Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

Abstract

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys (FG7142/RO15-1788 ABSTRACTThe selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic g3-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, R015-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

“…As noted above, acute administration of noncompetitive NMDA receptor antagonists is associated with a dramatic activation of dopamine transmission in forebrain (Doherty et al 1980;Bowers and Hoffman 1984;Deutch et al 1987;Verma and Moghaddam 1996;Jentsch et al 1997a), and this effect is likely directly implicated in the cognitive dysfunction exhibited by subjects acutely treated with PCP or ketamine (Verma and Moghaddam 1996), because increased dopamine transmission in prefrontal cortex has been reported to impair spatial working memory (Murphy et al 1996a;Jentsch et al 1997d). In rodents, an acute dose of PCP seems to augment prefrontal cortical and ventral striatal dopamine transmission; whereas, the dopaminergic innervation of the dorsal striatum is relatively unaffected (Deutch et al 1987;Jentsch et al 1997a).…”

“…Likewise, novel antipsychotic agents, such as olanzapine and Seroquel, were observed to present PCP-induced prepulse inhibition deficits (Bakshi and Geyer 1995;Swerdlow et al 1996). Both clozapine and haloperidol have been reported to prevent stress-induced cognitive dysfunction in monkeys (Murphy et al 1996a), an effect mediated by heightened prefrontal cortical dopamine transmission (Murphy et al 1996b). Finally, we have reported that clozapine partially alleviated cognitive deficits in monkeys repeatedly treated with PCP (Jentsch et al 1997c).…”

Regulation of Working Memory by Dopamine D4 Receptor in Rats

“…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). These findings suggest that optimal functioning of PFC requires an intermediate level of dopamine input.…”

“…Chronic exposure to the D 2 -like receptor antagonist haloperidol results in disrupted working memory (Castner et al, 2000). Acute challenge with various D 2 -like receptor antagonists has been reported to impair working memory and delayspecific PFC neuronal activity in some studies (Arnsten and Goldman-Rakic, 1998;Didriksen, 1995;Murphy et al, 1996), but not others (Aultman and Moghaddam, 2001;Bushnell and Levin, 1993;Sawaguchi and Goldman-Rakic, 1994;Verma and Moghaddam, 1996;Williams and GoldmanRakic, 1995). Working memory deficits induced by the noncompetitive NMDA antagonist ketamine (Verma and Moghaddam, 1996), the benzodiazepine inverse agonist FG-7142, or physiological stress (Arnsten and Goldman-Rakic, 1998) (Van Tol et al, 1991).…”

Prefrontocortical Dopamine Loss in Rats Delays Long-Term Extinction of Contextual Conditioned Fear, and Reduces Social Interaction Without Affecting Short-Term Social Interaction Memory

“…However, the mesocortical dopaminergic neuromodulation is not straightforward, because the relation between prefrontal dopamine and 'cognitive performance' in memory tests depends on the nature of the task (Roberts et al, 1998). Thus, while prefrontal dopamine loss is known to impair performance on delayed alternation or delayed response in rats and monkeys (Murphy et al, 1996), the extinction of cued conditioned fear responses is delayed (Morrow et al, 1999), which indicates that the prefrontal cortex and its dopaminergic network 'organize' differently the behavioral response to varying motivational or mnesic demands (Roberts et al, 1998). In this respect, the effects of prefrontal dopamine loss in contextual fear conditioning or social interaction memory have not been explored.…”