Neurotransmitter Receptor-Mediated Myo-Inositol 1-Phosphate Accumulation in Hippocampal Slices

Summary

The agonist-dependent accumulation of [³H]inositol 1-phosphate was investigated in rat hippocampal slices that were preincubated with [³H]inositol. The addition of lithium to the incubation medium markedly amplified the effect of all agonists in stimulating [³H]inositol 1-phosphate accumulation. The response to a number of neurotransmitter receptor agonists was dependent on the amount of tissue (mg protein), and the concentrations of lithium, and [³H]inositol. The accumulation of [³H]inositol 1-phosphate in hippocampal slices was stimulated by carbachol an effect that was potently blocked by atropine, a muscarinic-cholinergic antagonist. [³H]Inositol 1-phosphate also accumulated in response to norepinephrine and this effect may be mediated by both α_l and α₂ adrenoreceptors, since the response was attenuated by relatively low concentrations of the selective α_l and α₂ adrenoreceptor antagonists, phentolamine and yohimbine, respectively. The accumulation of [³H]inositol 1-phosphate induced by serotonin was blocked by metergoline, but not by mianserin and therefore, appeared to be mediated via 5HT₁ receptors. Intracerebroventricular administration of 6-hydroxydopamine, a specific neurotoxin of noradrenergic neurons, resulted in an enhanced response to norepinephrine as well as carbachol and serotonin. In addition, acute or chronic administration of the tricyclic antidepressant imipramine (10 mg/kg daily) also resulted in an enhanced response to those same neurotransmitter agonists in vitro. Our results suggest that the measurement of agonist-induced [³H]inositol 1-phosphate accumulation, in the presence of lithium represents a sensitive method for studying receptor-mediated events in brain slice preparations and should prove useful in studying the neurochemical effects of various psychotropic drugs.