The functions of thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) can be conceptualized as performed by four anatomically distinct components that together comprise a general TRH homeostatic system. These components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the chrono...

Benzodiazepine potentiation of g-aminobutyric acid (GABA) neurotransmission is associated with the presence of a gamma-2 subunit in the GABAA receptor. A method was developed to modify the gamma-2 subunit expression in adult rat brain. Unilateral intracerebroventricular (i.c.v.) infusion of a 17-base phosphorothioate-modified antisense oligodeoxynucleotide (ASO) was performed every 12 hr for 3 ...

Ethanol inhibits L-type Ca channels, but little is known about its effect on other voltage-gated Ca channels. To examine non-L-type channels we used nerve growth factor-differentiated PC12 cells treated with the L channel blocker nifedipine. Using selective Ca channel antagonists, we found that Ntype and P/Q -type channels mediate most of the remaining depolarization-evoked Ca rise. Ethanol (10...

Tumor necrosis factor(TNF), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2 isobutyl-2 -(methanesulfonyl)-4-methylvalerohydrazide (Ro 327315), is a potent, orally active inhibitor of the TNFconvertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precurso...

Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14 -dihydroxy-4,5 epoxy-6 -[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate],...

Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidino moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibition of [H]nicotine and [H]methyllycaconitine binding to rat brain membranes assessed interaction with...

The present study explores the hypothesis that the new antiepileptic drug levetiracetam (LEV) could interfere with the inositol 1,4,5-trisphosphate (IP3)-dependent release of intracellular Ca initiated by Gq-coupled receptor activation, a process that plays a role in triggering and maintaining seizures. We assessed the effect of LEV on the amplitude of [Ca ]i response to bradykinin (BK) and ATP...

Activation of kappa receptors inhibits adenylate cyclase, enhances K conductance and reduces Ca conductance via pertussis toxin-sensitive G proteins. We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [S]GTPgS binding to CHO cell membranes were examined...

Drugs given in combination may produce effects that are greater than or less than the effect predicted from their individual potencies. The historical basis for predicting the effect of a combination is based on the concept of dose equivalence; i.e., an equally effective dose (a) of one will add to the dose (b) of the other in the combination situation. For drugs with a constant relative potenc...

Nicotine replacement therapy is believed to facilitate smoking cessation both by relieving withdrawal symptoms and by reducing the psychological reward from smoking. The latter might occur via down-regulation of nicotine receptors in the brain, which might require high levels of nicotine exposure. Our study examined the hypothesis that transdermal nicotine, dosed up to three times the doses cur...