Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys

Abstract

Dopamine (DA) D1 receptor compounds were examined in monkeys for effects on the working memory functions of the prefrontal cortex and on the fine motor abilities of the primary motor cortex. The D1 antagonist, SCH23390, the partial D1 agonist, SKF38393, and the full D1 agonist, dihydrexidine, were characterized in young control monkeys, and in aged monkeys with naturally occurring catecholamine depletion. In addition, SKF38393 was tested in young monkeys experimentally depleted of catecholamines with chronic reserpine treatment. Injections of SCH23390 significantly impaired the memory performance of young control monkeys, but did not impair aged monkeys with presumed catecholamine depletion. Conversely, the partial agonist, SKF38393, improved the depleted monkeys (aged or reserpine-treated) but did not improve young control animals. The full agonist, dihydrexidine, did improve memory performance in young control monkeys as well as in a subset of aged monkeys. Consistent with D1 receptor mechanisms, agonist-induced improvements were blocked by SCH23390. Drug effects on memory performance occurred independently of effects on fine motor performance. These results underscore the importance of DA D1 mechanisms in cognitive function, and provide functional evidence of DA system degeneration in aged monkeys. Finally, high doses of D1 agonists impaired memory performance in aged monkeys, suggesting that excessive D1 stimulation may be deleterious to cognitive function.

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

“…Other human and animal studies DA modulates responses to positive/negative rewards, salient events and arousal-producing stimuli (Everitt et al, 2000;Liberzon et al, 2003;Horvitz, 2000) CSF HVA levels are related to impulsivity in BPD (Coccaro, 1998;Chotai et al, 1998); to self-injurious and violent behavior (Winchel and Stanley, 1991;Soderstrom et al, 2001) DA receptor activity in the DLPFC modulates working memory and cognition (Arnsten et al, 1994;Goldman-Rakic, 1996;Arnsten and Goldman-Rakic, 1998) DA modulates emotional responses mediated by the amygdala-VTA-PFC circuits (Horvitz, 2000) DA dysfunction is involved in drug addiction (Modell et al, 1993;Volkow and Fowler, 2000) PCP-induced cognitive impairment correlates with DA levels in the DLPFC (Jentsch et al, 1997) Stress alters DA activity in the amydala and PFC (Finlay and Zigmond, 1997;Doherty and Gratton, 1999) DA mediates aggression and attack in rats (Wade et al, 2000;Vukhac et al, 2001) DA modulates cognitive processes at NMDA receptors (Williams and Goldman-Rakic, 1995) DA modulates conditioned fear responses (Guarraci et al, 1999) DA stimulates impulsive behavior in rats (Harrison et al, 1997) D1 agonist dilhydrexidine enhances cognitive performance and stimulates Ach release in the PFC (Steele et al, 1997;Schneider et al, 1994) Microdialysates of the PFC and the NAC suggest DA dysfunction is a risk factor for impulsivity (Van Erp and Miczek, 2000;Dalley et al, 2002) DA dysfunction in the DLPFC is related to cognitive impairment in SCZ, SPD, and normal subjects (Goldberg et al, 2003;Siever et al, 2002) DAFdopamine; CSF HVAFspinal fluid homovanillic acid; DLPFCFdorsolateral prefrontal cortex; PCPFphencylclidine; VTAFventral tegmental area; PFCFprefrontal cortex; AchFacetylcholine; NACFnucleus accumbens; SCZFschizophrenia; SPDFschizotypal personality disorder.…”

“…The DLPFC is important in the implementation of cognitive control, and the ACC in responding to incongruent stimuli, the monitoring of responses and initiating mid-course corrections in behavior (MacDonald et al, 2000;Shima and Tanji, 1998). D1 receptors predominate in the human cortical mantle (Hurd et al, 2001), and there is strong evidence that DA neurons projecting from the VTA to the DLPFC (Figure 1) serve to modulate working memory and cognition through their effects on D1 receptors (Arnsten et al, 1994;GoldmanRakic, 1996). The effect is bimodal.…”

“…In addition, this body of work does not consider evidence from animal and human studies that implicate DA activity in emotion information processing, impulse control, and cognition (Table 2). For example, DA modulates emotional responses to salient positive and negative events and arousalproducing stimuli (Everitt et al, 2000;Horvitz, 2000;Liberzon et al, 2003), and modulates working memory and cognition (Arnsten et al, 1994;Goldman-Rakic, 1996;Arnsten and Goldman-Rakic, 1998). There is evidence that CSF HVA levels may be related to impulsive behavior in patients with BPD (Coccaro, 1998;Chotai et al, 1998).…”

Regulation of Working Memory by Dopamine D4 Receptor in Rats

“…These studies have demonstrated an important role of the D 1 -like (D 1 ,D 5 ) receptors. Blockade of the D 1 -like receptors in PFC disrupts working memory (Arnsten et al, 1994;Sawaguchi and Goldman-Rakic, 1991). In animals with dopamine depletion, occurring either naturally with aging, or induced by reserpine treatment or chronic stress, the D 1 partial agonist SFK-38393 improves working memory (Arnsten et al, 1994;Mizoguchi et al, 2000).…”

“…Blockade of the D 1 -like receptors in PFC disrupts working memory (Arnsten et al, 1994;Sawaguchi and Goldman-Rakic, 1991). In animals with dopamine depletion, occurring either naturally with aging, or induced by reserpine treatment or chronic stress, the D 1 partial agonist SFK-38393 improves working memory (Arnsten et al, 1994;Mizoguchi et al, 2000). However, an overflow of dopamine activity, either by excessive dopamine release or overstimulation of postsynaptic D 1 receptor, can impair working memory (Arnsten and Goldman-Rakic, 1998;Cai and Arnsten, 1997;Murphy et al, 1996;Zahrt et al, 1997).…”