Arsenia Scotti de Carolis

Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors.

BEHAVIOURAL, AND biochemical evidence for the existence of a powerful specific postsynaptic interaction between adenosine A1, and dopamine D1 receptors in the mammalian brain was found. Behavioural data showed that A1 receptor stimulation induced a decrease in the D1-induced motor activation in reserpinized mice, and a decrease in the D1-dependent oral dyskinesia in rabbits. Biochemical data suggested that A1 receptor stimulation could produce a GTP-independent uncoupling of the rat striatal D1 receptor to the G protein. The A1-D1 receptor-receptor interaction might represent an important additional mechanism of action responsible for the motor depressant effects of adenosine agonists, and for the motor stimulant effects of adenosine antagonists, like the methylxanthines caffeine, and theophylline

Modulation of striatal adenosine A1 and A2 receptors induces rotational behaviour in response to dopaminergic stimulation in intact rats

The intraperitoneal injection of d-amphetamine (5 mg/kg i.p.), preceded (10 min before) by intrastriatal injection of an adenosine A2 receptor agonist (CGS 21680, 5-10 micrograms) or followed (5 min later) by an intrastriatal adenosine A1 receptor agonist (N6-cyclopentyladenosine, CPA, 30 micrograms), induced ipsilateral rotations in rats. The opposite effect (contralateral rotations) was observed with adenosine receptor antagonists (A2 antagonist, 3,7-dimethyl-1-propargylxanthine, DMPX, 10 micrograms; A1 antagonist, 8-cyclopentyl-1,3-dimethylxanthine, CPT, 2.5 micrograms). These results confirm that both adenosine A2 and A1 receptors modulate striatal dopaminergic neurotransmission.

Reduced hippocampal CA1 Ca2+-induced long-term potentiation is associated with age-dependent impairment of spatial learning

Expression of Ca(2+)-induced CA1 long-term potentiation (LTP) was analysed in hippocampal slices obtained from (1) 3-month-old and (2) 18-20-month-old Sprague-Dawley rats selected for their performances in the Morris water maze task. In all slices, a transient (10 min) increase of extracellular Ca2+ concentration (4 mM) caused a long-lasting enhancement of potentials evoked by electrical stimulation of radiatum fibers. However, a significant difference was found in the degree of potentiation among groups. In particular, increases of the CA1 response amplitudes were significantly lower in old rats impaired in spatial learning than in young at 30 (P < 0.05), 60, 90 and 120 min (P < 0.01) after restoring the normal Ca2+ concentration. On the contrary, no differences were observed between young animals and the old ones with good performances in spatial learning. The data suggest that amplitude of CA1 Ca(2+)-induced LTP in old rats is related to spatial learning abilities.

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.

CGS 21680 antagonizes motor hyperactivity in a rat model of Huntington's disease.

Abstract The influence of CGS 21680 (2-[ p -(2-carboxyethyl)phenethylamino]-5′-ethylcarboxamido-adenosine), and adenosine A 2 receptor agonist, was tested in an animal model of Huntingtons disease. Male Wistar rats received bilateral intrastriatal injections of quinolinic acid and then, 1 and 2 weeks later, they were treated with intrastriatal CGS 21680 (3 μg/2 μl) or saline. While quinolinic acid-lesioned rats not treated with CGS 21680 showed the typical motor hyperresponsiveness to d -aphetamine (1 mg/kg i.p.), the intrastriatal injection of CGS 21680 completely prevented this effect.

Nucleus basalis magnocellularis lesions impair mossy fiber system in rat hippocampus: a quantitative histochemical and ultrastructural study

Lesions of the nucleus basalis magnocellularis (NBM) cause depletion of choline acetyltransferase (ChAT) in the cerebral cortex and behavioral changes consisting of impaired ability to learn avoidance tasks. Since hippocampal mossy fibers (MF) are involved in the elaboration of passive avoidance responses, we analyzed MF by means of Timms histochemical technique and electron microscopy, to find out whether monolateral lesions of NBM had any effect on MF system. NBM-lesioned rats, 3 weeks after lesioning, showed a significant and progressive decrease in the density of Timm staining as well as significant changes of the morphology of synapic boutons of the MF. These results suggest that, although NBM does not send direct projections to the hippocampus, lesions of this nucleus may have a neurodegenerative effect on the intrahippocampal pathway involved in avoidance responses.

Protective actions of 21-aminosteroids and MK-801 on hypoxia-induced electrophysiological changes in rat hippocampal slices

The effects of the 21-aminosteroids, U-74500A and U-78517F (drugs endowed with lipid peroxidation inhibitor properties) were tested on hypoxia-induced functional failure in rat hippocampal slices. For comparison, the effects of the non-competitive N-methyl-D-aspartate antagonist, dizocilpine (MK-801) were studied. Perfusion of slices with 50 microM of MK-801 or with 50-100 microM of U-78517F, but not with 100-200 microM of U-74500A, significantly (P < 0.01) increased the incidence of reappearance of the CA1 population spikes after reoxygenation in rat hippocampal slices subjected to a 45-min hypoxic period followed by a 45-min reoxygenation period. Perfusion of slices with 12.5 microM of MK-801 plus 12.5 microM of U-78517F significantly (P < 0.05) increased the incidence of reappearance of the CA1 population spikes after reoxygenation with respect to perfusion of slices with 12.5 microM of U-78517F alone or with 12.5 microM of MK-801 alone. The results show that 21-aminosteroids have protective effects against hypoxia-induced functional failure in rat hippocampal slices. In addition, the data show that, under the same experimental conditions, the NMDA receptor antagonist, MK-801, was also able to improve hypoxia-induced functional failure. On the whole, the results suggest that the hypoxia-induced functional electrical failure might depend on both release of excitatory amino acids and oxygen free-radical-mediated membrane lipid peroxidation.

Absence of calcium-induced LTP-like response in the dentate area of seizure-prone gerbils and its relation to parvalbumin in the entorhinal perforant path synapse of this species

Mongolian gerbils (Meriones unguiculatus) are genetically predisposed to seizures, for which an involvement of hippocampal hyperexcitability and disinhibition has been suggested. The response in vitro of the hippocampal synaptic circuit upon exposure to an elevated extracellular calcium concentration is well known in the rat, and its dependence on inhibitory and excitatory transmission has been thoroughly studied. The purpose of the present investigation was to compare the influence of elevated extracellular calcium on inhibitory and excitatory transmission in the dentate area and the CA1 field of gerbil and rat hippocampal slices. Elevated calcium induced in the CA1 area of both animal species a long-term potentiation (LTP)-like response. Upon calcium exposure in the dentate area a decrease in population spike amplitude occurred in both gerbil and rat slices, indicating a similar degree of synaptic inhibition in the two species. However, in contrast to the effects known in the rat, elevated extracellular calcium failed to enhance the excitatory postsynaptic potential in the gerbil dentate area. This difference may depend on the species-specific, selective presence of the calcium-binding protein parvalbumin in perforant path terminals of the gerbil, which may be relevant to the susceptibility to seizures of this animal species.

Influence of nimodipine and diltiazem, alone and in combination, on phencyclidine-induced effects in rats: an EEG and behavioural study

The influence of nimodipine and/or diltiazem on the EEG and behavioural effects induced by phencyclidine (PCP) was assessed in adult male Wistar rats. Nimodipine (2 and 10 mg/kg i.p.) and diltiazem (25-100 mg/kg i.p.) significantly potentiated both EEG (increase in background activity voltage, incidence of clustered slow waves) and behavioural (ataxia mean intensity) effects of PCP (5 mg/kg i.p.). A synergistic effect between low, ineffective doses of both nimodipine (0.5 mg/kg i.p.) and diltiazem (5 and 10 mg/kg i.p.) was also found. These data confirm the recent finding of a positive allosteric modulation existing between benzothiazepine (diltiazem) and dihydropyridine (nimodipine) binding sites. They also suggest that the modulation of calcium channels may play a pivotal role in the expression of PCP-induced effects.

The role of the purinergic system in the control of stereotypy: Relationship to D-1/D-2 dopamine receptor activity

A behavioral study on the stereotypy induced by caffeine and carbamazepine or caffeine and haloperidol was assessed in adult male rabbits. The stereotypy induced by caffeine + carbamazepine was not reduced by pretreatment with haloperidol (0.1 mg/kg) or SCH 23390 (0.01 mg/kg). N-ethylcarboxamidoadenosine (NECA, 0.01 mg/kg), an A2 adenosine receptor agonist, completely prevented the appearance of caffeine + carbamazepine-, but not of caffeine + haloperidol-induced stereotypy. An EEG investigation was also performed in order to evaluate the influence of the blockade of D-1 and D-2 dopamine receptors on the desynchronized tracing induced by caffeine (50 mg/kg). Neither haloperidol (0.1 mg/kg) nor SCH 23390 (0.01 mg/kg) were able to influence this EEG effect of caffeine. Present data support the hypothesis that A2 adenosine receptors may be involved in the control of pathological movements. The relationship between the purinergic system and D-1/D-2 dopamine receptors is also discussed.