Serotonergic 5‐HT_2A Receptors Important for the Oestradiol‐Induced Surge of Lusteinising Hormone‐Releasing Hormone in the Rat

Abstract

Serotonin (5-HT) plays a role in mediating the oestradiol-induced surge of luteinising hormone (LH), but so far the 5-HT receptor subtype involved has not been identified. Our previous in-situ hybridization and pharmacological studies suggest that the action of 5-HT involves the 5-HT2A receptor. The aim of the present study was to investigate this possibility by the direct approach of determining whether 5-HT2A receptor antagonists block the oestradiol-induced surge of luteinising hormone releasing hormone (LHRH). Adult female Wistar rats, which had shown at least two consecutive 4-day oestrous cycles, were ovariectomised under halothane anaesthesia in the morning of dioestrus and injected with vehicle (arachis oil) alone or oestradiol benzoate (OB). At 12.00 h of the next day, presumptive pro-oestrus, the animals were injected intraperitoneally with one of three 5-HT2A antagonists, a selective 5-HT reuptake inhibitor (fluoxetine), or the appropriate vehicles; hypophysial portal blood was then collected under alphaxalone anaesthesia between 15.00 and 19.00 h. The amount of LHRH released into hypophysial portal blood during consecutive 30-min periods was determined by radioimmunoassay. As expected, oestradiol, but not oil, triggered a surge of LHRH in hypophysial portal blood with a peak at about 16.00 h of presumptive pro-oestrus. This oestradiol-induced surge of LHRH was blocked by ketanserin, ritanserin and the highly selective 5-HT2A receptor antagonist, RP62203, but not by fluoxetine. These results provide the first direct evidence that the 5-HT2A receptor plays an important role in the oestradiol-induced surge of LHRH.

Serotonin stimulates female preoptic area kisspeptin neurons via activation of type 2 serotonin receptors in mice

“…The two main populations of hypothalamic kisspeptin neurons may, therefore, have different functional 5-HT receptor make-ups. Nevertheless, our observations in RP3V KISS1 neurons are in line with previous reports that ritanserin prevents the LH surge in rats ( 33 , 34 ), and that activation of 5-HT 2A and 5-HT 2C receptors restores the LH surge in DR-lesioned female rats ( 26 ). Seeing the pattern and pharmacology of RP3V KISS1 neuron responses to 5-HT – and, as discussed above, that 5-HT may primarily inhibit female GnRH neurons ( 46 ) – we propose that the stimulatory effect of 5-HT we report here might be involved in mediating the previously reported excitatory influence of 5-HT neurotransmission on the LH surge ( 27 – 30 , 32 – 34 ).…”

“…Using a dual 5-HT application protocol like that described above, we tested the impact of 5-HT 2 receptor antagonists on RP3V KISS1 neuron responses to 5-HT. As illustrated in Figure 6A , the antagonist ritanserin (5 μM), which prevents the LH surge in rats ( 34 ), almost completely blocked the effect of 5-HT in RP3V KISS1 neurons. 69 out of 85 cells (81.2%) were stimulated by 5-HT in control conditions.…”

A Novel Mechanism for Endocrine‐Disrupting Effects of Polychlorinated Biphenyls: Direct Effects on Gonadotropin‐Releasing Hormone Neurones

“…For example, PCBs can alter the levels and metabolism of neurotransmitters such as dopamine (53), norepinephrine (54) and serotonin (55). These neurotransmitter systems are all implicated in GnRH and gonadotropin release (11, 56–59) and this may be an indirect route by which PCBs affect the reproductive axis. Interestingly, dopaminergic, noradrenergic and serotonergic neurones have all been shown to concentrate oestrogen and to express oestrogen receptors (60–62); thus, the regulation of reproductive function by these neurotransmitters can be altered directly by changes in oestrogen receptor binding by PCBs.…”

Changes in the 5-HT2Areceptor system in the pre-mammillary hypothalamus of the ewe are related to regulation of LH pulsatile secretion by an endogenous circannual rhythm

“…Regarding the functional role of 5HT2 A receptors, in ovariectomized rats, they seem to be involved in the negative feedback of oestrogens on LH release [49] and in the triggering of LH surge by oestradiol [50]. As previously exposed, it was shown in ewes, that the use of specific antagonists of 5HT2 A receptors liberates the inhibition of pulsatile LHRH/LH activity during refractoriness to short days [18,19].…”