International journal of neuropharmacology最新文献

Electrical stimulation of the crossed olivo-cochlear bundle (OCB) of the anesthetized cat produces an inhibition of sound-evoked VIII nerve action potentials. The OCB has been shown to contain acctylcholinesterase (Churchillet al., 1956) and synaptic vesicles (Engstroem, 1958). It was therefore suggested that the OCB exerted its inhibitory effect by neurohumoral means and that the neurohumor might be acetylcholine (ACh). Hemicholinium number 3 (HC-3) was employed in the present study as a means for testing the hypothesis that ACh is involved in OCB-induced inhibition.

Cats anesthetized with pentobarbital and with left middle ear muscle tendons severed were employed. Sound-evoked potentials were recorded from the left cochlear round window. The crossed OCB was stimulated electrically. All experimental drugs were injected via a cannula in the left axillary artery. Atropine (0.5–5 mg/kg), dihydro-β-erythroidine (2–10 mg/kg) and mecamylamine (2–5 mg/kg) infections did not antagonize OCB-induced inhibition. HC-3 (5 mg/kg) in the majority of cats reduced the OCB-induced inhibition. Choline injections and resting the preparation momentarily reversed the effect of HC-3. Under similar conditions, d-tubocurarine (2 mg/kg) produced no change in OCB-induccd inhibition.

Male rats were subjected to environmental stresses consisting of flashing lights, audiogenic stimulation and oscillation for 20 weeks on a randomized schedule. The mean systolic blood pressure in the stressed animals rose to 150mm Hg±1.01 by week 8 and ranged between 150 and 160 mm Hg for the remaining 12 weeks, whereas the mean systolic pressure of the non-stressed animals fluctuated between 110 and 120mm Hg throughout this same period of time. Serum corticosterone level in the stressed animals were approximately 3 times higher than controls for the first 4 weeks of exposure; however, by the end of week 5. serum corticosterone declined dramatically in the stressed group and was significantly lower than controls, after which serum corticosterone levels exhibited a cyclic pattern at approximately 6-week intervals. No significant alterations were observed in brain NE and DA and serum FFA throughout the 20-week stress exposure. In a second study, rats received 100 mg kg p.o. ofL-α-methyltyrosine. At the end of weeks 2 and 4, brain NE was depleted by more than 80° in the stressed treated group, whereas brain NE in the non-stressed treated animals was depleted by approximately 45°. indicating a significant increase in the turnover of brain NE The elevated turnover of brain NE returned to control values by the end of the 6th week. In addition, a-MT prevented the stress-induced elevation in systolic blood pressure. These data indicate a close temporal relationship between brain NE synthesis rate and adrenocortical steroid secretion as well as demonstrating that a-MT is an effective antihypertensive agent in stress-induced hypertension.

In studies to determine the influence of adrenocortical deficiency on sensitivity to the volatile convulsant flurothyl, administered by inhalation, adult male rats were convulsed at 3-day intervals. Repetitive testing alone was found to decrease the latency to maximal convulsion in controls. However, adrenalectomy not only counteracted this effect, but also increased maximal seizure latency above pre-operative levels if the rats were maintained on tap water. In addition, adrenalectomy decreased the intensity of the maximal convulsion, but increased susceptibility to the minimal convulsive response (myoclonic jerk). This last effect is in accord with other reports of increased susceptibility to various experimentally-induced seizures after adrenalectomy, but in contrast to results with pentylenetetrazol seizures. Drinking 0.9 % NaCl reduced all effects of adrenalectomy on flurothyl convulsions.

The centrally mediated cardiovascular effects of prostaglandin E₁ (PGE₁) were investigated using cross-circulation procedures. PGE₁ was injected into the arterial inflow (IA-R) of vascularly isolated, ncurally intact heads of anesthetized recipient dogs. Following the administration of 5 and 10 μg/kg of PGE₁ (IA-R) consistent depressor responses occurred in the donor dogs and in the recipient's isolated trunk. The administration of 5 and 10 μg/kg of PGE₁ (IA-R) to debuffered recipients (carotid sinus-body areas bilaterally denervated) elicited centrally mediated pressor responses in the recipient's trunk paralleled by depressor effects in the donor and a decline in the recipient's perfusion pressure. Centrally mediated pressor responses of angiotensin II were inhibited by PGE₁ only in the non-debuffered recipients. Pressor responses to PGE₁ in debuffcrcd recipients were blocked by the ganglionic blocking agent, hexamethonium. These data plus results from the intra-artcrial administration of PGE₁ into the carotid sinus area before and after denervation suggest that the carotid sinusbody structures, most likely the baroreceptors, are primarily implicated in the hypotensive response to PGE₁ in the non-debuffered recipient's trunk. On the other hand, the central nervous systemper se appears to be involved in mediation of the central pressor responses obtained in the debuffered preparations. This study provides evidence for the involvement of the carotid sinus-body structures and the central nervous system as additional loci for the cardiovascular effects of PGE₁.

A series of antihistamines with widely differing chemical structures and pharmacological profiles have been compared to the standard antidepressants, imipramine and amitriptyline, in four laboratory antidepressant tests. Dexchlorpheniramine and tripelennamine are examples of antihistamines which were effective antagonists of tetrabenazine ptosis in mice, mouse-killing behavior in rats, and reserpine hypothermia in both species. Other antihistamines such as cyproheptadine, pyrilamine and promethazine were ineffective in these tests. The effectiveness of dexchlorpheniramine and tripelennamine in these procedures was equal to or greater than that of imipramine or amitriplyline. Potentiation of methamphetamine-induced excitation differed from other antidepressant tests because amitriplyline was ineffective, whereas promethazine, ineffective in other antidepressant tests, was a potent potentiator of methamphetamine.

After screening a series of nineteen clinically effective antihistamines for ability to prevent tetrabenazine-induced ptosis, it was found that all antihisiamines tested which are structurally related to pheniramine (alkylamine type) were effective tetrabenazine antagonists. Structural modifications of chlorpheniramine which cause severe reductions in antihistamine potency, did not affect anti-tetrabenazine activity. It is concluded that there is no correlation between antihistamine activity and activity in the aforementioned selected tests for antidepressant activity.

The effect of various drugs on the turnover rate of heart NE was determined from the product of the endogenous NE concentration and of the rate constant of NE-H³ declinc after injection of the radioactive amine in tracer doses. Chlorisondaminc, pcmpidinc. BW 392060, pargyline, and DMI inhibited the decline of NE-H³ and reduced the turnover rate by 30–50%. Only pargylinc and BW 392060 elicited detectable changes in the NE level. It is proposed that by decreasing the efflux of neurohormonc these drugs produce a slight rise in intrancuronal NE which leads to an inhibition of synthesis. The data support the concept that an autorcgulatory mechanism maintains the constancy of NE levels in the heart.

p-Chloropherrylalaninc, a drug that selectively inhibits the synthesis of serotooin, has been used in order to invcstigate the localization of this amine in nerves of the pineal gland of rats. Glands of normal and treated rats were studied under the electron microscope, after fixing with osmium tetroxide and glutaraldehyde, and applying specific histochemistry for catechol and indolamines. Fluorometric determinations of scrotonin, noradrenalinc and dopaminc were also made in normal and treated glands. In normal glands about 35 % of granulated vesicles were observed in nerve endings fixed with osmium tetroxide or glutaraldehyde. After treatment with p-chlorophenylalanine the dense core of the granulated vesicles disappeared in glands fixed with glutaraldehyde but remained unchanged or increased in number in those fixed in osmium tetroxide. p-Chlorophcnylalanine produced an 87% decrease in serotonin content of the pineal gland while noradrenalinc and dopamine content did not diminish, The correlation between morphological and biochemical data suggests that both catechol and indolamines are stored in granulated vesicles in the pineal nerves of the rat. This assumption was confirmed with the specific histochemical technique of wood to differentiate catechol and indolamines.

The present investigation was concerned with the effects of long-term administration of d-amphetamine in the daily drinking water of rats on weight and three behavioral tasks. No tolerance to the drug was found for weight measures, nor in the behavioral measures of lever pressing for illumination change or gross activity. Drug animals were significantly lighter than non-drug animals, pressed more for illumination change, and were more active. No difference was found between performance of drug and non-drug animals in an avoidance conditioning task. It may be that tolerance to the drug does not appear when measured by situations not employing strong motivational conditions (e.g. pressing for illumination change and activity), but where such conditions are employed (e.g. shock), tolerance as reflected in the lack of difference between drug and non-drug groups does appear.

The regional development of AChE in six areas of cat brain from the 43rd gestational day to adulthood has been studied. Consistent increases were found in the course of development in all areas, the greatest percent increase occurring from the 43rd gestational day to birth. No significant sex differences were found. Comparison of AChE values for cat with other species reveals a close similarity for subcortical structures but less so for the cortex. Cats reared in social isolation showed no consistent differences in regional AChE activity at 20, 30 and 60 days of age as compared with their maternally reared littermates.