The role of brain serotonin in the electroconvulsive shock-induced changes in behavioural effects of intra-hippocampally injected clonidine.

The influence of central serotonin depletion upon behavioural effects of intra-hippocampally injected clonidine in the electroconvulsive shock-treated rats (ECS), was studied. Repeated ECS significantly attenuated the depressive influence of clonidine upon the locomotor activity of the rats in the open field test. Chemical lesions to the median raphe nucleus (MR) did not significantly affect ECS-induced changes in clonidine activity in this test. In the forced swimming the MR lesions revealed the stimulatory potency of clonidine microinjections upon rat active behaviour. In animals pretreated with repeated ECS, clonidine also significantly potentiated swimming activity, but no evident synergism of ECS and MR lesion could be observed. Taking into account these and other data it is concluded that central serotonin depletion might differentially affect the adaptive processes occurring in the alpha 2-adrenoceptors in the course of treatment with tricyclic antidepressants and ECS, but it does not seem to be a strong phenomenon. Moreover, it is suggested that clonidine effects in the open field and forced swimming tests may be mediated by different neuronal substrates within the rat hippocampus.

Brain neurotransmitter systems mediating behavioral deficits produced by inescapable shock treatment in rats.

The effect of inescapable footshock (IS) upon rats' motor activity (the open field and forced swim tests) was studied in rats subjected to drugs, and neurotoxin treatments, affecting their central neurotransmitter systems. The agonists of GABA-receptor complex, dopamine, noradrenaline and serotonin neuronal systems, as well as the cholinergic antagonist, partially reversed motor suppression induced by IS, while the dopamine agonist, chlorpromazine, and the cholinergic antagonist, physostigmine, potentiated it. The effects of chemical lesions of the brain monoaminergic neurons with p-chlorophenylalanine (pCPA), N-chloro-ethyl-2,2-bromo-benzylamine (DSP-4), 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (5,7-DHT) were more complex, depending upon the extent of monoamine depletion, and the kind of test applied. It is concluded that a decrease in the brain noradrenergic, serotonergic, dopaminergic and GABAergic neuronal activity, as well as the central cholinergic hyperactivity, might contribute to the behavioral suppression after IS. Thus the central mechanisms of behavioral deficits produced by IS involve multiple neurotransmitter systems, and the analysis of their role in more complicated behavioral patterns must also take into account changes in animals' baseline and stimulated motor activity.

Interactions between calcium channel compounds and adenosine systems in brain of rat.

A number of organic ligands of calcium channels were investigated for possible actions on several aspects of adenosine systems in the cerebral cortex of rat. The principle findings of the present study were that a number of antagonists of calcium channels and the agonist compound Bay K 8644 inhibited binding to adenosine receptors, binding to nucleoside transporters, and the accumulation of [3H]adenosine with a low microM potency. 2-Nitrophenyl dihydropyridine derivatives were more potent than 3-nitrophenyl dihydropyridine or non-dihydropyridine ligands of calcium channels at inhibiting binding to adenosine receptors. Dihydropyridine ligands of calcium channels were more potent than non-dihydropyridine ligands of calcium channel in inhibiting the binding of [3H]nitrobenzylthioinosine to cortical membranes or inhibiting the accumulation of [3H]adenosine into synaptoneurosomes. However, unlike the case of adenosine receptors, no distinction between 2-nitrophenyl and 3-nitrophenyl dihydropyridine derivatives was observed. In addition, the non-dihydropyridine ligand of calcium channels, diltiazem was a weak inhibitor of the accumulation of [3H]adenosine. These results demonstrate that organic ligands of calcium channels, particularly dihydropyridine compounds, can interact with several aspects of adenosine systems.

Brain adenosine receptors in Maudsley reactive and non-reactive rats.

Previous work in our laboratory has shown that the Maudsley reactive (MR) strain of rats cannot be differentiated from the Maudsley non-reactive (MNR) strain regarding the number or affinity of their brain benzodiazepine binding sites. In the present study we show that the number of cerebellar adenosine receptors (as studied using [3H]cyclohexyladenosine, [3H]CHA, as the ligand) are increased by 15-30% in the MR strain. This alteration was corroborated by quantitative autoradiographic analysis and found to be localized to the molecular layer of the cerebellum where adenosine receptors are believed to reside on parallel fibers of cerebellar granule cells.

The effect of 5,7-DHT-induced lesions of the median raphe nucleus and chronic desipramine administration upon motor behaviour of rats given intrahippocampal clonidine injection.

The role of serotonergic (5-HT) innervation of rat hippocampus in clonidine- induced behavioural effects was studied in naive and desipramine-pretreated animals. 5,7- DHT-lesions of the median raphe nucleus (MR) produced about 50 per cent decrease of serotonin and 5-hydroxyindoloacetic acid (5-HIAA) content in the rat cortex and hippocampus. Lesions of the MR also accelerated the attenuating effect of desipramine upon locomotor inhibition produced by intrahippocampal clonidine injections. In the forced swim test (FST) the MR lesion revealed the stimulatory potency of clonidine upon rat active behaviour, which was statistically significant. However, no further potentiation by MR lesions of DMI effects upon behavioural action of clonidine could be observed in this test. It is concluded that hippocampal serotonergic innervation plays a minor role in the antidepressant-induced changes in behavioural effects of clonidine, which probably occur via modulation of local alpha-adrenoceptors. It is also conceivable that the stimulatory effect of intrahippocampal clonidine injections in the forced swim test in MR-lesioned rats, may be due to the increase in the alpha-(1)-adrenoceptor function in this brain area.

Ethanol-induced hypothermia. Cross tolerance with morphine.

The development of tolerance to ethanol-induced hypothermia and hypnosis, and cross-tolerance with morphine was studied in mice and rats. Ethanol significantly decreased the body temperature in rats (3.0 and 3.2 g/kg) and in mice (3.5 and 4.0 g/kg). Chronic administration of ethanol resulted in the tolerance not only to ethanol hypothermia but also to hypothermic effects of morphine in examined animals. Implantation of morphine pellets caused the development of cross tolerance to ethanol-induced hypothermia in rats but not in mice. The hypnotic effect of ethanol was significantly shorter in chronic alcoholized rats but not in morphine-implanted rats. Neither chronic ethanol administration nor implantation of morphine pellets changed the duration of ethanol-induced hypnosis in mice. These results seem to support the hypothesis on the opiate-like mechanism of ethanol action.

'Peripheral' and 'central' type benzodiazepine receptors in Maudsley rats.

In this study the binding to 'central' and 'peripheral' benzodiazepine receptors in various brain areas in MR/N and MNR/N rat strains was investigated. The specific ligands [3H]BCCE and [3H]RO 5-4864 were used for binding to 'central' and 'peripheral' benzodiazepine receptors, respectively. Neither [3H]BCCE nor [3H]RO 5-4864 binding was changed in MNR/N strain in comparison to MR/N rat strain in cerebral cortex, cerebellum, hippocampus and medulla-pons. Scatchard analysis of [3H]BCCE or [3H]RO 5-4864 binding to cerebellar membranes also revealed no changes in either affinity or density in both types of benzodiazepine receptors. Autoradiographic analysis of brain regions using microdensitometry shows no differences in [3H]flunitrazepam binding between the MR/N and MNR/N strains. Our results, therefore, fail to confirm a previous report showing alterations in benzodiazepine receptors in Maudsley rats.

The development of cross tolerance between ethanol and morphine.

The development of tolerance to ethanol-induced analgesia and cross tolerance between ethanol and morphine was studied in mice and rats. Chronic administration of ethanol resulted in the tolerance to its analgesic effects in rats (2.8 and 3.0 g/kg) as well as in mice (2.8 and 4.0 g/kg). Implantation of morphine pellets caused the development of cross tolerance to analgesic effect of 3.0 g/kg of ethanol in rats and 2.8 g/kg of ethanol in mice. The tolerance developed to antinociceptive effects of morphine (10 mg/kg) in chronic alcoholized mice but not in chronic alcoholized rats. These results seem to support the hypothesis on the opiate-like mechanism of ethanol action.

Brain benzodiazepine binding sites in ethanol dependent and withdrawal states.

The brain benzodiazepine system has been implicated to be important in both the mechanism, and treatment of ethanol related syndromes. In this report evidence is presented which indicates that "peripheral type" benzodiazepine binding sites are probably more relevant than "central type" receptors for the neurochemical consequences of ethanol dependence and withdrawal states. Utilizing radioreceptor binding techniques 20-50% increases in the binding of [3H]RO-5-4864 (a "peripheral type" ligand) to brain membranes derived from rat cerebral cortex, cerebellum and hippocampus are observed in ethanol dependent rats. These increases persist for 3 days after cessation of ethanol. The number of [3H]RO-5-4864 binding sites in cerebellum returns to normal during 4-7 days after ethanol withdrawal. In all brain areas examined no changes were observed in the "central type" benzodiazepine receptor as judged by [3H]-ethyl-Beta-carboline-3-carboxylate, BCCE binding. Scatchard analysis revealed that the number of [3H]RO-5-4864 binding sites is increased in each brain area while the affinity was unchanged.

Response to ethanol reduced by past thiamine deficiency.

Ethanol-induced intoxication and hypothermia were studied in rats approximately 7 months after severe thiamine deficiency, when treated rats appeared to have recovered their physical health. Previously induced thiamine deficiency without prior ethanol exposure significantly decreased the area under the curve plotted for the concentration of ethanol in blood and also decreased behavioral impairment and hypothermia due to ethanol exposure. Pathophysiologic changes resulting from thiamine deficiency may contribute to both the pharmacodynamic and pharmacokinetic tolerance to ethanol in chronic alcoholics.

Ethanol-opioid interaction in mice.

The influence of opiate receptor antagonists: naloxone, naltrexone and diprenorphine, and of an agonist: morphine on ethanol-induced sleep, hypothermia and motor coordination impairment was investigated. Naloxone and naltrexone evidently antagonized the sleep and hypothermia, and improved the motor coordination impaired by ethanol. Naltrexone was the most, and diprenorphine the least potent ethanol antagonist. Morphine potentiated only ethanol-induced sleep, and this effect was opiate dependent (reversible by naloxone). The present results may partially support the hypothesis about participation of opioid system in ethanol action. However, ethanol effects were affected only by high doses of opiate antagonists, exceeding by far the doses antagonizing the morphine effects. Therefore the participation of additional, unspecific mechanisms, in addition to an opiate-mediated one, cannot be excluded.