Lynda Uphouse

Multiple serotonin receptors: Too many, not enough, or just the right number?

In this manuscript, current knowledge about central nervous system serotonin (5-HT) receptors is discussed with an emphasis toward describing the functional significance of the multiple 5-HT receptors. Five characteristics of 5-HT receptors, which are hypothesized to contribute to this functional significance, are discussed: (a) 5-HT has varying affinity and potency for the different receptor subtypes; (b) multiple transduction pathways are used by the different receptor subtypes; (c) receptor subtypes differ in their susceptibility to agonist-mediated desensitization/downregulation; (d) receptor subtypes interact in mediating cellular responses to the neurotransmitter; and (e) receptor subtypes respond differently to changes in the physiological environment. It is hypothesized that these characteristics of the multiple neurotransmitter receptors provide the nervous system with a capacity for coding and decoding of 5-HT-mediated neuronal transmission that could not take place with a single neurotransmitter receptor. Serotonergic regulation of female reproduction and regulation of glucocorticoid release are used to illustrate the integrative potential deriving from the existence of multiple 5-HT receptors.

Estrous cycle modulation of extracellular serotonin in mediobasal hypothalamus: role of the serotonin transporter and terminal autoreceptors

In vivo microdialysis was used to examine extracellular serotonin (5-HT) in the mediobasal hypothalamus (MBH) of male and female Fischer (CDF-344) rats. Females from the stages of diestrus, proestrus, and estrus were used. Additionally, ovariectomized rats, primed subcutaneously (s.c.) with estradiol benzoate or estradiol benzoate plus progesterone were examined. Extracellular 5-HT in the MBH varied with stage of the estrous cycle and with the light/dark cycle. Proestrous females had the highest microdialysate concentrations of 5-HT during the light portion of the light/dark cycle and lowest concentrations during the dark portion of the cycle. Diestrous females had the highest levels during the dark portion of the cycle, while males and estrous females showed little change between light and dark portions of the cycle. In ovariectomized rats, there was no effect of 2.5 microg or 25 microg estradiol benzoate (s.c.) on extracellular 5-HT; but the addition of 500 microg progesterone, 48 h after estrogen priming, reduced microdialysate 5-HT near the threshold for detection. In intact females and in males, reverse perfusion with 3 microM fluoxetine, a selective serotonin reuptake inhibitor (SSRI), or 2 microM methiothepin, a 5-HT receptor antagonist, increased microdialysate concentrations of 5-HT. Estrous females and males showed nearly a 4-fold increase in microdialysate 5-HT in response to fluoxetine while smaller responses were seen in diestrous and proestrous rats. In contrast, proestrous rats showed the largest response to methiothepin. Estrous females showed a delayed response to methiothepin, but there was no methiothepin-induced increase in extracellular 5-HT in males. These findings are discussed in reference to the suggestion that extracellular 5-HT in the MBH is regulated in a manner that is gender and estrous cycle dependent. The 5-HT terminal autoreceptor may exert a greater role in proestrous females; the serotonin transporter appears to play a more active role in the regulation of extracellular 5-HT in estrous females and in males.

Female gonadal hormones, serotonin, and sexual receptivity

The inhibitory and facilitatory effect of serotonergic (5-HT) receptor agonists and antagonists on the female rat lordosis reflex is reviewed. Emphasis is placed on the role of 5-HT(1A) and 5-HT(2) receptors. The effect of estrogen and progesterone on the lordosis response to 5-HT receptor-selective compounds is reviewed and potential mechanisms for hormonal modulation of the 5-HT system are suggested. Evidence that 5-HT modifies the females position relative to a threshold for lordosis is presented. Finally, it is hypothesized that 5-HTs dual regulation of lordosis contributes to the females ability to regulate mating behavior so that it occurs under physiological and environmental conditions that are conducive for individual, as well as species, survival.

Gender and estrous cycle differences in the response to the 5-HT1A agonist 8-OH-DPAT.

The effects of the 5-HT1A agonist, 8-hydroxy-2-9(di-n-propylamino)tetralin (8-OH-DPAT) on eating behavior and on rectal temperature were examined in adult male rats and in diestrous, proestrous, and estrous female rats. The 5-HT1A agonist produced evidence of hyperphagia at some dose (0.125, 0.25, 0.5 and 1.0 mg/kg) in all groups examined. However, hyperphagia was most evident in diestrous females and least evident in proestrous and estrous rats. These findings are interpreted as an estrous cycle modulation of somatodendritic 5-HT1A autoreceptors. The hypothermic response to 8-OH-DPAT was present in all females and at all doses of 8-OH-DPAT (0.1, 0.25 and 0.5 mg/kg). These findings suggest that postsynaptic 5-HT1A sites involved in 8-OH-DPAT-induced hypothermia do not vary during the estrous cycle. However, males showed less hypothermia following 8-OH-DPAT than did females. The gender difference was evidenced primarily as a slower onset of hypothermia in males treated with the lower doses of the drug.

Gender and estrous cycle effects of the 5-HT1A agonist, 8-OH-DPAT, on hypothalamic serotonin

Effects of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.04, 0.25, or 1.0 mg/kg), on hypothalamic serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and their ratio were determined in adult male rats and in diestrous, proestrous, and estrous female rats. Consistent with its action at the somatodendritic 5-HT1A autoreceptor, 8-OH-DPAT decreased the 5-HIAA/5-HT ratio, but the decrease was least evident in proestrous females and in males. Similar to hypothalamic tissue, there was also a decline in the 5-HIAA/5-HT ratio in the hippocampus after treatment with 0.25 mg/kg 8-OH-DPAT. When ovariectomized rats were treated with oil or estradiol benzoate followed 48 h later by oil or progesterone, 0.25 mg/kg 8-OH-DPAT produced a decrease in the hypothalamic 5-HIAA/5-HT ratio in every group except those rats treated with progesterone without estrogen priming. Treatment with estradiol benzoate increased hypothalamic 5-HIAA, and both progesterone and 8-OH-DPAT reduced the metabolite to the level of the ovariectomized control. These results suggest that both estrogen and progesterone contribute to an estrous cycle modulation of the 5-HT1A somatodendritic autoreceptor.

Effects of the 5-HT1A agonist, 8-OH-DPAT, on sexual behaviors of the proestrous rat

The effects of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were examined in intact, proestrous rats. Although this compound has been reported to inhibit sexual receptivity of hormonally primed, ovariectomized rats, this is the first report of its effect in intact females. After intraperitoneal treatment with 8-OH-DPAT (0.01 to 0.25 mg/kg), there was a dose-dependent suppression of lordosis behavior. The inhibition occurred within 10-15 min after the higher doses and lasted at least an hour after treatment. When females were treated with 1 mg/kg trifluoromethylphenyl piperazine (TFMPP) 30 min prior to treatment with 0.1 mg/kg 8-OH-DPAT, females recovered more rapidly from the inhibitory effects of 8-OH-DPAT. After bilateral, intrahypothalamic infusion of 50 to 1000 ng 8-OH-DPAT, inhibition of sexual behavior resembled that seen following systemic treatment with 0.1 mg/kg 8-OH-DPAT, females recovered more rapidly from the inhibitory effects of 8-OH-DPAT. After bilateral, intrahypothalamic infusion of 50 to 1000 ng 8-OH-DPAT, inhibition of sexual behavior resembled that seen following systemic treatment. Cannula locations in the ventromedial hypothalamus, but not the posterior hypothalamus, produced rapid inhibition of lordosis behavior. Both the frequency and the quality of lordosis behavior were reduced within 5 to 10 min after bilateral infusion of 200 to 1000 ng (but not 50 ng) 8-OH-DPAT, and females often successfully avoided attempted mounts by the male. These results suggest that activation of ventromedial hypothalamic 5-HT1A receptors reduces lordosis behavior.

Facilitation of female rat lordosis behavior by hypothalamic infusion of 5-HT2A/2C receptor agonists

Ovariectomized rats were hormonally primed with 0.5 microg estradiol benzoate and 500 microg progesterone to produce two groups of rats differing in their lordosis behavior. Females with a lordosis to mount (L/M) ratio < 0.5 were used to test the hypothesis that 5-HT(2A/2C) receptor agonists could facilitate lordosis behavior. Females with L/M ratios > or = 0.5 were used to evaluate the potential suppressive effect of 5-HT(2A/2C) receptor compounds. Lordosis behavior was examined following bilateral infusion of drugs into the ventromedial nucleus of the hypothalamus (VMN). Drugs examined were the 5-HT(2A/2C) receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), the 5-HT(2A/2C) receptor antagonist, 3-[2-[4-(4-fluorobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quinazoli nedione tartrate (ketanserin tartrate), and the non-selective 5-HT receptor agents, 2-(1-piperazinyl)quinoline dimaleate (quipazine) and N-(3-trifluoromethylphenyl)piperazine HCl (TFMPP). Drugs with agonist action at 5-HT(2A/2C) receptors increased lordosis behavior in rats with low sexual receptivity. The 5-HT(2A/2C) receptor antagonist, ketanserin, inhibited lordosis behavior in sexually receptive rats. DOI attenuated the lordosis-inhibiting effect of ketanserin, but ketanserin was less effective in preventing DOI from increasing lordosis behavior. These results strengthen prior inferences that activation of 5-HT(2A/2C) receptors can facilitate lordosis behavior and that the VMN is one site at which such facilitation can occur.

Estradiol modulation of the hyperphagia induced by the 5-HT1A agonist, 8-OH-DPAT.

Ovariectomized rats were primed with sesame oil or estradiol benzoate followed 48 h later by either sesame oil or progesterone. Four hours later, rats were treated with either saline or 0.25 mg/kg 8-hydroxy-2-9(di-n-propylamino)tetralin (8-OH-DPAT). Rats were allowed to eat for 4 h after this final treatment. Animals in all hormonal conditions showed hyperphagia following 8-OH-DPAT. However, the hyperphagia was significantly attenuated by pretreatment with estradiol benzoate. There was no effect of progesterone on the hyperphagic response. These results suggest that previous findings of an estrous cycle modulation of the hyperphagic response to 8-OH-DPAT arise from the modulatory effects of estradiol, and not progesterone, during the female reproductive cycle.

Prior Treatment with Estrogen Attenuates the Effects of the 5-HT1AAgonist, 8-OH-DPAT, on Lordosis Behavior

The effects of repeated treatment with estradiol benzoate to ovariectomized rats on the lordosis-inhibiting action of the 5-HT1A agonist, 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT), were examined. In the first week of hormonal priming, when rats were injected with estradiol benzoate (2.5-50 micrograms) plus 500 micrograms progesterone, all groups were inhibited by intraperitoneal (i.p.) treatment with 0.15 mg/kg 8-OH-DPAT. However, in the second week of hormone treatment, the effects of 8-OH-DPAT on lordosis behavior were dose-dependently attenuated by estradiol benzoate. Such attenuation was present when animals were treated with estradiol benzoate on the day of ovariectomy and when the first estradiol benzoate treatment was delayed for 2 weeks after ovariectomy. At least 3 days after the first injection with estradiol benzoate were required before the inhibitory effects of i.p. treatment with 8-OH-DPAT were attenuated. Although the magnitude was reduced, higher doses of 8-OH-DPAT (0.4, 0.45, and 0.5 mg/kg) continued to inhibit lordosis behavior even after the second hormonal priming. When 8-OH-DPAT was infused directly into the ventromedial nucleus of the hypothalamus (VMN), the lordosis-inhibiting effects of 8-OH-DPAT were reduced as soon as 2 days after the first estradiol benzoate injection. These data are interpreted as evidence that (1) estradiol benzoates attenuation of the effects of 8-OH-DPAT on lordosis behavior is both dose and time dependent; (2) 5-HT1A receptor action in the VMN is attenuated by the hormone treatment; and (3) female gonadal hormones reduce the potency of the 5-HT1A agonist, 8-OH-DPAT, in inhibiting lordosis behavior.

Estrogen and progesterone dose-dependently reduce disruptive effects of restraint on lordosis behavior

Ovariectomized rats were hormonally primed with various doses of estradiol benzoate (EB; 0.5-10 microg) in combination with various doses of progesterone (2.5-500 microg) to induce sexual receptivity. Females were then subjected to 5 min restraint and the effect on lordosis behavior was monitored for the next 30 min. Such mild stress has been previously shown to transiently reduce lordosis behavior of ovariectomized females hormonally primed only with 10 microg EB. In the current study, doses of progesterone of 25 microg or more in combination with 10 microg EB reduced the effects of restraint. Also priming doses of EB from 4.0 to 10 microg in combination with 250 microg progesterone prevented the lordosis-inhibiting effects of restraint. These findings reinforce prior observations of the dose-dependency of both estrogen and progesterone in the facilitation of lordosis behavior and introduce the females lordosis response to mild restraint as a potentially useful index of the females response to stress.