Neuropharmacology
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The Gbeta5 protein, which is similar in sequence to other G-protein beta subunits, mainly associates with the G-protein gamma-like (GGL) domains of the R7 subfamily of regulators of G-protein signalling (RGS) proteins. This paper reports the presence of the Gbeta5 protein and its mRNA in all areas of mouse CNS, and also its involvement in the cellular signals initiated at mu- and delta-opioid receptors. The expression of Gbeta5 and RGS9-2 proteins (member of the R7 subfamily of RGS) was reduced by blocking their mRNAs with antisense oligodeoxynucleotides (ODN). ⋯ This treatment did not alter the incidence of jumping behaviour precipitated by naloxone 3 days after commencing with chronic morphine. These results show differences in the signalling regulation of G-proteins when activated by mu or delta opioid agonists. For mu opioid receptors, acute tolerance, but probably not long-term tolerance, appears to depend on the function of Gbeta5 subunits and associated RGS proteins.
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General anaesthetics exhibiting enantioselectivity afford valuable tools to assess the fundamental mechanisms underlying anaesthesia. Here, we characterised the actions of the R-(+)- and S-(-)-enantiomers of etomidate. In mice and tadpoles, R-(+)-etomidate was more potent (approximately 10-fold) than S-(-)-etomidate in producing loss of the righting reflex. ⋯ S-(-)-etomidate exerted qualitatively similar, but weaker, actions. In a model of locomotor activity, fictive swimming in Xenopus laevis tadpoles, R-(+)- but not S-(-)-etomidate exerted a depressant influence via enhancement of GABAergic neurotransmission. Collectively, these observations strongly implicate the GABAA receptor as a molecular target relevant to the anaesthetic action of etomidate.
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Different patterns of psychostimulant intake can elicit widely varying behavioral and neurochemical consequences. Accordingly, rats were studied during withdrawal from either of two schedules of amphetamine administration, one consisting of 6 days of low-dose (1.5 mg/kg, i.p.) daily intermittent (INT) amphetamine (AMPH) injections, and the other of 6 days of moderately high-dose (1-5 mg/kg, i.p.) escalating (ESC) AMPH injections, for the effects of these treatments on numbers of FosB-positive nuclei and monoamine utilization in dopaminergic target areas. Withdrawal from AMPH pretreatment according to the ESC schedule markedly increased FosB expression in the nucleus accumbens shell and basolateral amygdala. ⋯ Post-mortem neurochemical analyses of these same brain regions did not reveal effects of withdrawal from either INT or ESC administration of AMPH. These results suggest that withdrawal from a moderately high-dose AMPH regimen modifies patterns of gene expression in mesocorticolimbic dopaminergic target nuclei without significantly affecting basal monoamine levels. The strength of these effects in the nucleus accumbens shell and basolateral nucleus of the amygdala are consistent with behavioral and clinical data indicating the importance of these areas in the neuroadaptive changes which characterize addiction and withdrawal states.
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The present series of experiments were designed to examine the contribution of metabotropic glutamate receptor subtype 5 (mGluR5) to neuropathic pain by determining the effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine) on neuropathy-induced cold hypersensitivity. Unilateral chronic constriction injury (CCI) to the sciatic nerve in rats produced an increase in the number of hind paw withdrawals from a cold surface (4 +/- 2 degrees C) which was dose-dependently inhibited by systemic (i.p.) injection of MPEP (ID(50) = 11.3 mg/kg). In vivo brain mGluR5 receptor occupancy following systemic (i.p.) MPEP revealed that >90% occupancy is required for behavioral efficacy. ⋯ Intrathecal (500 nmol; i.t.) or intraplantar (300 nmol; i.pl.) injection of MPEP was ineffective in reversing CCI-induced cold hypersensitivity. These results demonstrate that mGluR5 contributes to cold hypersensitivity following peripheral neuropathy exclusively at supraspinal sites in the CNS. Additionally, mGluR5 in the RVM significantly contributes to the maintenance of cold hypersensitivity, likely via activation of descending nociceptive facilitatory systems.
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Comparative Study
Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens.
The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. ⋯ Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.