V.G. Longo

A pharmacological model of paradoxical sleep: The role of cholinergic and monoamine systems

Abstract Rabbits, cats and rats with chronically implanted electrodes were employed in the study of the EEG and behavioral actions of eserine following reserpinization. In reserpinized animals eserine induces what may be referred to as a pharmacological model of the paradoxical sleep. EEG desynchronization, hippocampal theta waves, ocular movements and complete relaxation of the muscles, particularly of the neck, were conspicuous, especially in the rabbit and cats. Tertiary, but not quaternary, atropine completely antagonized these phenomena. The action of eserine at various times after reserpinization was explored; the effectiveness of eserine in inducing the phenomena in question seemed to run parallel with the kinetics of the depleting actions of reserpine. Small, repeated doses of reserpine were effective in inducing, in conjunction with eserine, the phenomena described. The importance of the cholinergic system for the PS is envisaged; its interplay with other systems is discussed.

An investigation on the central effects of harmine, harmaline and related β-carbolines

Abstract The behavioural and EEG effects of harmine, harmaline and 5 related β-carbolines were studied in rats and rabbits bearing chronically implanted electrodes in various cortical and subcortical areas. Based on the results obtained, the 7 derivatives can be divided into 3 groups. The first group includes harmine and harmaline, which caused excitation, tremors, and ataxia both in the rat and in the rabbit. The modifications of the cerebral electrical activity during the tremors consisted of an increase in frequency and in voltage, observed in the cortical leads. Harmol, tetrahydro-harmane and 3-methyl-harmane had a different toxic effect, consisting of a depressive syndrome, which can extend to complete paralysis in the rat. Harmane and nor-harmane produced, at low doses, a motor depression having a catatonic component; higher doses led to clonic and tonic-clonic type convulsions; tremors were never observed. In the rabbit, but not in the rat, l -DOPA was effective in antagonizing the tremors and the other toxic symptoms caused by the two drugs. These results suggest that the tremors induced by harmine and harmaline may be caused by an effect on the extrapyramidal dopaminergic system.

A neuropharmacological investigation of some trans-tetrahydrocannabinol derivatives

Abstract A study of the central action of six cannabinoids has been carried out. The compounds studies (see table) were (−)Δ9THC and (−)Δ8THC, the racemic Δ8THC, the α methyl, and α, α dimethyl derivatives of (−)Δ8THC, and (−)cannabidiol. The effects of these drugs have been studied on the cerebral electrical activity and on spontaneous and conditioned behavior of cats, rabbits, and rats with chronically implanted electrodes. In the rabbit and in the rat, (−)Δ9THC, (−)Δ8THC, and the two methylated derivatives of (−)Δ8THC proved to have a similar effect; they induced a flattening of the EEG tracing, the disruption of the theta waves of the hippocampus and they gave rise to trains of high voltage spike-and-waves. These EEG modifications were accompanied by corneal arreflexia and other signs of motor deficit, together with a state of excitation and a reduced response to painful stimuli. The racemic Δ8THC, although provoking the same picture, proved less active. (−)Cannabidiol provoked motor paralysis and corneal arreflexia, these symptoms were accompanied by an EEG synchronization. In the cat, the performance of a conditioned instrumental discrimination exercise was blocked by the administration of 2 mg/kg of Δ9THC; this effect was accompanied by a synchronization of the EEG. These results are discussed also in relation to the human effect of some of these compounds. It is suggested that the flattening of the EEG and the appearance of the spike-and-waves may be the EEG counterpart of the psychodysleptic action of the tetrahydrocannabinols in man.

Action of two hypothalamic factors (TRH, MIF) and of angiotensin II on the behavioral effects of L-DOPA and 5-hydroxytryptophan in mice.

Abstract Melanocyte stimulating hormone release-inhibiting factor (MIF), thyrotropin releasing hormone (TRH) and angiotensin II, injected i.p. to mice, potentiate the behavioral effect of L-DOPA and 5-hydroxytryptophan.

A study of the central effects of sympathomimetic drugs: EEG and behavioural investigations on clonidine and naphazoline.

Abstract The effect of clonidine and naphazoline on the EEG and behaviour of rats, rabbits and cats, and the modifications of these effects by α-adrenolytic drugs and other compounds acting on the sympathetic system, have been studied. Clonidine and naphazoline induced behavioural depression and EEG synchronization in all animal species studied. These effects were prevented by the administration of tolazoline, phentolmine and yohimbine, but not by phenoxybenzamine. Pretreatment with α-methyl- p -tyrosine was only partially effective in preventing the EEG synchronization due to clonidine. Reserpine was without effect. Amphetamine proved able to reverse the effects of clonidine and furthermore, clonidine attenuated the behavioural and EEG changes due to amphetamine. These data suggest that clonidine and naphazoline induce sedation and EEG synchronization through stimulation of the central α-adrenergic receptors.

Intensification of central catecholaminergic and serotonergic processes by the hypothalamic factors MIF and TRF and by angiotensin II

Abstract The present work deals with the action of MIF (melanocyte stimulating hormone release-inhibiting factor), TRF (thyrotropin releasing factor), and angiotensin II on the behavioral effects of L-DOPA and of D,L-5-hydroxytryptophan (5-HT) in mice. The influence of MIF and TRF on the antagonistic effect of L-DOPA of harmine tremors in rabbits was also studied. MIF and TRF, injected i.p., intensify the effects of L-DOPA in mice. The minimal dose of MIF required to induce a +3 response is 0.1 μg/kg; TRF is active at 500 μg/kg. When MIF or TRF are injected into the brain, potentiation of L-DOPA is obtained with exceedingly small quantities of MIF (0.1 pg); the effective dose of TRF is 1 μg. The behavioral effects of 5-HTP are potentiated by TRF only, at doses of 0.1 μg/kg, i.p. When TRF is administered intracerebrally, the active dose per mouse is 0.1 ng. Harmine (5 mg/kg i.v.) induces, in the rabbit, sustained whole body tremors; if L-DOPA (5 mg/kg) is administered i.v. at the peak of the harmine effect, the tremors subside. When the rabbit is pretreated with MIF, administered i.p. 1–2 hr before harmine, in doses devoid of an antitremor effect per se (10 μg/kg), the L-DOPA antagonism appears at lower doses. Also dopamine (5–10 mg/kg i.v.) proved effective in abating harmine tremors; previous treatment with MIF (50 μg/kg) potentiated the antagonistic effect of dopamine. According to the prevailing theories on the mechanism of neurotransmission, some hypothesis will be discussed to explain the observed potentiation: impaired uptake, impaired degradation, interference with the turnover of the bioamines, supersensitivity of the receptors.

Neuropharmacological investigations on muscimol, a psychotropic drug extracted from Amanita muscaria.

SummaryThe effects of muscimol on the EEG and on the spontaneous and conditioned behavior of cats, rabbits, and rats were studied. High voltage 3 c/sec. waves appear in the EEG tracing of rabbits and rats treated with 0.5–1 mg/kg of the drug; after higher doses (2 mg/kg) spikes appear, intermingled with the slow waves. Administration of eserine (0.2 mg/kg) only slightly influences the EEG “synchronization” induced by muscimol. Muscimol-treated rabbits receiving small doses of diazepam or pentobarbital exhibit a flaccid paralysis accompanied by an EEG pattern similar to that of the deep stages of anesthesia. In cats and rabbits trained to an instrumental reward discrimination task, muscimol disrupts the conditioned performance at doses of 0.5–1 mg/kg. Spikes appear on the EEG of the cats treated with the drug and unable to perform the conditioned task. These results are discussed in relation to the hallucinogenic and confusional effects reported for muscimol in man.

Dopamine receptor subtypes and arousal.

Publisher Summary The study of events induced by centrally acting dopaminergic (DAergic) agents is a classic means of investigating the pharmacology and function of DA within the central nervous system (CNS). This chapter focuses on the activity of selective agonists for D-1 and D-2 receptors. The series of experiments demonstrates that DA receptor systems, especially the D-1 subtype, are primarily involved in the generation of arousal in laboratory animals. From the data, it appears that both D- 1 and D-2 receptors, when stimulated, can influence to different extents this physiological event. However, of the two receptors, D-1 seems more concerned with the generation of cortical and behavioral arousal. At the cellular level, the differential function in arousal process between D-1 and D-2 receptors might well depend on the different cascade of events that are initiated by the stimulation of each receptor site. The formation of the second messenger cAMP and the activation of the polyphosphoinositide system could certainly be responsible for differences in the ultimate biological response. In addition, it is well known that the DAergic system may be intimately related with the noradrenergic system in the control of behavior. Experimental and theoretical reviews have proposed that multicenter anatomical systems with multiple neurochemical signatures are involved in the elaboration of the sleep-waking states.

EEG and behavioral effects of morphine, enkephalins and derivatives administered into the lateral cerebral ventricles of rats and rabbits*

Summary An investigation on the behavioral and EEG effects of met-enkephalin, leu-enkephalin, D-Ala 2 -MePhe 4 -Met(O) 5 -ol enkephalin (FK 33284) compared to morphine, has been carried out. The drugs were injected into the lateral cerebral ventricle of rats and rabbits bearing chronically indwelling canulas and electrodes. The parameters considered were: EEG records from cortical and subcortical areas, gross behavioral changes, occurrence of analgesia. Enkephalins and morphine induce similar modifications of EEG and behavior of rats and rabbits. The relative potency of these compounds in inducing such changes is: FK 33284 D-Ala-enkephalinamide morphine Leu-enkephalin Met-enkephalin. In the rabbit, however, morphine exhibited a convulsant effect which the enkephalins did not possess.

EEG and behavioral effects of natural, synthetic and biosynthetic cannabinoids

The pharmacological effects of marihuana in man and animals have been attributed to Δ1 and Δ6 tetrahydrocannabinol (THC).Recently, one of the metabolites of THC, 7-OH-THC, has been reported to have intoxicating properties. A comparative study was carried out on the EEG and behavioral effects of cannabinol, cannabidiol, Δ6-THC, 7-OH-Δ6-THC and 7-Acetoxy Δ6-THC acetate in six chronically implanted rabbits bearing cortical and subcortical leads. Drugs were dissolved in polyethyleneglycol and administered i.v. once every 7 days in a crossover experimental design. 7-OH-Δ6-THC and 7-Acetoxy-Δ6THC acetate proved to be at least twice as active as Δ6-THC in inducing EEG changes (disruption of theta waves, appearance of spikes and waves, blockade of the “arousal” reaction) and behavioral alterations (excitation, exophthalmus, mydriasis, corneal arreflexia, ataxia and swaying). Pretreatment with 1 or 2 mg/kg of reserpine, s.c., did not substantially alter the subjects response to THC.Amphetamine 2 mg/kg, i.v., in animals pretreated with 2 or 4 mg/kg Δ6-THC, reverses in part the depression induced by THC.