Elsevier

Brain Research

Volume 821, Issue 2, 13 March 1999, Pages 414-425
Brain Research

Research report
Modification of sexual behavior of Long–Evans male rats by drugs acting on the 5-HT1A receptor

https://doi.org/10.1016/S0006-8993(98)01129-9Get rights and content

Abstract

Modulation of the sexual behavior of male rats by the anxiolytic buspirone (S-20499) and its analog gepirone were compared to the effects of 8-OH-DPAT (or DPAT, a selective 5-HT1A reference agonist), and BMY-7378 (a selective 5-HT1A partial agonist). Long–Evans rats were used; modulation of copulatory behavior and alteration of penile reflexes were examined. Modulation of copulatory behavior was assessed by three indices: frequency and length of intromission, and latency of ejaculation. DPAT, at doses of 1–8 mg/kg, reduced these three indices in a time dependent manner such that the effects peaked at 45 min and normalized at 90 min. The dose–effect relationship (assessed 45 min after DPAT injection) is bell-shaped with an ED50 approximately 1 mg/kg on the ascending limb of the curve. The effects of buspirone (2 mg/kg) and gepirone (2 mg/kg) on copulatory behavior were indistinguishable from control. BMY-7378 alone and in combination with these other 5-HT1A agonists reduced copulatory behavior, though not statistically significant. Penile reflexes, including number of erections, cups and flips, were inhibited by these agents: DPAT>buspirone>gepirone (inactive at 2 mg/kg). Furthermore, the latency period to erection was at least doubled by DPAT (2 mg/kg). Buspirone and gepirone, however, reduced the latency period to erection. BMY-7378 inhibited penile reflexes when administered alone and even more in combination with DPAT or buspirone. Two butyrophenone analogs, spiperone (a 5-HT1A and dopamine D2 antagonist) and haloperidol (a D2 antagonist), were also tested for their interaction with DPAT. Both of these drugs (at 0.25 mg/kg, 60 min after administration) reduced all indices of penile reflexes and copulation. Furthermore, in combination with DPAT (2 mg/kg, 45 min), the effects were synergistic such that sexual activity came nearly to a standstill. These opposing effects on putatively brain originated copulatory behavior and spinal mediated penile reflexes indicate that the effects of buspirone and DPAT on sexual behavior in the male rat may be possible at different parts of the central nervous system. If a tentative shared target site by DPAT and buspirone is the 5-HT1A receptor, than the same 5-HT receptor sub-type at different locations (brain, raphe nuclei, spinal cord and autonomic ganglia) may modulate rat sexual behavior in opposing ways.

Introduction

Drugs that act upon the central nervous system (CNS) are known to modulate sexual behavior in a variety of species 5, 17, 28, 45. Noradrenergic 11, 12and dopaminergic role(s) 25, 42in sexual behaviour are well characterized. The role of the serotonergic system, however, is still controversial [19].

Serotonergic compounds are more difficult to study than adrenergics and dopaminergics because they appear to have an inhibitory effect on sex drive centrally, but an erectogenic effect peripherally. For example, 5-methoxy-N,N-dimethyltryptamine (5-MXDMT, a non-specific 5-HT agonist)[52]was studied for its effects upon penile reflexes in intact and spinal cord transected rats. The authors postulated that the stimulation of serotonin receptors located on autonomic preganglionic or lumbar spinal motor neurons were responsible for ejaculation, followed by suppression of erection. In contrast, DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin), which acts as a specific 5-HT1A agonist in brain [52], and selectively labels the 5-HT1A binding sites [24], was reported to enhance rat copulatory activity primarily by shortening the latency to ejaculation [38]. The results on male sexual behavior is more complex [21]. For example, penile erections are elicited by agents that stimulate 5-HT1B and 5-HT2C receptor sites [10]. In contrast male rat copulatory behavior is inhibited by agents that stimulate 5-HT1B and 5-HT2C[36]or 5-HT2 receptor sites [54], but facilitated by agents that stimulate 5-HT1A receptor sites [33]. Recently, similar results have been found in the rhesus monkey [41].

Sexually dimorphic motor neurons that regulate penile reflexes in the rat have been shown to be located within the anterior horn of the lumbosacral spinal cord [49]. Spinal cord transection studies in rats, and observations in spinal cord injured patients, have demonstrated that penile reflexes are subject to inhibitory supraspinal control [30]. The penile reflexes elicited in the restrained supine rat whose spinal cord is intact, with the penile sheath retracted, are believed to be the counterpart of penile activity during copulation [40].

In this study we report on modulation of both copulatory behavior and penile reflexes elicited in male Long–Evans rats by DPAT, buspirone, and its analog gepirone, as well as BMY-7378 (a proposed 5-HT1A partial agonist). In addition, the interaction of two butyrophenone analogs, spiperone 13, 14, 53(a 5-HT1A and dopamine D2 antagonist) and haloperidol [4](a D2 antagonist) were tested alone and in combination with DPAT.

Section snippets

Animals

Five-month-old male Long–Evans rats (Simonsen Labs, Gilroy, CA; n=96) were used, each weighing between 200–300 g. All rats were fed Purina lab rodent chow, and housed in groups of two. Light was cycled on from 0700 to 1900; temperature and humidity were constant. All 96 rats selected had been shown to respond with reflexes and copulation during three screening procedures. Since the original observations of sexual behavior modifications by DPAT were made on male Sprague–Dawley rats [2], it was

Dose and time-dependent copulatory responses to DPAT, buspirone and gepirone

Five of the six rats treated with saline and all those treated with these drugs displayed full copulatory behavior prior to any drug administration. The time-dependent effects of DPAT (2 mg/kg) upon indices of copulation are shown in Fig. 1. Frequency of intromission (Fig. 1A), length of intromission (Fig. 1B), and latency of ejaculation (Fig. 1C), nadired at approximately 45 min, and normalized either partly or completely by 90 min. This pattern was consistent and it allowed for reassessment

Discussion

Sexual behavior in the male rat involves the activation of two different mechanisms. The first, the arousal mechanism, mediates the initiation and maintenance of sexual excitement. This culminates in a copulatory response, a manifestation of the second aspect. The gain of the arousal mechanism is reflected in the latencies of mounting and intromission. The execution of copulatory and ejaculatory reactions is held to be dependent upon the copulatory mechanism, the gain of which is reflected in

Acknowledgements

The authors thank Dr. Benjamin Sachs for his advice. This work was supported in part by grant GM 34852 from the National Institute of General Medical Sciences.

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