Neuropharmacology
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Anabaseine is a marine worm toxin that is a relatively non-selective nicotinic agonist, activating both muscle-type and neuronal nicotinic acetylcholine receptors (nAChR) with varying efficacy. While anabaseine has significant activity with muscle-type and neuronal alpha 3 beta 4 and alpha 4 beta 2 receptors, benzylidene anabaseine (BA) derivatives have high selectivity for the alpha 7 receptor subtype. Two BA compounds with substituents at the 2 and 4 positions of the benzylidene ring, GTS-21 and 4OH-GTS-21, may have therapeutic potential for treating neuropathological disorders such as Alzheimer's disease due to their alpha 7 selectivity. ⋯ Increased potency and receptor binding affinity was obtained with a 4-hydroxyl substitution. Two other 4-substituted benzylidene anabaseines, 3-(4'-methylthiobenzylidene)anabaseine (4-MeS-BA) and 3-(4-trifluoromethylbenzylidene) anabaseine (4-CF(3)-BA), offered very little agonist activity for any nicotinic receptors and instead were antagonists for both alpha 7 and neuronal alpha 3 beta 4 and alpha 4 beta 2 receptors. Since the relative amounts of agonist and antagonist activities for specific BA compounds vary with the specific drug/receptor combinations, benzylidene anabaseines provide valuable tools for nAChR drug-receptor structure-function relationships.
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Comparative Study
Enhanced group III mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala.
Pain has a strong emotional component. A key player in emotionality, the amygdala is also involved in pain processing. Our previous studies showed synaptic plasticity in the central nucleus of the amygdala (CeA) in a model of arthritic pain. ⋯ The inhibitory effect of LAP4 was reversed by a selective group III mGluR antagonist (UBP1112). During the application of LAP4, paired-pulse facilitation was increased, while no significant changes in slope conductance and action potential firing rate of CeA neurons were observed. These data suggest that presynaptic group III mGluRs are involved in the regulation of synaptic plasticity in the amygdala in an arthritis pain model.
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Comparative Study
Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats.
The role of mu-, delta1- and delta2-opioid receptors in the nucleus accumbens in pivoting was investigated in freely moving rats. Unilateral injections of the mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 1 and 2 microg) and the delta2-opioid receptor agonist, deltorphin II (1 and 2 microg), but not the delta1-opioid receptor agonist, [D-Pen(2,5)]-enkephalin (DPDPE, 1-4 microg), into the shell or the core of the nucleus accumbens significantly induced contraversive pivoting. The pivoting induced by DAMGO (2 microg) and deltorphin II (2 microg) was inhibited significantly by the mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 0.1 and 1 microg), and the delta2-opioid receptor antagonist, naltriben (NTB, 0.1 and 1 mg/kg, i.p.), respectively. ⋯ The contraversive pivoting elicited by the cholinergic agonist, carbachol (5 microg), into the core was inhibited by co-administration of the muscarinic M1 antagonist, pirenzepine (1 microg), but not cis(Z)-flupentixol (1 microg). The results suggest that unilateral activation of mu- or delta2-opioid, but not delta1-opioid, receptors in the core and/or shell of the nucleus accumbens elicits contraversive pivoting that requires intact dopamine D1/D2 receptors in the shell, but not intact muscarinic M1 mechanism in the core. The study also shows that delta2-opioid, but not mu- and delta1-opioid, receptors in the core and/or shell modulate the shell-specific, dopamine D1/D2 receptor mechanisms involved in the production of pivoting.