Enhancement of Working Memory in Aged Monkeys by a Sensitizing Regimen of Dopamine D₁Receptor Stimulation

Abstract

A natural consequence of aging is a loss of dopamine function and associated deficits in working memory in both human and nonhuman primates. Specifically, deficiency of D 1 receptor signaling has been implicated in age-related cognitive decline. Here, we report that an intermittent, sensitizing regimen of the D 1 dopamine agonist ABT-431 dramatically enhances working memory performance in aged rhesus monkeys, while either producing impairment or having little effect on performance in young adult monkeys. Importantly, cognitive enhancement in the aged monkeys was still evident for Ͼ1 year after cessation of D 1 treatment. Because intermittent exposure to low doses of amphetamine and other stimulants has been shown to enhance responsiveness to subsequent stimulant exposure, our findings suggest that sensitization of D 1 signaling may provide a novel neurobiological mechanism for improving a core cognitive process in conditions in which dopamine function has deteriorated, such as in normal aging and Parkinson's disease.

Phenotype of schizophrenia: a review and formulation

“…144,145 Consistent with this idea, human brain imaging ligand studies suggest abnormalities in D1 receptor density in the frontal cortex of persons with schizophrenia. 146,147 Support of this idea also derives from postmortem studies showing that dopaminergic transmission may be abnormal in parts of neocortex.…”

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

“…Precedence for persisting drug effects exists in the dopamine system literature, e.g. the sensitization to motor activation effects of psychostimulants (Hummel and Unterwald 2002;Kalivas and Stewart 1991;Robinson and Berridge 2000;Vanderschuren and Kalivas 2000) or long lasting improvement in cognition due to repeated, intermittent stimulation of prefrontal D1 receptors (Castner and Goldman-Rakic 2004;Castner et al 2000). It is therefore possible that chronic effects of APD treatment persist beyond the cessation of treatment, and subdividing schizophrenia subjects into drug treated and drug free at the time of death is only accounting for acute effects of the APDs on gene expression.…”

Tonic Dopaminergic Stimulation Impairs Associative Learning in Healthy Subjects

“…Thus, dopamine is implicated in the internal reward system (Schultz, 2002) and the regulation of the prefrontal cortical circuitry underlying working memory (Castner and Goldman-Rakic, 2004;Marie and Defer, 2003). Additionally, dopamine is linked to attention and arousalFpossibly through conversion of dopamine to noradrenaline (Nutt and Fellman, 1984).…”