Abstract Neurotransmitter receptor plasticity is an important part of the compensatory processes by which the central nervous system adapts to pathological insult, long-term exposure to drugs or neuronal loss with advanced age. Receptor plasticity can be manifest as changes in the number of receptors (i.e., up- or down-regulation), changes in expression of mRNA for discrete receptor proteins, or alterations in receptor coupling to signal transduction systems. Evidence exists for impaired plasticity of neurons in the aged brain, which results in decreased ability to adjust to changes in their environment. However, such data are highly dependent on the neurotransmitter examined, the stimulus for receptor regulation and the animal model chosen for study. For example, senescent rats show an age-related impairment of muscarinic receptor up-or down-regulation after long-term exposure to cholinergic drugs. Thus, young rats exposed to chronic (three weeks) intracerebroventricular infusions of methylatropine or oxotremorine exhibit compensatory changes in the density of muscarinic receptors in frontal cortex and hypothalamus. In contrast, 3H-QNB binding is unaltered in the same brain regions of identically treated senescent rats. Similar observations of impaired muscarinic receptor plasticity in senescent animals have been confirmed by other investigators. Age-related differences in coupling of brain muscarinic receptors to G-proteins and in muscarinic receptor-stimulated phosphoinositide hydrolysis have also been reported. Interestingly, neuropeptides such as neurotensin, cholecystokinin and VIP can potentiate carbachol-stimulated phosphoinositide hydrolysis in frontal cortex of both young and aged rats. This adds another level at which cholinergic neurotransmission may be modulated in senescent animals. Potential age-related differences in the effects of chronic drug treatments or experimental brain lesions on muscarinic receptor coupling to second messenger systems or on expression of mRNA for particular muscarinic receptors are currently unknown. Hence, it is possible that senescent animals may show additional deficiencies in plasticity of muscarinic receptor mediated signal transduction or expression of muscarinic receptors subtypes. Neuronal damage resulting from age-related brain disorders, such as Parkinson's disease, ischemia or stroke, multiinfarct dementia, and Alzheimer's disease, can precipitate compensatory, adaptive processes, including changes in neurotransmitter receptors and signal transduction systems. Receptor plasticity in the aged brain depends on the neurotransmitter examined, the stimulus for receptor regulation and the animal model or human disease state chosen for study (1). Loss of afferent neurons may induce an increase in the number, or less often the affinity, of postsynaptic receptors. This receptor up-regulation is also seen after chronic exposure of the central nervous system (CNS) to antagonist drugs. Conversely, down-regulation of receptors may occur after chronic overstimulation of afferent pathways or after long-term administration of agonists. Mechanisms of such receptor plasticity are poorly understood, but could include changes in the expression or translation of mRNA for receptor proteins, in the interaction of receptors with other proteins within the microenvironment of lipid membranes, or in the rates of receptor desensitization or degredation.