Robert George

A cholinergic mechanism in the brainstem reticular formation: Induction of paradoxical sleep

Abstract Microinjection of oxotremorine (a muscarinic agent) or carbachol into the pontomesencephalic reticular formation in conscious cats causes atonia, cortical desynchronization and synchronization of hippocampal activity. Some animals present a behavioral and electrographic picture indistinguishable from paradoxical sleep (PRS), while others, judging from EEG patterns and eye activity, appear to be alert despite the absence of muscular tone. These effects may be induced by as little as 0.2 of either drug, and persist for 45–60 min; they are antagonized by atropine sulfate administered either focally into the same sites, or systemically. These findings constitute evidence for the existence of a cholinergic mechanism in this area of the reticular formation. It is concluded that the receptor sites involved are muscarinic, and that the effects described most probably occur as a result of the selective activation of inhibitory neurones. A method for recording sleep cycles, based upon the measurement of hippocampal theta wave activity, is presented.

Diurnal Variations in Plasma Corticosterone and Growth Hormone as Correlated with Regional Variations in Norepinephrine, Dopamine and Serotonin Content of Rat Brain

Statistically significant diurnal variations in plasma growth hormone (GH) were found to occur in handled male rats. Peak GH values (at miday) appeared to be inversely correlated with the diurnal peak of plasma corticosterone(CS) which occurred after the onset of darkness. Brain amines were examined in the following regions: cortex, striatum, septum, amygdala, pons, midbrain, and hypothalamus. Statistically significant diurnal cycles of serotonin (5-HT) concentration were found in the amygdala and midbrain, significant diurnal alterations in norepinephrine (NE) levels. Ultradian dopamine (DA) cycles were significant in all regions examined. Plasma GH changes were found to be directly correlated with midbrain and amygdala 5-HT levels and with DA levels of all areas except the amygdala, Plasma CS was found to be inversely correlated with striatal and cortical DA and with 5-HT levels of amygdala.

Characterization of the effects of the acute and repeated administration of MK-801 on the release of adrenocorticotropin, corticosterone and prolactin in the rat

In addition to its producing profound changes in behavior, phencyclidine (PCP) disrupts neuroendocrine function in the rat. Because PCP binds to PCP as well as sigma receptors, it is not known which receptor type mediates the various effects of the drug. The purpose of the present study was to characterize the effects of the acute administration of enantiomers of MK-801, a compound with a high degree of selectivity for PCP over sigma receptors, on the release of ACTH, corticosterone and prolactin in the rat. In addition, MK-801 was administered daily for eight days in order to test whether tolerance develops to MK-801-induced ACTH and corticosterone release after repeated administration. While both enantiomers of MK-801 markedly increased plasma levels of ACTH and corticosterone, the (+) enantiomer was more potent. Tolerance developed to MK-801-induced increases in ACTH and corticosterone after repeated administration. Plasma prolactin levels were not affected by either the acute or the repeated administration of MK-801. These results suggest that the decrease in plasma levels of prolactin produced by PCP-like drugs is not mediated by PCP receptors, and may be a marker for a sigma receptor-mediated effect.

Endocrine influences on the actions of morphine: IV. effects of sex and strain

The antinociceptive and temperature responses to morphine were compared in male and female rats from two different strains. Males of both the Sprague-Dawley and Wistar-Furth strains were slightly more responsive to the acute actions of morphine than were females of the same strain. However, Wistar-Furth animals required approximately twice the dose of morphine to display equivalent antinociceptive responses and four times the dose of display equivalent hypothermic responses when compared with Sprague-Dawley animals. During chronic morphine treatment, the development of tolerance was slightly more rapid in males than in females and in Sprague-Dawley animals than in Wistar-Furth animals. Gonadal hormones also influenced morphine responses. Ovariectomized rats were significantly more responsive acutely to morphine and developed tolerance less rapidly than estradiol-treated females. However, alterations of gonadal hormones in males did not affect morphine responses. These results indicate that morphine responses vary considerably between strains of animals and are influenced by gonadal hormones of females, but not of males.

Acute tolerance to morphine following systemic and intracerebral injection in the rat

Abstract Morphine produces hypothermia in rats when administered intravenously or directly into the anterior hypothalamus. When the dose was repeated in 3–4 hr there was evidence of acute tolerance and the dose had to be increased two to four times to produce a comparable response. Four days after an initial injection the dose had to be increased by 50% to produce a comparable fall in temperature. Tolerance to systemic administration was evident for over 20 days after an initial injection. Many animals developed hyperthermia following a second dose of morphine and this appears to be a stimulatory effect of the drug to which tolerance does not develop.

Effect of Hypothalamic Stimulation on Blood Glucose in the Rabbit

Studies were carried out in rabbits to localize by electrical stimulation the sites in the hypothalamus that are concerned with the production of hyperglycemia, and to determine the contribution of the sympathetico-adrenal system in producing this effect. Stimulation of the anterior hypothalamic area, paraventricular nuclei, and rostral border of the ventromedial nuclei produced a significant elevation of blood glucose in normal rabbits and also in adrenal-demedullated animals. Corticotropin (ACTH), 2 U/kg, produced a hyperglycemia comparable to that observed following electrical stimulation, whereas growth hormone (GH), 2.5 mg/kg, had no effect on blood glucose. The data indicate that the anterior hypothalamus plays a part in the regulation of blood glucose, which is independent of the sympathico-adrenal system. It is suggested that the hyperglycemia produced by hypothalamic stimulation in these studies is due to the release of one or more anti-insulin factors by the anterior pituitary.

Thyroid Activity Following Intracerebral Injection of Morphine in the Rat

Injection of microquantities of morphine into two sites in the hypo-thalamus was found to depress the release of radioiodine from the thyroid gland of rats. These sites lay in the supraoptic or the su

Heat production and heat loss in the rat following intracerebral and systemic administration of morphine.

Abstract The fall in core temperature of the rat following either intravenous administration of morphine sulfate or injection of the drug into the anterior hypothalamus is accompanied by a pronounced reduction in oxygen consumption. No significant change in skin blood flow occurred after morphine. The mean rate of fall in temperature in the group of animals injected systematically was greater than that of the animals receiving intracerebral injections. This difference is regarded as an action of morphine apart from the effect of the drug on the thermoregulatory centers. It is concluded that the hypothermic effect of morphine is due to a reduction in metabolic heat production rather than to an increase in heat loss.

Comparison of the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat

Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.

Thyroid activity following administration of morphine in rats with hypothalamic lesions

Abstract The inhibitory effect of morphine on pituitary-thyroid activity in the rat is abolished by bilateral electrolytic lesions involving the region of the medial mammillary nuclei of the hypothalamus whereas rostral hypothalamic lesions do not alter the response to morphine. It is suggested that the action of morphine may be due to activation of areas inhibiting the release of TSH from the pituitary gland.