Role of the neurokinin-1 receptors in ejaculation in anesthetized rats.

INTRODUCTION: Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. AIM: The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. METHODS: Ejaculation was induced in anesthetized rats by intracerebroventricular (i.c.v.) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (i.p.), i.c.v., or intrathecal (i.t.) (third lumbar spinal segment; L3) administration. MAIN OUTCOME MEASURES: Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. RESULTS: Upon i.p., i.c.v., or i.t. administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following i.c.v. or i.t. administration. CONCLUSION: These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors.

Peripheral neural lesion-induced stress urinary incontinence in anaesthetized female cats.

OBJECTIVES: To characterize the effect of acute unilateral and bilateral lesion of the pelvic and pudendal nerves, and nerves innervating the iliococcygeous and pubococcygeous muscles during sneezing in anaesthetized female cats, on intravesical pressure (IVP), urethral pressure (UPs) and external urethral sphincter (EUS) activity. MATERIALS AND METHODS: In seven anaesthetized female cats UPs along the urethra (UPs1-4) and IVPs were recorded in the emptied bladder during sneezing before and after unilateral and then bilateral peripheral neural lesions. UPs were measured using microtip transducer catheters with UP4 positioned in the distal urethra where the EUS is located. Urine leakage was also noted, after urethral catheter removal and bladder filling. RESULTS: During sneezing, in intact cats, the magnitude of UP4 was larger than those of IVP and UPs1-3. The area under the curve of both anal sphincter and EUS electromyography was increased. There was no urine leakage. After unilateral neural lesions, the mean magnitude of response was similar all along the urethra and in the bladder. The distal UP response was significantly lower than that recorded in intact cats. In addition, there was urine leakage in six of the seven cats. Bilateral neural lesions caused permanent urine leakage and significant decreases in all the UP responses. CONCLUSION: In female cats, during sneezing, neurally driven reflex contractions of EUS leading to an increase in distal UP contribute to active urethral closure mechanisms and ensure urinary continence.

Central neurophysiology and dopaminergic control of ejaculation.

Although premature ejaculation (PE) represents the most common male sexual dysfunction, brain mechanisms controlling ejaculatory process remain poorly understood. Recently a group of neurons, identified in the lumbar spinal cord, has been proposed to constitute a spinal ejaculation generator. This key site in ejaculation control, relaying sensory inputs to the brain, is under supraspinal excitatory (medial preoptic area, paraventricular nucleus of the hypothalamus) and inhibitory (nucleus paragigantocellularis) controls. Activation of brain excitatory areas by dopamine (DA) or DA agonists being demonstrated to facilitate ejaculation, it seems particularly interesting to further understand the implication of central DA in the complex process leading to ejaculation. Moreover, the fact that dopaminergic pathways are involved in sexual behavior and that DA release in some brain regions is an important facilitator of male sexual behavior reinforces the crucial implication of DA. Clearly, a better understanding of DA incerto-hypothalamic pathways and targeting brain DA receptor subtypes mediating ejaculation (especially D(3) receptors) will benefit the development of new pharmacological strategies to treat ejaculatory dysfunction including PE.

Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat: therapeutic potential for migraine.

Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) is implicated in the generation and propagation of SD has itself been available for more than 15 years. However, to date, there are no reports of NMDA-R antagonists being developed for migraine therapy. In this study, an uncompetitive, pan-NMDA-R blocker, memantine, approved for clinical use, and two antagonists with selectivity for NMDA-R containing the NR2B subunit, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25-6981), were investigated to assess their protective effects against SD in the rat. Under isoflurane anesthesia, d.c. potential and the related cortical blood flow and partial pressure of O2 (pO2) were recorded simultaneously at separate cortical sites. Drugs (1, 3, and 10 mg/kg i.p.) were given 1 h or 30 min before KCl application to the brain surface. Core temperature and arterial pCO2,pO2, and pH measurements confirmed physiological stability. KCl induced 7.7+/-1.8 (mean+/-S.D.) SD events with d.c. amplitude of 14.9+/-2.8 mV. Memantine and CP-101,606 dose-dependently decreased SD event number (to 2.0+/-1.8 and 2.3+/-2.9, respectively) and SD amplitude at doses relevant for therapeutic use. Ro 25-6981 also decreased SD events significantly, but less effectively (to 4.5+/-1.6), without affecting amplitude. These results indicate that NR2B-containing NMDA receptors are key mediators of SD, and as such, memantine- and NR2B-selective antagonists may be useful new therapeutic agents for the treatment of migraine and other SD-related disorders (e.g., stroke and brain injury). Whether chronic, rather than acute, treatment may improve their efficacy remains to be determined.

Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine.

Pharmacological effects of amantadine on dopaminergic transmission are proposed to result from an uncompetitive antagonism at glutamate N-methyl-D-aspartate (NMDA) receptors. However, our previous studies examining amantadine-mediated dopamine receptor regulation in the rat striatum revealed a discrepancy from a direct interference with glutamate transmission. Preliminary in vitro binding data from the literature suggested the interaction of amantadine with the sigma1 receptor. Therefore, we have now further characterized the pharmacological properties of amantadine and memantine at this receptor and investigated its involvement in the modulation of striatal dopaminergic transmission. Our binding studies using [3H]-(+)SKF-10,047 indicated that amantadine and memantine behave as ligands of the sigma(1) receptor in rat forebrain homogenates (Ki values of 7.44 +/- 0.82 and 2.60 +/- 0.62 microm, respectively). In NG108-15 neuroblastoma cells, both drugs (amantadine (100 microm) and memantine (10 microm)) potentiated the bradykinin-induced mobilization of intracellular Ca2+, mimicking the effect of the sigma1 receptor agonist PRE-084 (1 microm). Finally, we previously showed that in striatal membranes from amantadine-treated rats, the functional coupling of dopamine receptors with G-proteins was enhanced. Similarly, PRE-084 dose-dependently increased the [35S]GTPgammaS binding induced by dopamine (Emax 28 and 26% of basal, 0.3 and 1 mg/kg PRE-084, respectively). By contrast, BD1047, which is without effect on its own, antagonized the effects of amantadine and PRE-084. Together, these data demonstrate that aminoadamantanes behave as sigma1 receptor agonists, and confirm an involvement of this receptor in modulating dopamine receptors exerted by therapeutically relevant concentrations of amantadine.

Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum.

Striatal glutamatergic inputs are known to participate in the modulation of dopaminergic transmission. Accordingly, the non-competitive N-methyl-D-aspartate receptor antagonists memantine and amantadine increase striatal dopamine levels, the latter being widely used in Parkinson's disease therapy. Based on our previous work revealing increased function of dopamine receptors and dopamine transporter after amantadine treatment, we studied the effects of repeated memantine administration on dopaminergic neurotransmission. On rat striatal membranes, dopamine-stimulated [(35)S]GTPgammaS binding was significantly reduced (20%) after 2 days injection with memantine (20 mg/kg per day, i.p.) but not after longer treatments (4 or 7 days). Evaluation of [(3)H]SCH 23390 and [(3)H]spiperone specific bindings only revealed a significant increase in D1 receptor density after 4 or 7 days treatment. Finally, none of these treatments were found to change the activity of the neuronal dopamine transporter in striatal synaptosomes. This shows that amantadine and memantine differentially affect striatal dopaminergic transmission, which could indicate that these two related aminoadamantanes display distinct pharmacodynamic properties.

Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine.

Amantadine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to increase dopamine synthesis and release in the striatum, is frequently associated with L-DOPA in the treatment of Parkinson's disease. However, the biochemical mechanisms involved in the effect of amantadine and the consequences of its repetitive administration on the modulation of striatal dopamine transmission still need to be clarified. We have investigated the effects of short-term amantadine treatments on the expression of dopamine receptors and the functional coupling to G proteins in rat striatal membranes. Dopamine-induced stimulation of guanosine 5'-[gamma-35S]triphosphate ([35S]GTPgammaS) binding was significantly enhanced (40%) in striatum homogenates from rats treated for 4 days with amantadine (40 mg/kg, i.p.) compared to vehicle-treated animals. This effect was specific for dopamine receptors and was transient as no significant modifications were observed when animals were treated for either 2 or 7 days. Administration of amantadine did not directly affect the animal behaviour. However, treated animals exhibited hypersensitive dopamine transmission since rats treated for 4 days showed exacerbated responses to a single apomorphine administration (enhanced locomotor activity and reduced stereotypy). Since the effects of amantadine administration differ from those usually observed with direct dopamine receptor agonists or other NMDA receptor antagonists, we suggest that multiple biochemical mechanisms contribute to the modulation of dopamine transmission by amantadine.