Neuroscience
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The modulation of GABA-gated ion channel responses to GABA, pentobarbital and diazepam by muscarine was studied in freshly isolated rat dorsal root ganglion neurons using a whole-cell patch-clamp technique. Muscarine enhanced current activated by 5 microM GABA dose-dependently with an EC50 of 40 +/- 2 microM. This potentiation was not blocked by pirenzepine, gallamine and atropine, the specific and non-specific muscarinic receptor antagonists. ⋯ However, muscarine attenuated the facilitatory effect of saturating concentrations of diazepam (> 100 nM). The potentiating effect of muscarine was blocked by 1 nM ethyl-beta-carboline-3-carboxylate, the inverse agonist of benzodiazepine receptors. These results suggest that GABA-gated ion channel responses to GABA and pentobarbital were potentiated by muscarine and the binding site(s) for muscarine might be related to those for diazepam.
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Melanocortin peptides (alpha-melanocyte-stimulating hormone, adrenocorticotropin and fragments thereof) have been shown to have numerous effects on the central nervous system, including recovery from nerve injury and retention of learned behaviour, but the mechanism of action of these peptides is unknown. A family of five melanocortin receptors have recently been discovered, two of which (melanocortin-3 and melanocortin-4 receptors) have been mapped in the rat brain. We have tested the hypothesis that the expression of one or more of the messenger RNAs for three melanocortin receptors (melanocortin-3, melanocortin-4 and melanocortin-5 receptors) would be altered in rat brain following unilateral transient hypoxic-ischaemic brain injury. ⋯ In a small group of animals, this induction was not blocked by treatment with the anticonvulsant, carbamazepine. Expression of melanocortin-3 receptor messenger RNA in the brain was not altered in this hypoxic-ischaemic injury model and melanocortin-5 receptor messenger RNA was not detected in either control or hypoxic-ischaemic injured rat brains. We hypothesize that the up-regulation of melanocortin-4 receptor messenger RNA expression in the contralateral striatum may be involved in transfer of function to the uninjured hemisphere following unilateral brain injury.
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Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. ⋯ Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.
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Comparative Study
Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments.
The nucleus accumbens septi is the major target of mesolimbic dopamine neurons originating in the ventral tegmental area of the mesencephalon. Studies involving experimental manipulation of dopamine transmission by drugs and by lesions, as well as in vivo monitoring of extracellular dopamine concentrations, have provided evidence that the dopamine transmission of the nucleus accumbens plays an important role in behaviour motivated by conventional (e.g., food, sex) and drug reinforcers. Motivated behaviour is distinguished into an appetitive (preparatory/anticipatory) phase consisting of flexible response patterns intended to search and approach the reward itself, and a consummatory phase, consisting of fixed response patterns (eating, drinking, copulating, etc.) finalized to the utilization of the biological resources of the reward (caloric, metabolic, genetic, etc.). ⋯ Unpredicted consumption of Fonzies preferentially stimulated dopamine transmission in the shell as compared to the core. Appetitive food stimuli (perforated Fonzies-filled boxes) phasically stimulated dopamine transmission in the core but not in the shell and sensitized the dopamine response to feeding in the core but inhibited that in the shell. These clear-cut differences between nucleus accumbens shell and core suggest that phasic dopamine transmission in each compartment of the nucleus accumbens subserves different roles in motivated behaviour.
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The neuromodulatory actions of dopamine in the striatum and nucleus accumbens are likely to depend on the distribution of dopamine receptors on individual postsynaptic cells. To address this, we have visualized D1- and D2-like receptors on living medium-spiny GABAergic neurons in cultures from the striatum and nucleus accumbens using receptor antagonist fluoroprobes. We labeled D1-like receptors with rhodamine-SCH23390, D2-like receptors with rhodamine-N-(p-aminophenethyl)spiperone and synaptic sites with K+-stimulated uptake of the activity-dependent endocytic tracer FM-143. ⋯ The extensive presence of D1- and D2-like receptors on presynaptic varicosities of medium-spiny neurons suggests that the receptors are likely to play an important and interacting role in the presynaptic modulation of inhibitory synaptic transmission in the striatum and nucleus accumbens. The significant overlap in labeling suggests that D1-D2 interactions, which occur at the level of individual postsynaptic cells, the circuit level and the systems level, may also be mediated at the presynaptic level. Finally, the ability to visualize dopamine, as well as GABA(A), receptors on the individual synapses of living neurons now makes possible physiological studies of individual mesolimbic system synapses with known receptor expression.