Central cholinergic systems are significantly altered in laboratory animals and in man as a function of normal aging. Profound cholinergic deficits have also been observed in postmortem brain tissue of patients with Alzheimer's disease. This form of senile dementia eventually may be treated with drugs which stimulate central cholinergic activity (direct-acting cholinergic agonists, anticholinesterases or precursor drugs, like choline or lecithin). Elderly patients also receive a variety of centrally-active drugs which have significant anticholinergic activity (antipsychotics, antidepressants, antiparkinsonian drugs). However, very little is known about the ability of central cholinergic systems in aged individuals to compensate or adapt to long-term treatment with cholinergic agonists or antagonists. The objective of this proposal is to quantitate receptor alterations following chronic cholinergic drug administration and assess the functional relevance of such pharmacodynamic adaptations. Age-related differences in receptor plasticity will be determined by comparing these effects in young, adult and senescent rats (3, 9 and 27 months). Drug-receptor interactions will be measured by radioligand binding techniques using 3H-QNB, a sensitive and highly selective ligand for muscarinic cholinergic receptors. Changes in the number of binding sites or the affinity of 3H-QNB for muscarinic receptors will be quantitated in specific regions of rat brain (frontal cortex, hippocampus, hypothalamus and striatum) following the chronic intracerebroventricular administration of oxotremorine or methylatropine. This particular route of administration will minimize potential problems of differential drug metabolism or distribution in young versus senescent animals. Functional correlates of central cholinergic activity to be assessed include analgesia (prolonged tail-flick latency) and hypothermia observed after challenge doses of oxotremorine and scopolamine-induced increases in spontaneous locomotion activity. The combination of pharmacodynamic and behavioral assays will provide conclusive data regarding the adaptability of muscarinic cholinergic systems in aged rat brain. The ultimate goal of these studies is to understand neurotransmitter receptor plasticity, and hence neuronal communication and pharmacological mechanisms, as a function of advanced age. Intensive research into the etiology and treatment of age-related diseases is essential to solve urgent medical problems facing our society today.
| Pedigo Jr, N W (1988) Pharmacological adaptations and muscarinic receptor plasticity in hypothalamus of senescent rats treated chronically with cholinergic drugs. Psychopharmacology (Berl) 95:497-501 |
