Noradrenaline and dopamine elevations in the rat prefrontal cortex in spatial working memory.

The role of prefrontal cortical dopamine (DA) in the modulation of working memory functions is well documented, but substantial evidence indicates that the locus ceruleus noradrenergic system also modulates working memory via actions within the prefrontal cortex (PFC). This study shows that PFC noradrenaline (NA) and DA dialysate levels phasically increase when rats perform correctly in a delayed alternation task in a T-maze, a test of spatial working memory. However, NA levels were markedly enhanced in animals trained to alternate compared with rats that acquired the spatial information about the location of food in the maze but were untrained to make a choice to obtain the reward. In contrast, PFC DA elevations occurred independently of whether the animal had acquired the trial-specific information for correct task execution. The contribution of anticipatory responses to catecholamine efflux was also evaluated by exposing rats to an environment signaling the presence of the reward in the successive alternation task. No conditioned NA efflux was observed in either group. In contrast, in both groups, DA efflux increased in the anticipatory phase of the test to the same levels of those reached during the task. These data provide the first direct evidence for a selective activation of PFC NA transmission during a spatial working memory task. We propose that, in the working memory task, DA is primarily associated with reward expectancy, whereas NA is involved in the active maintenance of the information about a goal and the rules to achieve it.

Inhibition of nitric oxide release in vivo by ethanol.

OBJECTIVE: Previous studies indicate that the nitric oxide (NO(.)) pathway is involved in the acute or chronic effects of ethanol on the central nervous system. However, direct evidence for the effect of ethanol on NO(.) production in vivo is lacking, and it is not clear whether it is inhibition or stimulation of the NO(.) pathway that contributes to the behavioral effects of ethanol. Herein the release of NO(.) in the rat striatum in vivo in response to NMDA receptor activation--the dominant mechanism controlling NO(.) formation-has been investigated after systemic or local injections of ethanol. METHODS: NMDA-induced release of authentic NO(.) was measured directly in the striatum of urethane-anesthetized (1.2 g/kg intraperitoneally) male Sprague-Dawley rats by using a direct-current amperometric method coupled to an electrically modified carbon microelectrode. An injector cannula was implanted in the proximity of the electrode (250 microm apart) for focal drugs application. RESULTS: Local application of NMDA (1 microl, 100 microM) produced a sharp and transient NO(.) signal. Systemic ethanol, 1 or 2.5 g/kg intraperitoneally, caused a long-lasting, dose-dependent inhibition of NMDA-induced NO(.) release to 12.2 +/- 5.9 and 6.4 +/- 3.7% of control, respectively, 60 min after ethanol administration. Dizocilpine (0.5 mg/kg intraperitoneally) mimicked the ethanol effect, inhibiting NO release to 1.6 +/- 0.66% of control. Local application of ethanol (1 microl, 2.5% v/v) in the striatum reduced the NMDA-induced response to 28.6 +/- 3.8% of control. Focal application of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (100 microM) or the nonselective NO synthase inhibitor L-N(G)-nitro-arginine methyl esther (100 microM) also caused inhibition of NMDA-induced NO(.) release to 2.4 +/- 0.7 and 4.3 +/- 0.9% of control, respectively. CONCLUSIONS: Ethanol, at pharmacologically significant doses, strongly inhibits striatal NO(.) production and release apparently through inhibition of NMDA receptor function. Inhibition of NMDA receptor-mediated activation of the NO(.) pathway could be a primary neurobiological mechanism contributing to the effects of ethanol.

Pulse of nitric oxide release in response to activation of N-methyl-D-aspartate receptors in the rat striatum: rapid desensitization, inhibition by receptor antagonists, and potentiation by glycine.

Increased activity of glutamate N-methyl-d-aspartate (NMDA) receptors is the dominant mechanism by which nitric oxide (NO.) is generated. By using a selective direct-current amperometry method, we characterized real time NO* release in vivo in response to chemical stimulation of NMDA receptors in the rat striatum. The application of NMDA caused the appearance of a sharp and transient oxidation signal. Concentration-response studies (10-500 microM) indicated an EC(50) of 48 microM. The NMDA-induced amperometric signal was suppressed by focal application of the nitric-oxide synthase inhibitor L-nitro-arginine methyl ester (L-NAME, 100 microM) or D-(-)-2-amino-5-phosphonopentanoic acid (AP-5, 100 microM) or by systemic injection of dizocilpine (1 mg/kg i.p.), drugs that, when given alone, had no effect on baseline oxidation current. Repeated injections of NMDA at short intervals (approximately 80 s) resulted in a progressive reduction of the amperometric signal with a decay half-life of 1.36 min. Sixty min after the last NMDA application the amperometric response was restored to initial levels. Finally, the coapplication of glycine (50 or 100 microM), which, when given alone had no effect, potentiated the NMDA-induced response. Thus, NMDA receptor-mediated activation of striatal NO* system shuts off quickly and undergoes rapid desensitization, suggesting a feedback inhibition of NMDA receptor function. To the extent of NO* release can represent a correlate of NMDA receptor activity, its amperometric detection could be useful to assess in vivo the state of excitatory transmission under physiological, pharmacological, or pathological conditions.

Bidirectional modulation of spatial working memory by ethanol.

BACKGROUND: It is common knowledge that ethanol causes cognitive and memory impairments. Although these deficits are attributed to its central depressant properties, ethanol has biphasic effects and at low doses can produce excitatory actions. METHODS: Here we examined whether ethanol could have biphasic effects on performance in a delayed alternation task in a T-maze, a behavioral test of working memory. RESULTS: A dose-response study showed that intermediate doses of ethanol (1 g/kg) were associated with impairments of working memory in rats, as assessed at short intertrial intervals (10 sec). In contrast, at longer delays (120 sec), when the delayed alternation performance was reduced markedly in controls, a lower dose of ethanol (0.5 g/kg) significantly improved working memory. CONCLUSIONS: These results demonstrate a dose-dependent, bidirectional effect of ethanol on working memory and implicate the prefrontal cortex, the site of working memory function, as a target of ethanol action. The cognitive improvements caused by low, excitatory doses of ethanol may be perceived as rewarding and could have relevance for chronic ethanol consumption in humans.