Regulation of Working Memory by Dopamine D4 Receptor in Rats

Abstract

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D 1 and D 2 receptors, with most evidence suggesting a dominant role for the D 1 receptor. Since the dopamine D 4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D 4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D 4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D 4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D 4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D 4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D 4 receptor in working memory, and suggest innovative, D 4 -based, treatment of cognitive deficits associated with neuropsychiatric disorders.

Reversal of Clozapine Effects on Working Memory in Rats with Fimbria–Fornix Lesions

“…D 4 receptor antagonist effects of clozapine may contribute the differential effects seen in the fimbria-fornixlesioned and sham-operated rats in the current study. Zhang et al (2004) found that a selective D 4 receptor antagonist impaired working memory performance in rats performing at high levels of accuracy, but improved working memory performance in rats with poor baseline performance levels. This is similar to the finding in the current study.…”

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

“…We propose, on the basis of the functional properties and expression of ErbB4 and D4Rs in PV+ interneurons in the dorsal lateral prefrontal cortex (21,25) and hippocampus (this study), as well as their effects on KA-induced γ oscillations and plasticity (18,19), that these receptors are well situated to modulate network activity that impacts cognition. The fact that D4R-specific antagonists were found to be ineffective as antipsychotics for the treatment of schizophrenia (44,45) does not negate the potential use of D4R targeting drugs to treat cognitive deficits, as suggested by studies in primates and rodents (39,40,46,47). The colocalization of D4 and ErbB4 receptors on PV+ interneurons, activity of which is critically important for regulating excitatory/inhibitory balance and cognitive functions (31), perhaps by optimizing "signal-tonoise" ratio of cortical microcircuits (15), makes these receptor systems attractive targets for modulating network activities that underlie cognition.…”

Low Doses of Δ-9 Tetrahydrocannabinol (THC) Have Divergent Effects on Short-Term Spatial Memory in Young, Healthy Adults

“…Follow-up work indicates that the contribution of DA to spatial working memory is mediated by the D 1 (Arnsten et al, 1994;Sawaguchi and Goldman-Rakic, 1991) and D 2 families of receptors (Arnsten et al, 1995;Zhang et al, 2004) that may influence mnemonic and response aspects of information processing within primate PFC (Wang et al, 2004;Williams and Goldman-Rakic et al, 1995). Other research attests to the importance of NA transmission, and the balanced activity of a 1 -and a 2 -adrenoceptors, in protecting the cognitive functions of the lateral PFC from the deleterious effects of stress (Arnsten, 2000;Arnsten and Contant, 1992;Arnsten and Jentsch, 1997;Birnbaum et al, 2000).…”