The effects of idazoxan and 8-OH-DPAT on sexual behaviour and associated ultrasonic vocalizations in the rat.

Two experiments were performed studying the effects of 8-OH-DPAT and idazoxan on sexual behaviour and ultrasonic communication of male rats. In addition, the reactions of the females towards drug-treated males were studied. 8-OH-DPAT (a very specific 5-HT1A agonist) and idazoxan (an alpha 2-adrenergic antagonist) differentially affected sexual behaviour: 8-OH-DPAT (0.1 and 0.4 mg/kg IP) markedly facilitated ejaculations, a feature indicated by decreased numbers of mounts and intromissions preceding ejaculation and a reduction in ejaculation latency. This drug concomitantly reduced the postejaculatory refractory period. Idazoxan reduced the number of intromissions before ejaculation only at the highest dose (10 mg/kg IP), but did not markedly facilitate other parameters. Both drugs markedly and dose-dependently suppressed the postejaculatory 22 kHz ultrasounds normally recorded during the postejaculatory refractory period. Ultrasound frequencies above 30 kHz first appear at the end of the absolute refractory period, even when the refractory period is shortened by 8-OH-DPAT. Idazoxan increased the number of these 30 kHz ultrasounds, whereas 8-OH-DPAT had no effect on them. No effects were observed on ultrasound production (either 22 kHz or above 30 kHz) before an ejaculation. The behaviour of the females towards 8-OH-DPAT-treated males was also affected, with the females showing more darting and lordosis before and after ejaculation, but less sitting after ejaculation. Idazoxan treatment of the males resulted in more hopping and earwiggling of the females before ejaculation. Following ejaculation, females treated with the antagonist showed more darting, hopping, earwiggling and lordosis, but sitting was decreased. It has been suggested in the rat that the emergence of ultrasounds higher than 30 kHz indicates the end of the absolute refractory period and signals to the female that the male is capable of resuming sexual activity. The significance of 22 kHz ultrasound in sexual behaviour remains puzzling because these vocalizations could be easily uncoupled from the refractory period by drugs acting via different receptor mechanisms without disturbing sexual behaviour per se. A failure to produce postejaculatory sounds appears to disinhibit (proceptive) behaviour by the females.

Naloxone reverses post-ejaculatory inhibition of sexual behaviour in female rats.

Sexual receptivity was inhibited in ovariectomized rats treated with oestradiol benzoate (OB: two injections of 2 micrograms) and progesterone (0.5 mg) immediately after ejaculation by the male and restored after the end of the post-ejaculatory refractory period in the male. The post-ejaculatory inhibition of sexual receptivity was reversed by i.p. (5 mg), intracerebroventricular (50 micrograms) or intrathecal (50 micrograms) injection of the opioid peptide receptor antagonist naloxone. The concentration of serum beta-endorphin-like immunoreactivity in ovariectomized rats treated with OB plus progesterone was unaltered by sexual interactions with males (18.3 +/- 6.0 (S.E.M.), 26.4 +/- 2.1 and 21.8 +/- 6.1 pmol/l before sexual activity, after ejaculation and after the end of the post-ejaculatory interval) but reduced to non-detectable by hypophysectomy. Subcutaneous injection of 10 micrograms beta-endorphin raised serum concentrations of beta-endorphin-like immunoreactivity but did not affect the display of sexual behaviour. The behaviour was also unaffected by intracerebroventricular injection of 0.1, 0.2 or 1.0 microgram beta-endorphin or by injections of 0.25 microgram beta-endorphin in the periaqueductal central grey of the mesencephalon. The results show that ejaculation by male rats causes a transient inhibition of sexual receptivity in the female which may be dependent upon opioid peptide receptor mechanisms in the brain and spinal cord. It is unlikely that the peptide is beta-endorphin.

Lidocaine does not affect myocardial electrical heterogeneity: implications for low proarrhythmic actions.

An area of unidirectional conduction block is one requirement for reentrant arrhythmias to occur. Functional block caused by dispersion of repolarization and refractoriness is the most probable mechanism of drug-induced unidirectional conduction block. We assessed the effects of lidocaine on spatial dispersion of myocardial repolarization and refractoriness in the intact porcine heart. Monophasic action potential duration at 90% repolarization, effective refractory period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at two endocardial and one epicardial sites at baseline and during a treatment phase with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as the difference between the maximum and minimum values of the three recording sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration, and intraventricular conduction time. It did not change basal levels of dispersion in repolarization and refractoriness. Lidocaine produced changes in myocardial electrophysiology that are uniform across the myocardium and thus did not change myocardial electrical heterogeneity. This may be a mechanism of the agent's lower proarrhythmic effects compared with other sodium channel blockers that increase myocardial electrical heterogeneity.

Post-ejaculatory vocalization in castrated rats treated with various steroids.

Five groups of rats were observed for sexual behavior as intact subjects and in the 3 weeks following castration. Particular emphasis was placed upon ultrasonic vocalization recorded during the refractory period (RP) following ejaculation. All rats received daily injections (100 mug test steroid + 100 mug dihydrotestosterone propionate, DHTP) from the day of castration. Treatment groups were: Testosterone propionate (TP) + DHTP, N = 5; 19-hydroxytestosterone propionate (19HTP) + DHTP, N = 6; Oestradiol dipropionate (OP) + DHTP, N = 5; DHTP (200 mug/day), N = 6; Vehicle only, N = 7. Ejaculation and normal RPs were maintained with TP, 19HTP and OP treatments. In rats treated with DHTP alone or vehicle only ejaculatory ability declined and RPs increased in length. Ultrasonic vocalization was normal in all rats except those treated with OP, where it was either reduced or absent. In Week 4 treatments in TP + DHTP and OP + DHTP groups were reversed. During Weeks 5-7 vocalization was gradually restored in rats that previously received OP and partially inhibited in animals previously treated with TP. These results indicate that; (1) vocalization may not be dependent on the presence of testicular androgens and, (2) OP has a gradual inhibitory effect on vocalization when given at high doses and this effect is reversible.

Control of motor seizures by brotizolam with maintenance of stable refractory periods for self-stimulation.

In recent years, we have been pursuing our mapping investigations of the substrate for brain-stimulation reward in regions of the anterior hypothalamic and lateral preoptic areas. However, one problem is that stimulation of these sites often generates overt seizures so that their suppression via a pharmacological means would be very useful. The sedative-hypnotic benzodiazepine, brotizolam, is reportedly a long-lasting anticonvulsant. Hence, its effects on motor seizures elicited from stimulation of the lateral preoptic area were evaluated in the first experiment. Both tested doses (5.0 and 7.5 mg/kg) of the drug were shown to significantly decrease the number, and marginally, the severity of stimulation-induced seizures; furthermore, this effect was relatively long lasting, up to about 3 h. The higher dose of brotizolam did not alter the single-pulse thresholds for self-stimulation, a requirement for evaluations of poststimulation excitability, the purpose of the second experiment. Here, our interest was in documenting whether the membrane properties of the stimulated neurons, as assessed by refractory periods, were altered by brotizolam. No differences in the time course of recovery were observed; refractoriness began between 0.4 and 0.8 ms, and reached 50% recovery by 2.0 ms, which is consistent with the pattern of poststimulation excitability typically measured at these sites. Thus, in addition to its long-lasting suppression of motor seizures in rats, brotizolam does not alter the time course of recovery from refractoriness of the neurons that mediate brain-stimulation reward in the lateral preoptic area.

Interactions between 5-hydroxytryptamine (5-HT) and testosterone in the control of sexual and nonsexual behaviour in male and female rats.

Two 5-hydroxytryptamine2 (5-HT2) agents, ritanserin and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (both at 0.25 mg/kg IP), were administered to castrated males bearing graded testosterone implants (empty, 2.5-, 5-, and 10-mm length) and to normal and neonatally androgenized ovariectomized females bearing 10-mm testosterone implants. The results indicate that testosterone stimulates male sexual behaviour and appears to have a dose-related anxiolytic effect, but no effect on other nonsexual activities. 5-HT and testosterone had opposite effects on male sexual behavior, with ritanserin (5-HT antagonist) enhancing activity in both sexes and DOI (5-HT agonist) inhibiting behaviour in males, the latter being testosterone-dependent. Independent of testosterone, ritanserin reduced locomotion and exploration and increased anxiety in males, while DOI increased locomotion and exploration in both sexes. Ritanserin had a gender-specific effect on anxiety which was independent of testosterone, since in castrated males it was anxiogenic whether they bore testosterone implants or not, while in females it was anxiolytic whether the female were neonatally androgenized (250 micrograms/pup testosterone proprionate [TP] on day 1) or not. These results show that 5-HT and testosterone have opposite effects on male sexual behaviour and these may be interrelated. In adulthood, their effects on nonsexual activities are not inversely related and are independent of each other in contrast to the relationship seen in the neonatal period.

Constraints on information processing under alcohol in the context of response execution and response suppression.

This study tested the degree that alcohol restricts information processing on tasks requiring response execution and response suppression. A dual task required 12 participants to respond to 2 task stimuli (Tasks 1 and 2) presented in close succession. The task was performed before and after receiving 3 alcohol doses (placebo, 0.45 g/kg, and 0.65 g/kg) administered on separate days in a counterbalanced order. Alcohol increased task interference, as evidenced by increased time to respond to Task 2. Impairment was comparable regardless of whether Task 1 required a response to be executed or suppressed. The evidence supports a resource limitation account that argues that alcohol reduces capacity to process information required for execution and suppression of responses.

Effects of energy drinks mixed with alcohol on information processing, motor coordination and subjective reports of intoxication.

The consumption of alcohol mixed with energy drinks (AmED) has become a popular and controversial practice among young people. Increased rates of impaired driving and injuries have been associated with AmED consumption. The purpose of this study was to examine if the consumption of AmED alters cognitive processing and subjective measures of intoxication compared with the consumption of alcohol alone. Eighteen participants (nine men and nine women) attended four test sessions where they received one of four doses in random order (0.65 g/kg alcohol, 3.57 ml/kg energy drink, AmED, or a placebo beverage). Performance on a psychological refractory period (PRP) task was used to measure dual-task information processing and performance on the Purdue pegboard task was used to measure simple and complex motor coordination following dose administration. In addition, various subjective measures of stimulation, sedation, impairment, and level of intoxication were recorded. The results indicated that alcohol slowed dual-task information processing and impaired simple and complex motor coordination. The coadministration of the energy drink with alcohol did not alter the alcohol-induced impairment on these objective measures. For subjective effects, alcohol increased various ratings indicative of feelings of intoxication. More importantly, coadministration of the energy drink with alcohol reduced perceptions of mental fatigue and enhanced feelings of stimulation compared to alcohol alone. In conclusion, AmED may contribute to a high-risk scenario for a drinker. The mix of behavioral impairment with reduced fatigue and enhanced stimulation may lead AmED consumers to erroneously perceive themselves as better able to function than is actually the case.

Effects of bufetolol and propranolol on active and passive membrane properties of dog papillary muscle.

Effects of bufetolol and propranolol, adrenergic beta-receptor blocking and anti-arrhythmic drugs, on active and passive membrane properties of the dog papillary muscle were investigated with microelectrode and sucrose-gap methods. Bufetolol (10(-5) to 10(-4) g/ml) and propranolol (10(-6) g/ml) significantly decreased the maximum rate of rise of the action potential. The maximum responsive frequency to driving stimulus was decreased in the presence of bufetolol (3 X 10(-5) g/ml) and propranolol (10(-5 g/ml), whereas the effective refractory period was not affected. The critical threshold potential was shifted to more positive potential in the presence of the drugs. The passive membrane property, the space constant (lambda), the time constant (tau) and the current-voltage relations of the muscle membrane were not significantly altered by the drugs. It is concluded that bufetolol and propranolol suppress the excitability of the muscle membrane and this action may be ascribed to the decrease in the sodium conductance (gNa) and to the rise of gNa onset potential without alteration in the passive membrane property.

[The effects of imolamine on auriculo-ventricular conduction by recoil of His potential]. / Etude des effets de l'lmolamine sur la conduction aurticulo-ventriculaire par recuell du potentiel Hissien

The electropharmacological action of imolamine was studied using Hiss bundle electrography. In dogs with spontaneous sinusal rhythm, imolamine decreases Hiss-Purkinje and total intraventricular conduction, without affecting auriculoventricular conduction time. In dogs with paced sinusal rhythm (180/min), imolamine increases atrial and ventricular thresholds and atrial refractory period, and decreases intra-atrial and intraventricular conduction; no significant modification of auriculoventricular conduction was noted at therapeutic dosages. In ouabaïn-intoxicated dogs, imolamine suppresses digitalis rhythm disorders and antagonizes the action of the glycoside on A-V node, as does diphenylhydantoïne, but, in contrast to this drug, it increases slightly intraventricular conductivity.