The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Oct 1999
Endomorphin-1 and endomorphin-2 show differences in their activation of mu opioid receptor-regulated G proteins in supraspinal antinociception in mice.
Endomorphin-1 and endomorphin-2 are tetrapeptides of the brain whose binding profiles and analgesic activities indicate that they are endogenous ligands at micro opioid receptors. To analyze the classes of G transducer proteins activated by these opioids in the production of supraspinal antinociception, the expression of alpha subunits of the G(i) protein class, G(i1), G(i2), G(i3), G(o1), G(o2), and G(z), and those of the G(q) protein family, G(q) and G(11), was reduced by administration of antisense oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs. The ODN treatments promoted differences in the analgesic effects displayed by morphine, [D-Ala(2),N-MePhe(4), Gly-ol(5)]enkephalin (DAMGO), and the novel opioids endomorphin-1 and endomorphin-2. ⋯ Mice receiving the ODN to G(z)alpha subunits showed impaired response to all agonists. The knockdown of either G(o1)alpha, G(o2)alpha, G(q)alpha, or G(11)alpha had little or no influence on the antinociception induced by any of the opioids in the study. Thus, agonists exhibit differences in activating the variety of GTP-binding proteins regulated by mu opioid receptors.
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J. Pharmacol. Exp. Ther. · Oct 1999
Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat.
Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. ⋯ These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.
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J. Pharmacol. Exp. Ther. · Oct 1999
The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats.
Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In this article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozapine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)-evoked motor activities. LY354740 (1-10 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), and haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fine motor (nonambulatory) movements, and decreased time at rest evoked by PCP. ⋯ Haloperidol potently blocked all PCP and AMP effects, but only at doses associated with motor impairment. These data demonstrate that mGlu2/3 receptor agonists act via a unique mechanism to selectively block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.