Endocannabinoid system in sexual motivational processes : Is it a novel therapeutic horizon ?

Renata Androvicova, Jiri Horacek, Tibor Stark, Filippo Drago, Vincenzo Micale

Pharmacological Research, 2017, 115, 200–208

http://dx.doi.org/10.1016/j.phrs.2016.11.021

 

a b s t r a c t

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1
and CB2) for marijuana’s psychoactive ingredient 9-tetrahydrocannabinol (9-THC), the endogenous
ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation,
recently emerged as important modulator of emotional and non-emotional behaviors. For centuries,
in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use
in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated.

The identification of 9-THC and later on, the discovery of the ECS have opened a potential
therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment. In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.

Keywords : Endocannabinoids, 9-THC, Cannabinoid, CB1 receptor, Sexual behavior

 

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 200

2. Effects of pharmacological modulation of the endocannabinoid system on sexuality . . . 201

2.1. Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201

2.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . 204

3. Conclusive remarks and future prospective .  . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . 206

Conflict of interest. . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . .207

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . 207

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

 

1. Introduction

Sexual activity is a motivated behavior (or motivational pro-cess) performed by all vertebrates to ensure genetic variance withina species and guarantee its survival. It consists of two distinctphases: precopulatory phase, characterized by various species-specific attractive and courtship behaviors, and copulatory phase, characterized by the contact of male and female genitalia and semen emission. Within these phases, the appetitive aspect which reflects the motivation to engage in a particular behavior after adequate sensory stimulation and the consummatory aspect which is the physical performance and a completion of a particular motivational program are distinguished [1]. Both phases are regulated by the interaction among steroids, neuropeptides (e.g. prolactin, oxytocin) and neurotransmitters, such as dopamine (DA) or serotonin (5-HT), which facilitate or inhibit the appetitive phase, respectively [2–4].

Cannabis is the most frequently abused recreational substance in the Western society, which popularity is due to its capacity to alter sensory perception, to increase sociability and to induce euphoria [5]. Although Cannabis has been used by humans since time immemorial, only in the last five decades the identification of -9-tetrahydrocannabinol (9-THC) as the main psychoactive component of Cannabis in 1964 [6] and later on, the cloning of specific cannabinoid CB1 and CB2 receptors [7] and the discovery of the endogenous cannabinoid system (ECS) in the brain has triggered an exponential growth of studies which have suggested that its dysregulation (both in terms of cannabinoid receptors and endogenous ligands AEA and 2-AG) is associated with several pathological conditions such as pain and inflammation [8], obesity, metabolic [9],gastrointestinal [10], hepatic [11], neurodegenerative [12–14] and psychiatric disorders [15–20]. However, the exact pathophysiological mechanisms through which the ECS controls these functions are not fully elucidated yet.In addition to its recreational actions, the effects of Cannabis on sexual functioning had been documented for centuries, stressing the biphasic actions of Cannabis on sexual desire such as aphrodisiac and antiaphrodisiac effects, depending on timing, dosage and users [21]. Although the enhanced EC tone seems to inhibit sexual motivation, as the opioid or the 5-HTergic system [22]; this simple conclusion does not reflect the effects described in the pre-clinical and clinical studies. First, some factors (i.e. time delays in occurrence of some behavior or reaction) cannot be simply interpreted as a motivation inhibition, especially with cannabinoids which are known to change sense of time. Second, the cannabinoid CB1 receptors activation affects differently each phase of sexual motivation in animals (i.e. proceptive, receptive behaviors) [23] and last, but not least, human Cannabis users often reported “increased sexual pleasure” and “increased sexual arousal” [24]. Thus, the goal of this review is to outline the current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of all aspects of sexual motivation and behavior in preclinical and human studies (we will not discuss effects on conception and pregnancy as these are beyond the scope of this review). Furthermore, we try to suggest how the pharmacological modulation of the EC signaling could be a potential therapeutic target in sexual dysfunction.

2. Effects of pharmacological modulation of theendocannabinoid system on sexuality

2.1. Preclinical studies

It is well accepted that sexual behavior both in humans and in other mammals is regulated by different mechanisms (e.g.psychological, neurological, endocrinological) and modulated by physiological and pathological conditions which in turn are affected by several drugs; thus it is not surprising that often detrimental effects on sexual activity occur following pharmacological treatment. As consequence, pharmaceutical companies make all efforts to test “sexual health” compounds in a predictive and safe manner. Thus, of central importance to this approach is the availability of valid preclinical animal models, both for the evaluation of the potential efficacy of novel compounds and for further understand-ing of neural mechanisms that underlie the psychophysiological and pathological aspects of sexuality. Optimally, an experimental animal model should reflect the human sexual disorders in terms of face validity (reproduce the symptoms of the dysfunction observed in human), construct validity (the same neurochemical mechanisms in humans as in the animal model) and predictive validity (pharmacological treatment must reverse the phenotype of the animal model). In the case of sexual dysfunctions, although the experimental animal models are scarce and each with some limitations, they give us the opportunity to study several aspects of this disorder [25]. Due both to the highly developed observational analysis, and to the increased understanding of the neurobiology of physiological and pathological sexual functioning, animal sexual behavior was assessed in details and through different components in both sexes. In general, rat sexual behavior is an interaction between females and males in which they show several movements to attract the opposite sex and reach sexual excitement. It is divided into several phases :

1) attractivity, characterized by approaching the other sex and sniffing theanogenital regions to obtain pheromonal cues of sexual receptivity;

2) proceptivity, which consists of various female-mediated behaviors (i.e. hopping, darting and ear wiggling to maintain sexual interaction and further improve sexual arousal in herself and in a male counterpart);

3) receptivity (i.e. lordosis in female and repeated mounts and intromissions in male)

and 4) ejaculation in male rats, without scientifically validated counterpart in females (orgasm?) [1,26–28]. Interestingly, they seem to be driven by several neurotransmitter systems [29,30] and they could be evaluated under various hormonal regimens (e.g. physiological, ovariectomy, orchidectomy, estradiol- and progesterone-primed, testosterone-primed) [31–35].

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Androvicovaetal.2017PharmacolRes