ABSTRACT
Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.
Subject(s)
Antidepressive Agents/pharmacology , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M2/metabolism , Scopolamine/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout/metabolism , Motor Activity/drug effects , Muscarinic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley , Swimming/physiologyABSTRACT
An improved technique for perfused lung preparations adapted for absorption studies with organic aerosols is described. The model developed by Niemeier and Bingham (1972) was modified to place greater emphasis on the respiratory functions of the lung as an index of viability. Perfusion of this preparation for 2 hr showed that tidal volume, pulmonary blood flow, and visual appearance were the most sensitive indicators of physiological change. The importance of relevant criteria for assessment of viability is discussed. In addition, a simple technique for on-line computerized measurement of tidal volume and respiratory frequency is described.
