Neuroscience
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Dopamine-mediated behaviors and certain biochemical and molecular events associated with these behaviors were examined following continuous infusion of the D1 dopamine agonist SKF38393 or the D2 dopamine agonist quinpirole into mice for six days. SKF38393 produced a transient grooming behavior while quinpirole initially induced stereotypy, which was followed by an increased locomotor behavior. Continuous infusion of quinpirole caused a significant down-regulation of striatal D2 dopamine receptors without significantly changing the density of D1 receptors. ⋯ This treatment also induced a significant decrease in proenkephalin messenger RNA in striatum. Taken together, these results suggest that the down-regulation of D2 dopamine receptor and D2 receptor messenger RNA is the result of the persistent stimulation of D2 receptors and that the up-regulation of mu opioid receptors may be a compensatory response to a decreased biosynthesis of enkephalin. They suggest further that the biochemical and molecular changes that take place in dopaminergic and enkephalinergic systems following continuous treatment with dopamine agonists may underlie the mechanisms by which certain dopamine-mediated behaviors occur.
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The rostral ventrolateral medulla oblongata plays an important role in the control of arterial blood pressure and it has strong descending projections into the intermediolateral nucleus of the thoracic spinal cord, where the majority of sympathetic preganglionic neurons are located. The purpose of this study was to see whether these projections form synaptic contacts with sympathetic preganglionic neurons in the rat. Projections from both the lateral part of the rostral ventrolateral medulla (rostroventrolateral reticular nucleus) and from the more medial region (lateral paragigantocellular nucleus) were investigated separately in view of their different functional roles in sympatho-regulation and their different chemical composition. ⋯ Synaptic specializations were of both the symmetrical and asymmetrical type. The targets of boutons forming asymmetrical synaptic contacts differed according to their origin: boutons originating from neurons in the rostroventrolateral reticular nucleus were mainly in contact with dendrites of sympathetic preganglionic neurons, while those originating from the lateral paragigantocellular nucleus mainly innervated the cell bodies. Our observations provide anatomical support for the view that there are two distinct classes of sympatho-regulatory cells in the rostral ventrolateral medulla, each of which can directly influence the activity of sympathetic preganglionic neurons; they also emphasize the importance of detailed investigation of the subregions of the ventrolateral medulla with respect to their sympatho-regulatory functions.
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Withdrawal from opiates in dependent subjects produces strongly aversive psychological and autonomic responses which contribute to the chronic ingestion of opiates and the high incidence of relapse after withdrawal. A variety of evidence indicates that hyperactivity of noradrenergic locus coeruleus (LC) neurons is an important brain substrate of opiate withdrawal. In particular, only a few agents have been found to be clinically useful in alleviating these symptoms and treating opiate dependence, all of which potently attenuate the activation of noradrenergic neurons in the LC evoked by opiate withdrawal. ⋯ Two results from our laboratory led us to study the effect of enhanced serotonergic neurotransmission on withdrawal-induced LC hyperactivity: (i) a substantial part of such LC hyperactivity is mediated by an excitatory amino acid input to the locus coeruleus, and (ii) 5-HT selectively attenuates excitation of LC neurons mediated by excitatory amino acids. Here, we report that agents which increase serotonergic neurotransmission attenuate the hyperactivity of LC neurons induced by naloxone-precipitated withdrawal from chronic morphine exposure in rats. The 5-HT releaser/uptake blocker, d-fenfluramine, as well as the 5-HT reuptake blockers fluoxetine or sertraline, significantly attenuated the withdrawal-induced hyperactivity of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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The sensitization of peripheral nociceptors by different prostaglandins was studied in an in vitro preparation of the neonatal spinal cord with functionally attached tail. Nociceptors in the rat tail were activated by chemical (bradykinin, capsaicin) and thermal (heated saline) stimuli and responses were recorded as a depolarization of a ventral root in the lumbar region of the spinal cord (L3-L5). Responses evoked by bradykinin, capsaicin or submaximal thermal stimulation were enhanced in the presence of prostaglandin E1, prostaglandin E2, prostaglandin F2 alpha, prostaglandin I2 and the stable prostaglandin I2 analogue cicaprost, but not by prostaglandin D2. ⋯ Immunocytochemical localization of protein gene product 9.5 and growth associated protein 43 indicated that the neuronal innervation of subepidermal skin layers was preserved in the tail following removal of the most superficial skin layers which was performed in order to facilitate drug access to peripheral nerve endings. These results indicate that different prostaglandins and cyclic AMP sensitize peripheral nerve endings to noxious stimulation without directly activating nociceptors. The stimulation of nociceptors by bradykinin was only partially mediated via arachidonic acid metabolites whereas bradykinin-induced sensitization was independent of cyclo-oxygenase activity.
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We examined the effects of the 5-hydroxytryptamine2 receptor agonist, (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, on spontaneous and evoked discharge of locus coeruleus neurons in the rat. Extracellular recordings were obtained from single locus coeruleus neurons while (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane was injected systemically or locally into the locus coeruleus. Systemic, but not local, administration of (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane decreased spontaneous discharge of locus coeruleus neurons in a dose-dependent manner while simultaneously increasing responses evoked by somatosensory stimulation, consistent with previous studies using 5-hydroxytryptamine2 agonists. ⋯ Both of these effects could be completely reversed by systemic administration of the 5-hydroxytryptamine2 receptor antagonist, ketanserin. Furthermore, we report that: (i) the (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced decrease in spontaneous firing was blocked by local infusion of the GABA antagonists bicuculline or picrotoxin into the locus coeruleus, but not by local infusion of the alpha-2 adrenoceptor antagonist, idazoxan; and (ii) the enhancement of locus coeruleus sensory responses after high-intensity stimulation was blocked by local application of the selective antagonist of N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid, but not by local infusion of the preferential antagonist of non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione. Together, these results lead us to propose that systemic 5-hydroxytryptamine2 agonists influence locus coeruleus indirectly, causing tonic activation of a GABAergic input to the locus coeruleus, and facilitating sensory inputs that act via excitatory amino acid receptors within locus coeruleus.