Effects of acute and chronic administration of antidepressant drugs on the central cholinergic nervous system. Comparison with anticholinergic drugs.

The purpose of this investigation was to study the effects of antidepressant drugs on the central cholinergic system of the rat after acute and chronic administration. Drugs (antidepressants and non-antidepressants) were first divided into highly potent, moderately potent or weak anticholinergic categories based upon the ability of each compound to displace [3H]-QNB [( 3H]quinuclidinyl benzilate from synaptosomal membranes. One antidepressant drug and one non-antidepressant drug, with similar anticholinergic properties, were chosen as representative agents of each category of anticholinergic potency. Acute administration of amitriptyline or atropine (highly potent anticholinergics) increased the level of high affinity uptake of choline in the hippocampus and striatum. Imipramine and thioridazine (moderately potent anticholinergics) increased the uptake of choline only in the striatum. After acute administration, the effects of nomifensine and d-amphetamine (weak anticholinergics) differed on striatal uptake of choline. Following 30 days pretreatment with any drug, an acute challenge dose of that drug no longer altered the uptake of choline in either region. After chronic administration, amitriptyline increased the density of muscarinic receptors in the cortex whereas atropine increased the density of receptors in the cortex, hippocampus and striatum. The other agents did not alter receptor parameters in the regions examined. Since the central cholinergic actions of the antidepressants were similar to the central actions of the non-antidepressants, it is concluded that the effects of the antidepressants on the central cholinergic nervous system are more closely related to the side effects of these agents than to their therapeutic mechanism of action.