A. Scotti de Carolis

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.

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.

Age and strain differences in rat place learning and hippocampal dentate gyrus frequency-potentiation.

Induction of post-tetanic potentiation (PTP) and long-term potentiation (LTP) was analyzed in hippocampal slices obtained from (i) young (6 months old) rats of different strains (Sprague-Dawley, SD; spontaneously hypertensive rats, SHR; and Wistar-Kyoto, WKY), and (ii) from aged (20-24 months old) SD and Fischer 344 (F 344) rats, each group showing a different performance in the Morris maze test. After the application of an electrical tetanus (1 s, 100 Hz, 50 microA) in the stratum moleculare, a significant difference was found in the percent of induction of the dentate PTP in hippocampal slices obtained from rats of different strains and ages. In particular, the induction of the dentate PTP was significantly (P < 0.01) higher in slices obtained from young SD or spontaneously SHR rats, having the better performance in the Morris maze than in slices obtained from old SD or F 344 rats or young WKY rats which had poorer performances in the Morris maze. On the contrary, no significant differences were found in the percent of induction of the LTP in the dentate area of hippocampal slices obtained from rats of different strains and ages. Moreover, after the application of an electrical tetanus (1 s, 100 Hz, 50 microA) in the stratum radiatum, no significant differences were found in the percent of induction of both PTP and LTP in the CA1 area of hippocampal slices obtained from rats of different strains and ages.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium antagonists on hypoxic and NMDA injury in rat hippocampal slices

The effects of various calcium antagonists, acting at the different neuronal calcium channels, were studied towards two models of in vitro neuronal injury in rat hippocampal slices. In particular, the influence of the drugs were tested on the electrical failure induced by treatment of hippocampal slices with hypoxia or high concentrations of the excitatory amino acid N-methyl-D-aspartate (NMDA). The L-type calcium antagonists, nifedipine (100 microM) and diltiazem (100 microM) or the T-type calcium antagonist amiloride (100 microM) failed to significantly affect the recovery from the CA1 electrical failure induced by both hypoxia or NMDA (50 microM). The N-type calcium antagonists, omega-conotoxin GVIA (0.5 microM) and neomycin (300 microM) significantly (P < 0.01) increased the probability of the recovery of the CA1 population spike after hypoxia but not after NMDA (50 microM). The glutamate antagonist dizocilipine (50 microM), tested for comparison, significantly (P < 0.01) increased the probability of the recovery of the CA1 population spike after hypoxia and NMDA (50 microM). The results suggest an involvement of calcium channels especially of N-type in the genesis of hypoxic but not NMDA neuronal injury.

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.

Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning

Induction of posttetanic potentiation (PTP) and long-term potentiation (LTP) was analyzed in hippocampal slices obtained from a) young 6-month-old Sprague-Dawley (SD) rats, all of them performing well in the Morris Maze, and b) aged SD 20-month-old and Fischer 344 24-month-old rats showing different degrees of ability in the same test. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum radiatum, no significant differences were found in the percent of induction of both PTP and LTP in the CA1 area of hippocampal slices obtained from rats of different strains and ages. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum moleculare, a significant difference was found in the percent of dentate PTP induction in hippocampal slices obtained from rats of different ages. Specifically, dentate PTP induction was significantly (p < 0.01) higher in slices obtained from young SD rats, and from old SD rats with a better performance in the Morris maze, escape latency less than 10 s and 150 cm, than in slices obtained from old SD or Fischer 344 rats that had shown poor performance in the Morris Maze. On the contrary, no significant differences were found in the percent of dentate LTP in hippocampal slices obtained from rats of different strains and ages. The data demonstrate that the induction of hippocampal dentate high-frequency PTP is selectively reduced in old rats with impaired Morris Maze performance.

Behavioral and electrophysiological correlates of the quinolinic acid rat model of Huntington's disease in rats

The influence of bilateral intrastriatal injection of quinolinic acid (QA, 300 nmol) was studied in male Wistar rats. Behavioral and electrophysiological experiments were conducted in 15 lesioned plus 15 vehicle-injected (control) animals. With respect to control animals, QA-lesioned rats showed marked, statistically significant alterations from both the behavioral (greater motor activation in response to d-amphetamine, place-learning deficit in the Morris water maze), and the electroencephalographic (reduced voltage amplitude and EEG power at the level of frontal cortex) points of view. In addition, a significant loss in body weight and a marked striatal gliosis (GFAP staining) were observed in lesioned rats. Conversely, QA-lesioned rats did not show modifications in posttetanic potentiation (P.T.P.) or long-term potentiation (L.T.P.) in CA1 hippocampal area. The present results confirm that QA lesions of rat striatum may be regarded as a suitable model of Huntingtons disease (HD).

Behavioural and electroencephalographic interactions between haloperidol and PCP/sigma ligands in the rat

Phencyclidine (PCP) and sigma ligands produce a typical excitatory behaviour in rats, characterized by circling and head- and body-weaving. Excitatory amino acid antagonists such as 2-amino 5-phosphonovaleric acid (AP5) or 3-(±)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) also produce a PCP-like excitatory behaviour in rats. In the present paper, the interactions between PCP/sigma drugs or excitatory amino acid receptor antagonists and haloperidol have been investigated in rats. In addition, the influence of two other butyrophenones having a different affinity for the sigma/haloperidol receptors, such as spiperone and 3-(4-(3(4-fluorobenzoyl)-propyl-piperazino-1-ylisoquinolino (HR 375), has been tested on the behavioural and EEG effects of PCP/sigma drugs and excitatory amino acid antagonists. PCP (2.5–5 mg/kg IP), (+) or (−) SKF 10,047 (1–15 mg/kg IP), (+) or (−) cyclazocine (2–8 mg/kg IP) and AP5 (0.5 µmol ICV) dose-dependently and significantly (P<0.01) antagonized the haloperidol-induced catalepsy in the horizontal bar and podium tests in rats. On the other hand, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP) reduced the head-weaving induced by (+) SKF 10,047, PCP, or AP5. On the contrary, HR 375 (6 mg/kg IP) was ineffective in blocking the excitatory effects of these drugs. In addition, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP), but not HR 375 (6 mg/kg IP) reduced the amplitude increase of the fast (20–30 Hz) frequency/low (30–50 µV) voltage background cortical activity elicited by PCP or (+) SKF 10,047. The results demonstrate an interaction between dopamine and excitatory amino acid receptors. At the same time, the data reveal the scarce relevance of the high affinity sigma/haloperidol receptors in the interference between PCP/sigma drugs and butyrophenones.