Age-associated functional impairments of specific neurotransmitter systems: detection by pharmacological brain metabolism studies and criteria for design of human investigations.

Although brain aging is accompanied by measurable deficits in cognitive and motor function, and frequently by selective loss of neurons, neurotransmitters and their receptors, resting brain energy metabolism, purported to reflect neural function, undergoes little or no quantitative change during aging in experimental animals or in man. A method is described for assessing the functional capacity of aging neurotransmitter systems in rats by measuring changes in regional cerebral metabolic rates for glucose in response to drug administration. Preliminary studies identified the pharmacokinetic and pharmacodynamic factors that determine cerebral metabolic responses to drugs, and established a relation between those responses and altered brain function. In awake, aged Fischer-344 rats, cerebral metabolic responses to the dopaminergic agents haloperidol and bromocriptine and to the serotonergic agonist m-chlorophenylpiperazine were reduced when compared to responses in young adult rats, despite similar or greater concentrations of drug in the brains of older animals. The metabolic response to arecoline, a muscarinic cholinergic agonist, was age-invariant. It was concluded that the cerebral metabolic response to drug administration is a useful measure of the functional capacity of neurotransmitter systems. Pharmacological brain metabolism studies demonstrated selective functional impairments in certain transmitter systems of the aged rat brain that were not detected by metabolic measurements in the resting state, nor predicted by changes in transmitter receptors. Specific criteria are proposed for pharmacological brain metabolism studies in man, using in vivo imaging, to identify functionally impaired neurotransmitter systems in aging and neurodegenerative diseases.