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A large body of electrophysiological data has supported the hypothesis that an important role of norepinephrine in the central nervous system is to modulate the actions of other transmitter systems, particularly those utilizing the amino acid neurotransmitters. Noradrenergic potentiation of inhibitory responses, induced by locally-applied or synaptically-released gamma-aminobutyric acid (GABA) on cerebellar Purkinje neurons, has been observed by a number of investigators, who have suggested that activation of beta-adrenergic receptors plays a critical role in mediating this modulatory effect of norepinephrine (NE). Two postsynaptic receptors for GABA, termed A and B, have been identified and both subtypes have been found in the cerebellum of the rat. The purposes of this investigation were first to identify the subtype(s) of GABA receptor responsible for mediating the inhibitory effects of locally-applied GABA in the cerebellar cortex and second to identify which subtype of GABA receptor is modulated by a beta-adrenergic input. Inhibitory responses of cerebellar Purkinje neurons, in urethane-anesthetized rats, to iontophoretic or pressure-applied isoguvacine, a selective GABAA agonist, to baclofen, a GABAB agonist or to GABA itself, were examined before, during and after local application of isoproterenol or norepinephrine. Isoguvacine, but not baclofen, induced consistent and dose-dependent inhibition of the firing of Purkinje cells. At ejection currents that had no effect on spontaneous firing rate, iontophoretically-applied isoproterenol potentiated isoguvacine-induced inhibition. These data suggest that GABAA, rather than GABAB receptors, mediate GABA-induced inhibitions of cerebellar Purkinje neurons. Moreover, it appears that the modulation of GABA function by beta adrenergic agonists involves an interaction between a beta-adrenergic input and the GABAA receptor complex.

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The effects of the selective dopamine D1 and D2 receptor agonists, SKF 38393 and N-0437, respectively, on the firing rate of medial prefrontal cortex (PFC) neurons were studied in young (3-5 months old), and aged (18 and 26 months old) Fischer 344 rats. Multibarrel glass micropipettes, filled with 1 mM SKF 38393 and N-0437, were lowered into the anteromedial cortical target area (PFC) of the mesocortical dopamine system in urethane-anesthetized animals. The drug solutions were locally applied by pressure ejection. In young rats, both agonists produced dose-dependent and reversible reductions in firing rates. However, the D2 agonist was approximately 10 times more potent than the D1 agonist in suppressing firing rate. Even at the highest doses, SKF 38393 rarely produced complete cessation of firing in PFC cells. Moreover, no evidence of synergism was observed when the two drugs were simultaneously applied. PFC neurons in aged rats were significantly subsensitive to locally applied SKF 38393, whereas no change in sensitivity to N-0437 was observed. These results suggest that both D1 and D2 receptors are present in the PFC and that agonist occupancy of each of these receptors elicits an inhibition of PFC neuron discharge; furthermore, these data suggest an age-related change in D1 dopamine receptor-mediated processes with no concomitant change in processes linked to the activation of D2 dopamine processes.

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Diminished evoked response to repeated auditory stimuli, an example of sensory gating normally present in human subjects, is often absent in schizophrenics. To examine the mechanism of the normal response and to delineate possible sites of its abnormality in psychosis, it would be desirable to reproduce the phenomenon in laboratory animals. In this study, we show that the pattern of diminished response to the second of paired auditory stimuli is found in activity recorded from the CA3 region of the hippocampus of anesthetized rats. The evoked potential recorded from this area is predominantly an N40 wave, at identical latency to the prominent negative wave recorded from the skull surface of unanesthetized rats. Similar responses were not found in other areas, including the auditory neocortex and the medial geniculate nucleus. Amphetamine, which diminished sensory gating in both animals and humans, diminished the gating of the evoked potential recorded in the hippocampus. The effect of amphetamine was reversed by haloperidol. The rat hippocampus may therefore contain neurons that can be used to study the neurobiology of sensory gating.

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Spontaneous discharge rates of cerebellar Purkinje neurons were decreased in rats withdrawn from chronic treatment with alprazolam, diazepam, and lorazepam relative to discharge rates recorded from control rats. Prior treatment with 6-hydroxydopamine to deplete cerebellar levels of norepinephrine significantly reduced this effect of diazepam upon Purkinje cell firing rates. The data suggest that increased noradrenergic activity may be occurring during withdrawal from benzodiazepines.

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We have investigated the receptor subtype(s) mediating the noradrenergic inhibition of cerebellar Purkinje cell spontaneous firing rate using local application of specific agonists and antagonists, in situ, via pressure microejection. Extracellular action potentials were recorded from Purkinje neurons in anesthetized Fischer 344 rats. Timolol, a beta-receptor antagonist, did not affect norepinephrine (NE)-induced inhibition in 9 of 12 cells studied. Phentolamine, an alpha-receptor antagonist, blocked the effect of NE in 8 of 11 cells. To further determine the subtype of alpha-receptor involved, the effects of the alpha 1-antagonist prazosin and alpha 2-antagonists idazoxan and yohimbine were examined. While prazosin had no effect on NE-mediated inhibition, both idazoxan and yohimbine blocked NE effects. Idazoxan was also successful in blocking phencyclidine (PCP), an indirect noradrenergic agonist. The inhibitory action of NE upon Purkinje cell firing rate was mimicked by the selective alpha 2-agonist clonidine; this action of clonidine was blocked by idazoxan but not by timolol or prazosin. In addition, the alpha 1-adrenergic agonist phenylephrine and the beta-adrenergic agonist isoproterenol inhibited Purkinje cell firing rate. Phenylephrine effects were blocked by prazosin but not by timolol or idazoxan. Isoproterenol-induced inhibition was blocked by timolol but not phentolamine. Taken together, these studies suggest that both alpha- and beta-receptors alter Purkinje cell firing rate; the depressant action of locally applied NE, however, seems to be mediated primarily via an alpha 2-adrenergic receptor.

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Age-related changes in noradrenergic function in the rat cerebellum were examined using electrophysiological and electrochemical techniques. Sprague-Dawley and Fischer 344 rats showed subsensitivity to norepinephrine (NE) locally applied onto cerebellar Purkinje neurons. The modulatory actions of NE on Purkinje cell-evoked activity was also examined. In young rats NE preferentially inhibits spontaneous activity more than evoked excitations when compared to control. These modulatory actions of NE are not seen in senescent Fischer 344 rats. The intrinsic vs. extrinsic influences determining the loss of efficacy to NE were examined using three groups of rats with in oculo cerebellar grafts. The first group had young grafts grown in young hosts and these grafts showed a potent response to perfused NE. The second group, old grafts in old hosts, showed a diminished responsiveness to NE with respect to the first group. The third group consisted of young grafts in old hosts. These grafts demonstrated a responsiveness to NE that was indistinguishable from those in the first group. The integrity of the presynaptic NE fibers was examined in the grafts using electrochemical techniques. No difference in the release of NE was observed in the old grafts. Taken together, these results suggest a loss of postsynaptic NE function that is intrinsically determined. The change in NE modulation could influence information processing within the aged cerebellar cortex. This deficit could underlie behavioral changes seen in senescence.

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Age-related changes in the responsiveness of hippocampal pyramidal neurons to norepinephrine (NE) and serotonin (5HT) were investigated using electrophysiological techniques. Local application of each monamine via pressure micro-ejection was employed to establish the dose which elicited a 50% change in spontaneous discharge rate of single pyramidal neurons; these data were used to construct dose response curves for the population of neurons tested in 3-6, 11-13, 18-20, and 27-30 month old rats. The percentage of cells responding in rats 18-20 and 27-30 months old decreased for both NE and 5HT. There was also a progressive increase with age in the population ED50 for 5HT starting at 18-20 months. For neurons which demonstrated a response to NE, no decrease in the population ED50 was observed. Taken together these data indicate that there is a progressive age-related decline in the postsynaptic response to NE and 5HT in the rodent hippocampus.

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Intrinsic versus extrinsic determinants of changes in cerebellar noradrenergic transmission during senescence in the rat were measured using homologous cerebellar grafts in oculo. Postsynaptic sensitivity of Purkinje neurons to catecholamines was determined by perfusing the anterior eye chamber with known concentrations of norepinephrine (NE) dissolved in a balanced salt solution. NE elicited a dose-dependent slowing of spontaneous Purkinje neuron discharge in both young (3-6 months) and aged (20-22 months) cerebellar grafts. Hill plots demonstrated that the dose-response relationships in both age-groups were linear and parallel to one another. Aged transplant Purkinje neurons manifested a marked and highly significant subsensitivity to NE with an EC50 of 583 microM, as compared with an EC50 of only 15.9 microM in the young grafts. Young grafts in 15-21-month-old hosts manifested an EC50 of 20 microM for the depressant actions of NE. Collaterals of host iris sympathetic fibers innervate the grafts. Activity of these fibers can be reflexly altered by changing illumination of the retina. The dynamics of presynaptic NE release from these fibers was evaluated using in vivo electrochemistry with Nafion-coated graphite epoxy capillary electrodes, which are highly selective for the monoamine neurotransmitters. As illumination of the ipsilateral retina is increased, the release of catecholamine in the cerebellar graft decreases. A mean change in the extracellular electroactive species of 4.2 +/- 0.6 microM was found in young cerebellar grafts. Equivalent stimuli induced a mean change of 2.3 +/- 0.8 microM in aged grafts. However, this diminished release was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

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Deficiencies in noradrenergic neurotransmission have been found in the central nervous system of aged laboratory animals. The purpose of the present study was to determine if tricyclic antidepressants, such as desipramine, can overcome the diminished noradrenergic neurotransmission found in these animals. Using electrophysiological techniques, noradrenergic neurotransmission was examined in the cerebellar cortex of rats, a model system which has been used extensively to characterize the effects of norepinephrine in the central nervous system. The discharge rate of cerebellar Purkinje neurons is very sensitive to changes in the noradrenergic input from the nucleus locus coeruleus. In this model system in young rats, treatment with desipramine slowly augments noradrenergic neurotransmission over several weeks. Similar treatment in aged animals caused no increase in the age-related deficient noradrenergic neurotransmission. The decline in efficacy of desipramine with age could not be accounted for by differences between young and old rats in the distribution of the drug. Failure of desipramine to be effective in older rats may reflect the insensitivity of aged neurons to norepinephrine itself, so that treatment strategies which increase the amount of nerepinephrine released onto these neurons may be ineffective. The findings may have implications for the use of tricyclic antidepressants in aged depressed patients.

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Much controversy surrounds the actions of nicotine on mammalian central neurons, especially with respect to the question of presence of multiple nicotine receptors and with respect to similarities of responses to those induced by acetylcholine (ACh). To resolve some of these complexities, the authors determined the effects of pressure-ejected nicotine on identified neurons in the cerebellar cortex of Sprague-Dawley rats under urethane anesthesia. Purkinje cells and interneurons were identified by their anatomical localization, discharge characteristics and responses to electrical stimulation of superficial parallel fibers. Locally applied nicotine altered single-unit activity in a manner strictly dependent on cell type. Pressure-ejected nicotine inhibited Purkinje cells (50/51) and excited cerebellar interneurons (22/22). The effects of nicotine on cell discharge rate were probably receptor mediated because "classical" nondepolarizing nicotinic antagonists selectively blocked the agonistic actions of nicotine. A curare-sensitive site (neuromuscular type) was found to mediate the excitatory effects of nicotine, and a hexamethonium-sensitive site (ganglionic type) was found to mediate the inhibitory effects of nicotine. ACh mimicked the effects of nicotine on both cell classes although muscarinic interactions were also observed. The inhibitory effects of ACh on Purkinje cells were antagonized by the ganglionic blocker hexamethonium only if muscarinic receptors were simultaneously blocked via systemic administration of scopolamine. The excitatory effects of ACh on interneurons, on the other hand, were antagonized by the neuromuscular blocker curare even in the absence of a muscarinic antagonist. No interactions of curare and hexamethonium were observed with the amino acid transmitters gamma-aminobutyric acid (Purkinje cells) and glutamate (interneurons).

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