Very promising theory on PSSD being caused by changes in Kisspeptin expression
Posted: Fri Aug 26, 2022 6:51 pm
I was researching Kisspeptins after Dr. Healy put up his new RxISK Research Forum for Enduring Sexual Dysfunction. I think that these peptides could explain PSSD. See literature review below. I have also copied and pasted the passages that I found most relevant.
Mills, Edouard G., et al. "Current Perspectives on Kisspeptins Role in Behaviour." Frontiers in Endocrinology (2022): 1165.
https://www.frontiersin.org/articles/10 ... 28143/full
Humans with inactivating mutations of KISS1 or KISS1R display a phenotype of hypogonadotropic hypogonadism (6, 7), whereas activating mutations of KISS1 or KISS1R causes central precocious puberty (13).
Peripheral Kisspeptin Expression
Moreover, abundant Kiss1 and Kiss1r expression is detected in peripheral reproductive organs in rodents, including ovary (35), uterus (37) and testes (38). Regarding humans, KISS1 mRNA expression is principally found in the placenta and testis, as well as moderate expression levels in the liver, pancreas, small intestine (9, 11).
Sexual Partner Preference and Sexual Motivation
In a landmark study in 2007 which triggered much of the recent interest in kisspeptin and behaviour, whereas wildtype male mice spend >70% of their investigatory time with female stimulus animals, gonad intact Kiss1r knockout (KO) male mice exhibit no preference for either sex and spend an equivalent investigatory time with male and female conspecifics, despite normosmia (56). Of note, testosterone replacement in these mutant mice fails to restore normal partner preference (56), highlighting a key role for the kisspeptin receptor specifically in controlling sexual partner preference. Similarly, using the chemogenetic DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) approach to selectively stimulate kisspeptin neurons in the posterodorsal subnucleus of the MeA (MePD), doubles the time male mice spend investigating an oestrous female over another gonadally-intact male (57).
Moreover, a very recent study examined the effects of kisspeptin on sexual motivation and its dependence on testosterone levels in male rodents (58). In this study, behavioural effects with an oestrous female were evaluated following intranasal administration of a GnRH analogue (buserelin), intraperitoneal kisspeptin or intranasal kisspeptin. Intranasal buserelin increased circulating testosterone levels but did not affect behavioural measures of sexual incentive motivation, whereas intraperitoneal kisspeptin increased both circulating testosterone and sexual motivation. Notably, intranasal kisspeptin also increased sexual motivation, despite not affecting circulating testosterone levels (58). Taken together, these data provide interesting insight for GnRH/testosterone-independent kisspeptin-effects to stimulate sexual motivation in male rodents.
A similar critical role for kisspeptin-signalling in regulating sexual partner preference in female rodents has been observed in a key elegant study. Ovariectomised and hormone-primed Kiss1 KO mice fail to display normal male-directed preference, whereas a single peripheral injection of kisspeptin resolves this deficit (59). Interestingly, selective viral ablation of AVPV kisspeptin neurons also results in female mice failing to display any male-direct preference, which again resolves following a single peripheral injection of kisspeptin (59), indicating site-specificity of the AVPV for kisspeptins control of mate preference in female mice. Furthermore, exploiting a transgenic GnRH deficient mouse model (which progressively loses GnRH expression during adulthood) results in female mice displaying female rather than male-directed preference, which normalises following a single peripheral injection of GnRH (but not kisspeptin) (59). This indicates that kisspeptin signals through GnRH neurons to specifically mediate sexual partner preference.
Copulatory Behaviour and Arousal
Preclinical Animal Studies
The MeA is a key brain region involved in sexual behaviour. Lesioning of the MeA in rats suppresses male copulatory behaviours such as erections and intromissions (72, 73). Although androgen receptors are present in the MeA (74), direct administration of androgens does not cause spontaneous erections (75), suggesting that additional factors are required to stimulate this physiological pathway. In keeping with this, microinjections of kisspeptin directly into the MeA of male rats dose-dependently stimulates ex-copula erections, an effect blocked by pre-treatment with a kisspeptin receptor antagonist (76). Furthermore, when kisspeptin is infused into the intracerebroventricular space, no erections are observed (despite comparable rises in circulating LH), demonstrating site-specificity of the MeA for kisspeptin’s effects on rodent erections and crucially suggests its role in this aspect of sexual behaviour is independent of downstream GnRH, LH or testosterone (76).
Human Studies
In healthy heterosexual men, peripheral administration of kisspeptin enhances limbic brain activity (as determined by fMRI) in response to visual sexual stimuli, including the anterior and posterior cingulate and amygdala (78). Given that desire for sexual stimulation is an important component of the human sexual response (79), it is intriguing that in this study the greater kisspeptin enhanced limbic brain activity (including in the putamen) to sexual images, the less aversion to sex healthy men displayed (determined using behavioural tests). Moreover, in response to sexual images, kisspeptin was observed to activate limbic structures (including the hippocampus) more in men with lower baseline reward behavioural scores, which is highly relevant given that human sexual behaviour is closely associated with pleasure and reward.
Mood and Emotions
Kisspeptins antidepressant-like effects have been identified in male mice using a modified forced swimming paradigm (90). During this test, rodents are placed into a container filled with water and assessed for active (swimming and climbing) and passive (immobility) behaviours, suggestive of anti-depressant and depressant effects, respectively (91). This study revealed that intracerebroventricular delivery of kisspeptin increased antidepressant-like behaviours (climbing and swimming times), whilst reducing the duration of immobility (90). Regarding interplay with downstream systems, pre-treatment with a nonselective α-adrenergic, α2-adrenergic or nonselective 5-HT2 serotonergic receptor blocker abolished kisspeptins anti-depressive actions, whereas pre-treatment with a cholinergic, dopaminergic or GABAergic receptor blocker had no effect on kisspeptins actions. Therefore, the results from these receptor blockade experiments indicate that kisspeptin can interplay with downstream adrenergic and serotonergic systems to bring about antidepressant-like effects (90).
Given the interaction between kisspeptin and the serotonergic system, it is interesting to consider the brain regions involved in eliciting the antidepressant-like effects. In a recent study, adult male rats received four weeks of intraperitoneal escitalopram (92), a widely prescribed selective serotonin reuptake inhibitor for mood disorders, which increases serotonin activity in the brain by limiting its reabsorption. This experimental paradigm significantly upregulated Kiss1 mRNA expression in the amygdala (272% increase compared to saline treated rats). Furthermore, Kiss1r mRNA was highly increased in the hypothalamus, hippocampus and cerebellum by 170%, 177% and 131%, respectively (92). Indeed, these findings are congruent with a previous study demonstrating that intra-cerebroventricular injections of serotonin hydrochloride to male rats significantly enhances hypothalamic kisspeptin expression and resultant circulating LH concentrations (93). Collectively, these data garner further evidence for the interplay between kisspeptin and the serotonergic system in eliciting antidepressant actions, as well as evidence for the putative brain regions involved.
Mills, Edouard G., et al. "Current Perspectives on Kisspeptins Role in Behaviour." Frontiers in Endocrinology (2022): 1165.
https://www.frontiersin.org/articles/10 ... 28143/full
Humans with inactivating mutations of KISS1 or KISS1R display a phenotype of hypogonadotropic hypogonadism (6, 7), whereas activating mutations of KISS1 or KISS1R causes central precocious puberty (13).
Peripheral Kisspeptin Expression
Moreover, abundant Kiss1 and Kiss1r expression is detected in peripheral reproductive organs in rodents, including ovary (35), uterus (37) and testes (38). Regarding humans, KISS1 mRNA expression is principally found in the placenta and testis, as well as moderate expression levels in the liver, pancreas, small intestine (9, 11).
Sexual Partner Preference and Sexual Motivation
In a landmark study in 2007 which triggered much of the recent interest in kisspeptin and behaviour, whereas wildtype male mice spend >70% of their investigatory time with female stimulus animals, gonad intact Kiss1r knockout (KO) male mice exhibit no preference for either sex and spend an equivalent investigatory time with male and female conspecifics, despite normosmia (56). Of note, testosterone replacement in these mutant mice fails to restore normal partner preference (56), highlighting a key role for the kisspeptin receptor specifically in controlling sexual partner preference. Similarly, using the chemogenetic DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) approach to selectively stimulate kisspeptin neurons in the posterodorsal subnucleus of the MeA (MePD), doubles the time male mice spend investigating an oestrous female over another gonadally-intact male (57).
Moreover, a very recent study examined the effects of kisspeptin on sexual motivation and its dependence on testosterone levels in male rodents (58). In this study, behavioural effects with an oestrous female were evaluated following intranasal administration of a GnRH analogue (buserelin), intraperitoneal kisspeptin or intranasal kisspeptin. Intranasal buserelin increased circulating testosterone levels but did not affect behavioural measures of sexual incentive motivation, whereas intraperitoneal kisspeptin increased both circulating testosterone and sexual motivation. Notably, intranasal kisspeptin also increased sexual motivation, despite not affecting circulating testosterone levels (58). Taken together, these data provide interesting insight for GnRH/testosterone-independent kisspeptin-effects to stimulate sexual motivation in male rodents.
A similar critical role for kisspeptin-signalling in regulating sexual partner preference in female rodents has been observed in a key elegant study. Ovariectomised and hormone-primed Kiss1 KO mice fail to display normal male-directed preference, whereas a single peripheral injection of kisspeptin resolves this deficit (59). Interestingly, selective viral ablation of AVPV kisspeptin neurons also results in female mice failing to display any male-direct preference, which again resolves following a single peripheral injection of kisspeptin (59), indicating site-specificity of the AVPV for kisspeptins control of mate preference in female mice. Furthermore, exploiting a transgenic GnRH deficient mouse model (which progressively loses GnRH expression during adulthood) results in female mice displaying female rather than male-directed preference, which normalises following a single peripheral injection of GnRH (but not kisspeptin) (59). This indicates that kisspeptin signals through GnRH neurons to specifically mediate sexual partner preference.
Copulatory Behaviour and Arousal
Preclinical Animal Studies
The MeA is a key brain region involved in sexual behaviour. Lesioning of the MeA in rats suppresses male copulatory behaviours such as erections and intromissions (72, 73). Although androgen receptors are present in the MeA (74), direct administration of androgens does not cause spontaneous erections (75), suggesting that additional factors are required to stimulate this physiological pathway. In keeping with this, microinjections of kisspeptin directly into the MeA of male rats dose-dependently stimulates ex-copula erections, an effect blocked by pre-treatment with a kisspeptin receptor antagonist (76). Furthermore, when kisspeptin is infused into the intracerebroventricular space, no erections are observed (despite comparable rises in circulating LH), demonstrating site-specificity of the MeA for kisspeptin’s effects on rodent erections and crucially suggests its role in this aspect of sexual behaviour is independent of downstream GnRH, LH or testosterone (76).
Human Studies
In healthy heterosexual men, peripheral administration of kisspeptin enhances limbic brain activity (as determined by fMRI) in response to visual sexual stimuli, including the anterior and posterior cingulate and amygdala (78). Given that desire for sexual stimulation is an important component of the human sexual response (79), it is intriguing that in this study the greater kisspeptin enhanced limbic brain activity (including in the putamen) to sexual images, the less aversion to sex healthy men displayed (determined using behavioural tests). Moreover, in response to sexual images, kisspeptin was observed to activate limbic structures (including the hippocampus) more in men with lower baseline reward behavioural scores, which is highly relevant given that human sexual behaviour is closely associated with pleasure and reward.
Mood and Emotions
Kisspeptins antidepressant-like effects have been identified in male mice using a modified forced swimming paradigm (90). During this test, rodents are placed into a container filled with water and assessed for active (swimming and climbing) and passive (immobility) behaviours, suggestive of anti-depressant and depressant effects, respectively (91). This study revealed that intracerebroventricular delivery of kisspeptin increased antidepressant-like behaviours (climbing and swimming times), whilst reducing the duration of immobility (90). Regarding interplay with downstream systems, pre-treatment with a nonselective α-adrenergic, α2-adrenergic or nonselective 5-HT2 serotonergic receptor blocker abolished kisspeptins anti-depressive actions, whereas pre-treatment with a cholinergic, dopaminergic or GABAergic receptor blocker had no effect on kisspeptins actions. Therefore, the results from these receptor blockade experiments indicate that kisspeptin can interplay with downstream adrenergic and serotonergic systems to bring about antidepressant-like effects (90).
Given the interaction between kisspeptin and the serotonergic system, it is interesting to consider the brain regions involved in eliciting the antidepressant-like effects. In a recent study, adult male rats received four weeks of intraperitoneal escitalopram (92), a widely prescribed selective serotonin reuptake inhibitor for mood disorders, which increases serotonin activity in the brain by limiting its reabsorption. This experimental paradigm significantly upregulated Kiss1 mRNA expression in the amygdala (272% increase compared to saline treated rats). Furthermore, Kiss1r mRNA was highly increased in the hypothalamus, hippocampus and cerebellum by 170%, 177% and 131%, respectively (92). Indeed, these findings are congruent with a previous study demonstrating that intra-cerebroventricular injections of serotonin hydrochloride to male rats significantly enhances hypothalamic kisspeptin expression and resultant circulating LH concentrations (93). Collectively, these data garner further evidence for the interplay between kisspeptin and the serotonergic system in eliciting antidepressant actions, as well as evidence for the putative brain regions involved.