The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Sep 2005
3,4-Methylenedioxymethamphetamine (ecstasy) activates skeletal muscle nicotinic acetylcholine receptors.
Adverse 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) effects are usually ascribed to neurotransmitter release in the central nervous system. Since clinical features such as fasciculations, muscle cramps, rapidly progressing hyperthermia, hyperkalemia, and rhabdomyolysis point to the skeletal muscle as additional target, we studied the effects of MDMA on native and cultured skeletal muscle. We addressed the question whether malignant hyperthermia (MH)-susceptible (MHS) muscle is predisposed to adverse MDMA reactions. ⋯ The nAChR agonistic action of MDMA was confirmed by patch-clamp measurements of ion currents on human embryonic kidney cells expressing nAChR. We conclude that the neuromuscular junction is a target of MDMA and that an activation of nAChR contributes to the muscle-related symptoms of MDMA users. The drug may be of particular risk in individuals with abundant extrajunctional nAChR such as in generalized denervation or muscle regeneration processes and may act on central nAChR.
-
J. Pharmacol. Exp. Ther. · Aug 2005
Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.
Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. ⋯ From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists indicates that beta2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific beta-AR subtypes.
-
J. Pharmacol. Exp. Ther. · Jul 2005
D1 dopamine receptors modulate deltaFosB induction in rat striatum after intermittent morphine administration.
Induction of the transcription factor deltaFosB was studied to examine neurochemical adaptations produced by repeated opiate administration. The mechanism of this induction was also investigated. The 35- to 37-kDa isoforms of deltaFosB, also referred to as the chronic Fras, were measured in the nucleus accumbens, caudate putamen, and frontal cortex of male Sprague-Dawley rats after either an acute injection of morphine or an escalating dosing schedule of morphine for 10 days. ⋯ Heroin administered twice daily for 10 days by an intermittent escalating dose schedule also induced deltaFosB in the caudate putamen, but not in the nucleus accumbens or frontal cortex. Daily pretreatment with the selective D1-like dopamine receptor antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] significantly blocked morphine-induced deltaFosB induction in the nucleus accumbens and caudate putamen, but not in the frontal cortex. These results demonstrate that morphine-induced deltaFosB up-regulation in the striatum, but not in the frontal cortex, is modulated by D1 dopamine receptors, suggesting that the mechanisms involved in the up-regulation of these chronic Fras by morphine is brain region-specific.
-
J. Pharmacol. Exp. Ther. · Jul 2005
Interactions between delta and mu opioid agonists in assays of schedule-controlled responding, thermal nociception, drug self-administration, and drug versus food choice in rhesus monkeys: studies with SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and heroin.
Interactions between delta and mu opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the delta agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED50 = 0.43 mg/kg) and heroin (ED50 = 0.088 mg/kg) produced a dose-dependent and complete suppression of response rates in the assay of schedule-controlled responding. ⋯ Fixed ratio mixtures of SNC80 and heroin (1.6:1, 4.7:1, and 14:1 SNC80/heroin) produced additive effects in the assay of schedule-controlled responding and superadditive effects in the assay of thermal nociception. Also, SNC80 did not enhance the reinforcing effects of heroin, indicating that mixtures of SNC80 and heroin produced additive or infra-additive reinforcing effects. These results provide additional evidence to suggest that delta/mu interactions depend on the experimental endpoint and further suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists while either not affecting or decreasing the sedative and reinforcing effects of mu agonists.
-
J. Pharmacol. Exp. Ther. · Jul 2005
Roles for nicotinic acetylcholine receptor subunit large cytoplasmic loop sequences in receptor expression and function.
To evaluate possible physiological roles of the large cytoplasmic loops (C2) and neighboring transmembrane domains of nicotinic acetylcholine receptor (nAChR) subunits, we generated novel fusion constructs in which human nAChR alpha4, beta2, or beta4 subunit C2 or C2 and neighboring sequences were replaced by corresponding sequences from the mouse serotonin type 3A (5-HT3A) receptor subunit. Following stable expression in human SH-EP1 cells, we found that extensive sequence substitutions involving third and fourth transmembrane domains and neighboring "proximal" C2 sequences (e.g., beta2 H322-V335 and V449-R460) did not allow functional expression of nAChR containing chimeric subunits. However, expression of functional nAChR was achieved containing wild-type alpha4 subunits and chimeric beta2 (beta2chi) subunits whose "nested" C2 domain sequences K336-S448 were replaced with the corresponding 5-HT3A subunit sequences. ⋯ Ligand-binding analyses also revealed only subtle differences in pharmacological profiles of alpha4beta2-nAChR compared with alpha4beta2chi-nAChR. Nevertheless, there was heightened emergence of agonist-mediated self-inhibition of alpha4beta2chi function, greater sensitivity to functional blockade by a number of antagonists, and faster and more complete acute desensitization of alpha4beta2chi-nAChR than for alpha4beta2-nAChR. These studies are consistent with unexpected roles of nested C2 sequences in nAChR function.