Characteristics of muscimol accumulation in mouse brain after systemic administration

Studies on the chemical characteristics of tritiated substances accumulated in mouse brain and heart after intravenous administration of 3H-muscimol indicate that the bulk of this agent is chemically modified in the periphery with only a small amount (0.02%) of unchanged substance reaching the brain. In vivo competition experiments using unlabeled muscimol and bicuculline suggest that the 3H-muscimol present in the brain may not be specifically localized to synaptic GABA receptor sites. Comparison of 3H-muscimol, 3H-GABA and 3H-phenobarbital accumulation reveals that muscimol and GABA penetrate the brain to a similar extent which is at least an order of magnitude less than ph\ue9nobarbital. Chloroform/water partition coefficients of these three compounds indicate that GABA and muscimol have similar relative lipid solubilities, being 300 times less lipophilic than phenobarbital. These results suggest that the behavioral and biochemical effects observed after the systemic administration of muscimol may not be solely due to the presence of muscimol in brain, but rather may be related to the combined action of muscimol and some derivative or to the derivative alone

Differential effects of antidepressant treatment on brain monoaminergic receptors

Chronic (21 days) antidepressant administration to rats results in a decrease in both serotonin and beta-adrenergic, but not cholinergic muscarinic, receptor binding in selected brain regions, with the frontal cortex appearing to be somewhat more sensitive to this effect. Neither nisoxetine nor fluoxetine, potent and specific inhibitors of norepinephrine and serotonin uptake respectively, caused receptor binding changes after chronic administration, suggesting that inhibition of transmitter uptake, in itself, is insufficient to cause receptor subsensitivity. In vitro experiments indicated that antidepressants are relatively weak alpha 2-receptor blocking agents, but some are potent on the alpha 1-receptor system indicating that the norepinephrine releasing potency of some antidepressants may not be mediated by blockade of presynaptic autoreceptors

beta-Adrenergic regulation of alpha 2-adrenergic receptors in the central nervous system

Incubation of rat cerebral cortical slices with the beta-adrenergic agonist isoproterenol causes an increase in alpha 2-adrenergic receptor binding in addition to a decrease in beta-adrenergic receptor binding. The effects are rapid and reversible, show a parallel time course, and are blocked by sotalol, a beta-adrenergic receptor antagonist. The beta-mediated regulation of alpha 2-receptor sensitivity at brain norepinephrine synapses may be a mechanism for the homeostatic control of central noradrenergic activity

Effect of aging on neurotransmitter receptor binding in rat and human brain

\u3b2-Adrenergic and GABA receptor binding were measured in brain areas of rats 3 to 24 months of age. While GABA receptor binding was not significantly different across age in any area, \u3b2-adrenergic receptor binding was significantly reduced in the cerebellum and brain stem, but not cerebral cortex, of 24-month-old animals. The loss in \u3b2-adrenergic receptor binding does not correlate in a temporal fashion with the reported decrease in norepinephrine-stimulated cyclic AMP accumulation in the cerebellum which occurs as early as 12 months of age. An age-related reduction in \u3b2-adrenergic binding was also noted in human cerebellar tissue obtained at autopsy, suggesting that the cerebellar dysfunction seen with aging may be related to a loss of cerebellar neurons which receive noradrenergic input