resolutionmini

 

 

 

 

 

 

 

 

 

 

haut de page

mise à jour du
26 mai 2005
Eur J Neurosci
2003;17:1266-1272
Extra-cellular dopamine increases in the paraventricular nucleus of male rats during sexual activity
Melis MR, Succu S, et al.
Bernard B. Brodie Department of Neuroscience, University of Cagliari, Italy
 
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren
 

Chat-logomini

Introduction
 
The paraventricular nucleus of the hypothalamus (PVN) is considered a sort of integration centre between the central and the peripheral autonomous nervous system and is involved in the control of numerous functions, including male erectile function and sexual behaviour. Accordingly, bilateral electrolytic lesions of the PVN reduce drug- and oxytocin-induced erections, pheromone-mediated noncontact erections, seen in male rats put in the presence of an inaccessible receptive female, and impair copulatory behaviour, while its electrical stimulation induces erection. Several lines of evidence show that a group of oxytocinergic neurons originating in the PVN and projecting to extra-hypothalamic brain areas, such as the hippocampus, the medulla oblongata and the spinal cord play an important role in the control of erectile function and copulatory behaviour. When activated, these neurons facilitate erection and sexual activity, while a reduced erectile function and sexual activity is found when these neurons are inhibited. Among neurotransmitters and neuropeptides present in the PVN, those that activate oxytocinergic neurons and facilitate erection and sexual activity include dopamine, excitatory amino acids, and oxytocin itself, while GABA and opoioid peptides inhibit activity of these neurons and reduce penile erection and copulatory behaviour. Apparently, dopamine, excitatory amino acids and oxytocin activate pro-erectile oxytocinergic neurons by stimulating nitric oxide (NO) synthase, the Ca2-calmodulin enzyme which converts L-argimne to NO, and which is present in high concentrations in the PVN, including the cell bodies of oxytocinergic neurons. In line with this hypothesis, microdialysis studies have shown that dopamine receptor agonists, excitatory amino acids and oxytocin itself increase NO production in the PVN, when given at doses that induce penile erection; the latter effect is prevented not only by doses of NO synthase inhibitors that also inhibit the sexual response, but also by the opiate morphine, by GABAA receptor agonists given into the PVN and by oxytocin receptor antagonists. NO production also increases in the PVN during pheromone-induced noncontact erections and during copulation, both these physiological sexual response being reduced by NO-synthase inhibitors given in the PVN, by morphine, GABAA receptors agonists and by oxytocin receptor antagonists. In line with the above data, the oxytocin messenger RNA and NO synthase messenger RNA have been found to be lower and the opioid peptide messenger RNA higher in the PVN of impotent male rats, when compared to sexually potent male rats.
 
Although the above findings support the idea that paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord are activated during erection and copulation, paraventricular neurotransmitters and/or neuropeptides that activate these neurons in physiological contexts are still unknown. Our previous attempts to identify these neurotransmitters and/or neuropeptides, have revealed that noncontact erections are partially reduced by dizolcipine (MK-801), a potent noncompetitive excitatory amino acid receptor antagonist of the N-methyl-D-aspartic acid (NMDA) receptor ubtype, while dopamine receptor antagonists and d(CH2)5Tyr(Me))rn8-vasotocin, a potent oxytocin receptor antagonist, were ineffective. This led us to suggest that an increase in excitatory amino acidergic neurotransmission may be, at least partially, responsible for the activation of oxytocinergic neurons mediating erection and copulation.
 
However, the above results do not allow us to rule out a possible role of paraventricular dopamine in noncontact erections and copulation, as the failure of dopamine receptor antagonists to prevent the former sponses might be secondary to the experimental conditions used. Moreover, dopamine D2 receptor agonists are extremely potent in inducing erection when injected into the PVN of male rats and induce erection in both numerous laboratory animals and in humans. In order to provide direct evidence for a role of dopamine in the activation of paraventricular oxytocinergic neurons during sexual activity, the concentration of dopamine and its metabolite 3,4-dihydroxyphenylacetic Acid (DOPAC), which often reflects the amount of dopamine released tnd recaptured by dopaminergic synapses and dendrites, was measured in the paraventricular dialysate of male rats exposed to a receptive female both before and during copulation by means of a highly sensitive high pressure liquid chromatography (HPLC) method coupled to electrochemical detection.
paraventricular nucleus
Discussion
 
To our knowledge, this is the first report in which the concentrations of dopamine and its main metabolite DOPAC were measured in the dialysate obtained from male rats implanted with vertical microdialysis probes aimed at the PVN. Basal dopamine concentration was found to be approximately 0.05 nM, while that of DOPAC was approximately 0.4 nxl. As the recovery of authentic dopamine passed throughout the probes was found to be approximately 20%, dopamine concentration in the paraventricular extracellular fluid may be estimated to be close to 0.25 nM. This value is similar to that found in the dialysate obtained from the medial preoptic area of male rats .
 
The present results show that an increase in the concentration of dopamine and, to a lesser extent, of its metabolite DOPAC, occurs in the paraventricular dialysate of sexually potent male rats, which show noncontact erections when put in the presence of an inaccessible receptive female rat and which copulate with the female when permitted. The increase in dopamine and DOPAC found during copulation was higher than that found when copulation was not allowed. The increase of dopamine and DOPAC concentrations was not observed when male rats were placed with a nonreceptive female. To our knowledge, these findings provide the first evidence that dopaminergic neurotransmission increases in the PVN when penile erection occurs in physiological contexts, such as during noncontact erections and, to an even higher extent, during copulation, when 'in copula' erections occur. Indeed, the increase of dopamine parallel to that of DOPAC in the paraventricular dialysate of male rats, reasonably reflects the activation of paraventricular dopaminergic neurons during sexual activity. In this regard it is pertinent to recall that dopamine in the PVN is present in neurons and synapses that belong to incertohypothalamic dopaminergic neurons. These neurons have their cell bodies in the A13 and A14 dopaminergic groups of Dalhstrome and Fuxe, arborize extensively and impinge on neurons in several hypothalamic nuclei, including the PVN and the medial preoptic area.
 
These findings are in line with previous studies showing that dopamine D2 receptor agonists injected into the PVN induce penile erection, facilitate penile reflexes and influence copulation. As recalled in the Introduction, dopamine receptor agonists facilitate erectile function and copulatory activity when injected into the PVN by activating oxytocinergic neurons projecting to extra-hypothalamic brain areas, such as the hippocampus, and the spinal cord.
 
Accordingly, doses of apomorphine that induce erection, increase oxytocin content in the hippocainpus and in blood, and apomorphineinduced erections are abolished by bilateral electrolytic lesions of the PVN, which deplete oxytocm across the central nervous system or by oxytocin receptor antagonists given centrally, with a potency that is parallel to the potency of these compounds in blocking oxytocmergic receptors. Oxytocin receptor antagonists are also effective in reducing noncontact erections and copulatory behaviour of sexually potent male rats, as well as the facilitory effect of apomorphine on copulatory behaviour in sexually potent male rats.
 
The mechanism by which dopamine activates oxytocinergic neurons through the stimulation of D2 receptors located in the cell bodies of oxytocinergic neurons mediating erectile function is apparently mediated by an increased Ca 2+ influx inside the cell bodies of these neurons. This causes in turn the activation of NO-synthase, thereby increasing NO production in the PVN. NO in turn activates oxytocinergic neurons mediating erectile function by an as yet unidentified mechanism. Accordingly, apomorphine-induced penile erections, noncontact erections and copulation occur concomitantly with an increased NO production in the PVN, as measured by the increase in concentration of NO2 and NO3, the main metabolites of newly formed NO, in the dialysate obtained from the PVN during these sexual responses. Furthermore, the latter responses are all strongly reduced by NO synthase inhibitors injected into the PVN, which also reduce NO production in the PVN. Conversely, the injection of classic NO donors into the PVN induces erections indistinguishable from those induced by drugs (apomorphine, oxytocin and NMDA). Although numerous experimental data support the above hypothesis, other mechanisms of the action of dopamine in the facilitation of penile erection and sexual activity at the PVN level cannot be ruled out. As already extensively discussed, dopamine may also activate oxytocinergic neurons mediating erectile function by removing an inhibitory input on them other than by acting directly on D2 receptors located in their cell bodies. However, irrespective of D2 receptor location in the PVN, and of the fact that in many tissues D2 receptors inhibit Ca 2+ influx through voltage-dependent Ca 2+ channels, nanogram amounts of the potent N-type voltagedependent Ca 2+ channel inhibitor, w-conotoxin, injected into the PVN, prevent penile erection induced by apomorphine. This finding is in line with the hypothesis that an increased Ca 2+ influx into the cell bodies of oxytocinergic neurons plays a key role in the activation of these neurons and of penile erection by dopamine and its agonists.
 
The increase in the concentration of dopamine and DOPAC that occurs in the paraventricular dialysate of sexually potent male rats put in the presence of a receptive female, and to an even higher extent during copulation, resembles the increase of the concentration of dopamine and DOPAC that occurs in the dialysate obtained from the medial preoptic area of sexually potent male rats in similar experimental conditions. Also in these studies dopamine and DOPAC concentrations increased in the dialysate from the medial preoptic area only when sexually potent male rats were usd with a receptive female, while no increase was found when copulati ri did not occur or when castrated male rats were used. Another area in which microdialysis studies provided evidence of an increase in dopamine concentration during sexual activity, is the nucleus accumbens, which contains the nerve endings of mesolimbic dopaminergic neurons that play a key role in sexual motivation and rewarding. Together these findings suggest that dopamine in the PVN may play a role not only in erectile function (e.g. a component of the consumatory phase of sexuaI behaviour) but also in sexual motivation, as suggested for the medial preoptic area. However further studies are necessary to verify such a possibility.
 
Recently, we found that the mixed D1-D2 receptor antagonist cisflupentixol, the selective D1 receptor antagonist SCH 23390, and the selective D2 receptor antagonist raclopride, injected into the PVN were unable to prevent noncontact erections, as was the oxytocin receptor antagonist d(CH2)5-T'r(Me)Orn8-vasotocin, while th NMTDA receptor antagonist dizolcipine (MK-801) was able to reduce, although only partially, this sexual response. Apparently, these findings seem to support the hypothesis that dopamine in the PVN is not involved in pheromone-mediated noncontact erections. This contrasts with the findings of the present study which show that dopamine is increased in the paraventricular dialysate of male rats that show this sexual response when put in the presence of an inaccessible receptive female. Indeed, one would speculate that if dopamine activity were increased in the PVN during noncontact erections, these would have been found to be reduced by the prior administration of dopamine receptor antagonists into the PVN. However, in the light of the present results, this is unlikely. In fact, the inability of dopamine receptor antagonists to reduce noncontact erection might have been due to reasons other than a lack of a role for dopamine in this sexual response. For instance, the doses of dopamine receptor antagonists used in the previous study may have been too low or the volume injected not sufficient to spread and act across the entire PVN, as all dopamine antagonists were injected unilaterally. Alternatively, and most likely, the PVN might be a sort of node of parallel circuits that mediate either the precopulatory or the copulatory phase of sexual behaviour, so that all parallel circuits would have to be blocked in order to prevent this sexual response.
 
In conclusion, the present study further confirms that the PVN plays a primary role in the control of male rat sexual behaviour. Our results show for the first time that dopamine neurotransmission increases in this hypothalamic nucleus not only when sexual response is induced by drugs and/or neuropeptides, but also when it occurs in physiological contexts, such as noncontact erections or during copulation. In line with previous studies, it is likely that dopamine activates its own receptors, increasing in turn NO production inside paraventricular oxytocinergic cell bodies in the PVN, thereby activating oxytocinergic neurons projecting to extra-hypothalamic brain areas and in the spinal cord, which control erectile function and sexual behaviour. The PVN might be one of the sites in which dopamine receptor agonists (e.g. apomorphine) act to facilitate erectile function not only in rats but also in humans.