyramidal dentate gyrus. In addition, levels of binding at 5-HT1A receptors in the oriens and lacunosum moleculare layers of the CA1 region were significantly higher in female rats. Neither estradiol benzoate nor estradiol benzoate plus progesterone had effects on binding at hippocampal 5-HT1A receptors in ovariectomized rats, making it unlikely that the sex differences were related to stages of the estrous cycle. Stress-induced levels of corticosterone (CORT) were higher in females. Although CORT levels in blood obtained during restraint decreased from session 1 to session 5 in both male and female rats, the decrease became significant in females only. Female rats also displayed higher levels of activity in the open field. Although activity in the open field was reduced in male and female rats after restraint, these decreases were not significant. Results are discussed in relation to anxiety and depression.

Chronic testosterone propionate treatment decreases the concentration of [3H]quipazine binding at 5-HT3 receptors in the amygdala of the castrated male rat.

Chronic administration of testosterone propionate (TP) was found to decrease the concentration of [3H]quipazine binding at 5-HT3 receptors in the lateral and basal amygdaloid nuclei of the brains of castrated male rats. TP had no effect on the binding of [3H]quipazine at 5-HT3 receptors in the posterolateral or posteromedial cortical amygdaloid nuclei, or in the amygdalohippocampal areas. It is suggested that the effects of testosterone on sexual and other social behaviors in male rats may be mediated, at least in part, by decreases in the activation of 5-HT3 receptors in the amygdala.

Sex differences in the effects of 1-(m-trifluoromethylphenyl) piperazine and 1-(m-chlorophenyl) piperazine on copulatory behavior in the rat.

Peripheral administrations of TFMPP (0.2- 1 mg/kg) or MCPP (1 mg/kg) facilitated lordosis behavior in female rats treated with estradiol benzoate, and had no effects in females primed with estradiol benzoate and progesterone. In contrast, TFMPP (1 mg/kg) and MCPP (1 mg/kg) inhibited copulatory behavior in male rats. It is concluded that there are sex differences in the effects of TFMPP and MCPP on copulatory behavior in the rat. Moreover, it is suggested that the effects of these drugs on copulatory behavior may be mediated by activation of 5-HT1B and/or 5-HT1C receptors, or by blockade of activity at 5-HT3 receptors.

A correlational and factor analysis of anticipatory and consummatory measures of sexual behavior in the male rat.

This study investigated the relationship among measures of anticipatory and consummatory sexual behavior displayed by male rats in the bilevel chambers designed by Mendelson and Gorzalka (1987). Normative data from a standard test of sexual behavior were gathered from 80 intact, sexually experienced male Long-Evans rats and subjected to multiple correlational and factor analyses. The correlational analysis confirmed that several consummatory measures of copulation were related significantly, whereas the anticipatory measure, level changing, was statistically independent of consummatory measures. Factor analysis using orthogonal rotations revealed five factors that accounted for 95% of the intersubject variance for all measures: Copulatory Rate, Initiation, Hit Rate, Mount Count, and Anticipation. These results indicate that at least five conceptual mechanisms are required in any theoretical description of male sexual behavior in the bilevel chamber. In particular, the extraction of separate anticipation and initiation factors indicates that these aspects of male sexual behavior are distinct. The use of bilevel chambers thus may facilitate the identification of potential neurochemical or endocrine mechanisms associated with different aspects of male sexual motivation. In addition, several statistical techniques are discussed with the aim of reducing the elevated experiment-wise error that can occur when related measures of sexual behavior are analyzed independently.

Level searching: a new assay of sexual motivation in the male rat.

Mendelson and Gorzalka recently described a bilevel chamber for the evaluation of rodent sexual behavior. In initial studies it was observed that during 5 min adaptation periods prior to the introduction of a sexually receptive female rat, male rats with prior sexual experience in these chambers would move from level to level in apparent search for the female rat. In Experiment 1, we examined the acquisition of this level searching behavior in male rats. Sexually active male rats were given access to either sexually receptive or nonreceptive female rats following a 5 min period alone in the bilevel chamber. Only male rats that pursued and copulated to ejaculation with sexually receptive females in the bilevel chamber significantly increased the number of their level to level movements in subsequent tests during the 5 min periods prior to the introduction of the female rat. In Experiment 2, male rats that had acquired asymptotic rates of level searching showed a significant attenuation of this behavior when the presentation of a female rat into the chamber was discontinued. These findings lead us to conclude that the increase in level to level movement by the male rat represents a sexually motivated search for the female rat. We suggest that the analysis of the acquisition, maintenance, and extinction of level searching behavior might serve as a simple assay of sexual motivation in the male rat.

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.

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.

An improved chamber for the observation and analysis of the sexual behavior of the female rat.

A new chamber designed to evaluate the sexual behavior of rats was found to have distinct advantages over chambers typically described in the literature. The new testing chamber is narrow, which maintains a male and female rat in the optimal orientation for the observer to view sexual behavior, i.e., in the side view. Moreover, the chamber consists of an upper and lower level, which allows the females an avenue of escape from the male. In Experiment 1 it was shown that use of the chamber increased the reliability of data gathered in evaluating the lordosis behavior of female rats. In Experiment 2 it was shown that the new chamber could be used to evaluate the pacing of copulation by female rats.