Serotonin & Ejaculation : a psychopharmacological and neuroanatomical approach

Abstract

Ejaculatory dysfunctions, such as premature or retarded ejaculation, are common human disorders that can be very stressful for patients and their partners. In recent years it became clear that ejaculatory disorders have a neurobiological rather than a psychological cause, indicating that psychopharmacological drugs might be able to treat abnormal ejaculations. In the present thesis the neurobiology of ejaculation was investigated, to gain knowledge that can be used in the development of such drugs.

Selective Serotonin Reuptake Inhibitors (SSRIs) are popular antidepressants that may cause delayed ejaculation as a side effect. The ability of SSRIs to elevate extracellular serotonin (5-HT) levels in the central nervous system is thought to underlie their influence on both mood and ejaculation. However, while acute administration of an SSRI immediately raises serotonin levels, the antidepressant and ejaculation-delaying effects take several weeks of treatment to occur. Previous research has revealed that the onset of antidepressant effects requires down-regulation of negative feedback systems, which initially normalize serotonin levels. A major component of these negative feedback systems are presynaptic 5-HT1A autoreceptors that have been shown to desensitize during chronic SSRI-treatment. Since activation of 5-HT1A receptors with selective agonists, such as 8-OH-DPAT, strongly facilitates ejaculation in rats, it is possible that desensitization of 5-HT1A receptors underlies SSRI-induced delayed ejaculation. Indeed, chronic treatment with the SSRI paroxetine (Seroxat) both delays ejaculation and reduces the facilitating effects of 8-OH-DPAT on ejaculation in rats.

Using neuroanatomical techniques, the effects of paroxetine and/or 8-OH-DPAT on neuronal activity were studied in order to locate brain areas where serotonergic drugs might alter ejaculatory behaviour. The paraventricular hypothalamic nucleus (PVH) and the locus coeruleus (LC) appeared as likely candidates. Neurons in the PVH release oxytocin in the blood and central nervous system, and neurons in the LC release noradrenalin in the brain and spinal cord. Both oxytocin and noradrenalin stimulate ejaculation. The PVH and LC receive significant serotonergic input and show altered activation patterns following treatment with serotonergic drugs. Therefore, paroxetine-induced delayed ejaculation might require not only increased serotonin levels, but also reduced release of oxytocin and/or noradrenalin during copulation.

In contrast to paroxetine, the SSRI fluvoxamine (Fevarin) failed to delay ejaculation and to prevent the effects of 8-OH-DPAT on ejaculation in rats. This is consistent with the higher degree of delayed ejaculation reported by men treated with paroxetine compared to fluvoxamine. Apparently, the ability of SSRIs to relieve depression is not strictly related to the extent of their sexual side effects. Future research should focus on the neurobiological differences between SSRIs, for example in their effect on oxytocin- and noradrenalin release, which can be of the great importance for patients suffering of depression of ejaculatory disorders. In addition to these psychopharmacological and neuroanatomical experiments, a third approach to study ejaculatory dysfunctions was used. When male rats are allowed to interact with an estrous female for half an hour, the majority displays two or three ejaculations. However, a small portion of the rats in our lab either ejaculates much less or much more. This abnormal behaviour appeared to remain stable during six sexual behaviour tests, and did not correlate with anxiety levels, suggesting a neurobiological rather than psychological origin. Therefore, these rats might be used as an animal model for human ejaculatory disorders, and should be investigated further.