Cholinergic‐ and Adrenergic‐Stimulated Inositide Hydrolysis in Brain: Interaction, Regional Distribution, and Coupling Mechanisms

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Abstract
Carbachol and norepinephrine were used as agonists to compare and contrast cholinergic and adrenergic stimulation of inositide breakdown in rat brain slices. Carbachol acts through a muscarinic (possibly M1) receptor and norepinephrine acts through an α1 adrenoceptor. Studies in cerebral cortical slices indicated that both agonists stimulated the production of inositol-1- phosphate and glycerophosphoinositol. Although the initial rates for the stimulation of inositol phosphate release were similar for the two ligands, the response to norepinephrine continued for 60 min and was larger compared with carbachol which plateaued at 30 min. The presence of carbachol did not affect the ED50 for norepinephrine. Concentrations of carbachol near the ED50 in combination with norepinephrine resulted in an additive response whereas maximal concentrations of carbachol and norepinephrine resulted in a less than additive response in the cortex. This negative interaction was also seen in the hippocampus and hypothalamus but not in the striatum, brainstem, spinal cord, olfactory bulb, or cerebellum. Norepinephrine had a larger response than carbachol in the hippocampus, striatum, and spinal cord, but the reverse was true in the olfactory bulb. Manganese (1 mM) stimulated the incorporation of [3H]inositol into phosphatidylinositol (PtdIns) four- to fivefold but not into polyphosphoinositides. The stimulation by manganese of PtDIns labelling increased the monstimulated release of inositol phosphates but did not affect the stimulated release of inositol phosphates by carbachol or norepineph rine. These data suggest that: (a) there may be a common pool of inositides that can be hydrolyzed by cholinergic and/or adrenergic agonists in certain brain areas; (b) manganese may stimulate the labelling of a pool of PtdIns that does not interact with the receptor-coupled pool of inositides; and (c) there may be differences in the basic mechanisms coupling receptor occupation and inositide breakdown for cholinergic and adrenergic receptors.