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11 décembre 2003
Neurosci Letter
2003; 349; 1; 49-52
Potentiation of penile erection and yawning responses to apomorphine by cannabinoid receptor antagonist in rats
da Silva GE, MS Fernandes, RN Takahashi et al
Department de farmacologica, Universidad federal de Santa Catarina, Florianoplois, Brazil


Abstract : The effect of systemic administration of the cannabinoid antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide ) on penile erection and yawning induced by apomorphine was investigated in rats.
SR 141716A (2 mg/kg, i.p.) administered 40 min before apomorphine (40 and 80 microg/kg, s.c.) increased the number of penile erection and yawning responses. The administration of cannabinoid agonist Delta9-tetrahydrocannabinol (1.25 mg/kg, i.p.) 15 min before apomorphine (40 and 80 microg/kg, s.c.) did not affect penile erection, however it decreased yawning. The present results provide additional evidence that cannabinoid agonists interfere with dopaminergic systems and that SR 141716A together with a dopaminergic agonist could be useful to potentiate dopaminergic activity.

Penile erection is a behavior of pivotal importance in mammalian reproduction, the physiology of which involves a complex cascade of neuronal and neuroanatomical events. Yawning is a reflex or stereotyped event exhibited by all mammals and vertebrates. Although its mechanisms and physiological role are not entirely understood, it bas been used as a tool to study physiological responses to and mechanisms of action of some drugs and hormones. Penile erection and yawning are behavioral features that are under the control of several neurotransmitters and neuropeptides: acetylcholine, serotonin, dopamine, GABA, oxitocine, adrenocorticotrophin, opioid peptides and nitric oxide. Both behaviors can occur concomitantly under some conditions, and among them the administration of dopamine receptor agonists is certainly one of the most effective. Apomorphine, a nonselective dopamine agonist, bas been extensively studied in animals, primarily rodents, and is a prototypical dopaminergic initiator of erectile pathways, as well as yawning pathways in the brain. Accordingly, low doses of apomorphine elicit yawning and penile erection responses that may be mediated by a prefèrential activation of presynaptic dopamine receptor D2, which result in inhibition of dopamine release and a decrease of its synthesis.
Recent studies showed that administration of cannabinoid agonists is able to inhibit both behaviors induced by dopaminergic agonists. The colocalization of cannabinoid and dopamine in those brain areas which have a prominent role in regulating psychomotor activities has stimulated research in the field. Therefore, because of the possibility of interaction between endocannabinoids and dopaminergic systems for the modulation of behavior, in the present study we examined the action of the cannabinoid antagonist SR 141716A (N-(piperidin- 1 -yl)-5-(4-chlorophenyl)-4-methyl- 1 H-pyrazole-3-carboxyamide) in penile erection and yawning induced by apomorphine.
Male Wistar rats (250-300 g, 9-10weeks old) were maintained in groups in the colony room of the Department of Pharmacology under a light/dark cycle of 12 h (lights on at 7:00 a.m.) with food and water ad libitum. On the day of the experiment the animals were brought to the laboratory and placed in individual wire cages. During the 30 min period immediately following the administration of apomorphine (Sigma; 20, 40 or 80 µg/kg, s.c., diluted in saline with 0.1% Tween-80, vehicle) or control solution, the number of yawns and penile erections was counted. Penile erection was scored when the glans emerged from the prepucial sheath, an action that was usually accompanied by intense penile grooming and slight hip movements.
Yawning was scored when the rat sustained an open mouth for more than a second. Control solution and 9-tetrahydrocannabinol (9-THC) (obtained from the National Institute of Drug Abuse, Bethesda, MD, at 200 mg/ml in alcohol; 1.25 mg/kg, i.p., prepared immediately before use by evaporating the alcohol and emulsifying the residue with Tween-80) were administered 15 min before control solution or apomorphine, and SR 141716A (SanofiSynthelabo, Montpellier, France; 2.0 mg/kg, i.p., suspeniled in 1 ml/kg saline with 0. 1 % Tween-80) was injected 40 min before the first treatment. All measurements were taken in the afternoon, beginning at 2:00 p.m. The applied doses were chosen from previous experiments. Control solution was prepared with the corresponding vehicle. AU substances were administered at 1 ml/kg.
It's shows the effects of different pretreatments on apomorphine-induced penile erection (top) and yawning (bottom). Two-way ANOVA on the number of erections showed a significant effect for pretreatment (F(2,75) = 12.74, P < 0.00001), a significant effect for treatment (ffl,75) = 24.87, P < 0.000001) and a significant interaction between these factors (F(6, 75) = 3.99, P < 0.001). SR 141716A potentiated the penile erection induced by 40 µg/kg apomorphine (P < 0.001, NewmanKeuls test). Pretreatment with 9-THC (1.25 mg/kg) did not inhibit the penile erection induced by apomorphine (80 µg/ kg), although it did show a tendency towards inhibition (40 µg/kg, P < 0.07). Two-way ANOVA on yawning responses showed a significant effect for pretreatment (F(2,75) = 12.64, P < 0.00001) and treatment (ffl,75) = 17.07, P < 0.000001) and a significant interaction between these factors (F(6,75) = 3.39, P < 0.005). Pretreatment with 9-THC significantly decreased the number of yawns induced by 40 and 80 µg/kg of apornorphine (P < 0.02 and P < 0.04, respectively), while SR 141716A potentiated the yawning induced by 80 µg/kg apomorphine (P < 0.01).

The present results show that cannabinoids affect penile erection and yawning induced by apomorphine, a dopaminergic agonist, confirming that they can modulate the dopaminergic system. Such interaction has been previously shown in brain regions related to motor and emotional responses.

Although the present study did not investigate the neuroanatomical basis of penile erection and yawning, previous studies reported the importance of the paraventricular nucleus of the hypothalamus and dopamine to both behavioral responses. Potentiation of penile erection and yawning responses to apomorphine by the cannabinoid receptor antagonist, SR 141716A (2 mg/kg), suggests an antagonism of cannabinoid receptors, blocking endocannabinoid action and thereby decreasing dopaminergic activation, an action that remains to be clarified as a single dose was used in the present study. The finding that the stimulation of motor behavior elicited by systemic administration of the D2-like agonist quinpirole was increased by SR 141716A supports this interaction and led these authors to suggest that the endocannabinoid systern may modulate D2 dopamine activation of psychomotor activity. In line with this hypothesis it is noteworthy that there is an interaction between endocannabinoid and doparninergic systems in hypothalamic structures related to hypothermia and prolactin secretion. In addition, our finding that 9-THC significantly reduced yawning, although it did not fully reduce the number of penile erections, strongly supports the idea that cannabinoids might interact with dopaminergic receptors.

Several studies have shown that cannabinoid agonists can either increase doparninergic activity or produce a dopaminergic antagonistic-like effect. The antagonistic-like action of cannabinoid agonists might best explain the present findîngs since yawning responses were significantly reduced by 9-THC and no sign of stereotypy or hyperactivity was observed in animals treated with the combination of 9-THC with apomorphine. Moreover, additional support for this contention comes from our recent study examining the effects of cannabinoid agonists on yawning induced by pilocarpine, a cholinergic agonist, or apomorphine. Yawning induced by low doses of apomorphine was much more sensitive to antagonism by both 8-THC and 9-THC than that produced by pilocarpine. This antagonistic-like action of cannabinoid agonists may involve D2 dopamine receptor mediation. Beltramo et al. recently showed that both anandamide transport inhibitor AM 404 and anandamide by itself counteract two characteristic responses mediated by activation of D2 family receptors, that is, yawning induced by apomorphine in a dose equivalent to the highest one employed in our study (80 µg/kg s.c.) and quinpiroleinduced stimulation of motor behaviors.

The reduction of yawning by 9-THC could be attributed to its known hypotensive properties and/or motor suppressive effect. In regard to the former effect, our study cannot discard this possibility, but it is important to remember that SR 1411716A which dues not cause hemodynamic changes potentiated the penile erection responses. Concerning the latter effects of cannabinoid agonists, the locomotor activity data from the literature provide evidence against this possibility. That is, a study using the radial arm maze task did not observe differences in locomotor activity of rats treated with the same dose used here, 1.25 mg/kg . Furthermore, experiments evaluating the role of cannabinoids on movement found an increase in ocomotor activity in rats injected with either 1.5 or 2 mgfkg of 9-THC.

Taken together, the prescrit results show that although SR 141716A has no overt effect when administered alone, it enhances the dopaminergic effects induced by low doses of apomorphine, while the cannabinoid agonist, 9-THC, decreases these responses. As was mentioned before, there are many other systems that are known to modulate yawning and penile erection responses and certainly further studies are necessary to clarify this proposed mediation of these responses by cannabinoid and dopamine interaction.

Considering the importance of dopamine to motor and limbic functions and the number of reports that dopamine agonists are effective in various psychiatric conditions as well as neurological disorders, the possibility of SR 141716A increasing dopaminergic neurotransmission may be useful as a potential strategy to ameliorate dysfunctions related to this system.

voir site pharmacorama
Yawning and penile erection induced by apomorphine is potentited by cannabinoid recptors antagonist in rats
Eur Neuropsychopharmacol 2002;12; s3; S391
R.N. Takahashi. UFSC, Depto Farmacologia, Florianopolis SC, Brazil
It is known that cannabinoid and dopamine receptors are colocalised in brain areas that have important role in regulating motor and emotional responses. Yawning responses have been observed during the SR 141716 precipitated cannabis withdrawal in rats. Moreover, yawning and penile erection constitute behavioral patterns that occur concomitantly under the effects of dopamine receptors agonists. The present study was undertaken to examine the influence exerted by an acute treatment with SR 1411716, a specific cannabinoid receptor antagonist, on typical behavioral responses induced by low doses of apomorphine, a dopamine receptor agonist. Wistar male rats were injected with apomorphine (20, 40 or 80 mg/kg, se) and individually placed in wire cages. The number of yawns and penile erections were counted for a period of 30 min. Pretreatment with SR 141716 (2 mg/kg, ip) was given 40 min before apomorphine. A separate two-way ANOVA of penile erection and yawning data showed significant treatment effects [F(3, 49)= 21.2, p<O.Ol and F(3, 49)=14,3, p<O.OOl, respectively], a significant pretreatment effects [F(1, 49)=5.l8, p<0.027 and F( 1, 49)=4.12, p<O.047, respectively], and a significant interaction factors [F(3, 49)=2.80, p<O.049 and F(3, 49)=3.84, p<0.0l5, respectively]. Further comparisons indicated that penile erection elicited by apomorphine (40 mg/kg) and yawning elicited by the dose of 80 mg/kg was significantly potentiated by SR 141716 pretreatment (Tukey LSD test, p<O.O5). These results indicate that cannabinoid antagonists facilitate dopaminergic stimulatory responses and they also confirm the cross-talk between cannabinoid and dopaminergic systems.