Reversal of stable behavioural modifications through NMDA receptor inhibition in rats

In order to study the effect of long-term dizocilpine infusion on memory, two different paradigms of stably modified behaviour were used in rats. The first was the escape deficits (ED) induced and maintained either by repeated daily administrations of SKF 38393, a rather selective D1 dopamine receptor agonist, or by repeated stress; the second was sensitisation to the effect of cocaine on motility. Fluoxetine (FLX), imipramine (IMI) and clomipramine (CMI) were equally effective in reversing the reduced reactivity of animals in both ED models. Dizocilpine showed a similar efficacy to that of classic antidepressants on the pharmacologically-induced ED, but failed to affect the stress-induced ED. In rats previously sensitised to cocaine and then infused with dizocilpine for 7 days after suspension of cocaine administration, the state of sensitisation, remained intact; however, in animals receiving dizocilpine plus a concomitant daily injection of cocaine, dizocilpine significantly reduced cocaine sensitisation. These results potentially suggest a new approach to the treatment of drug addiction and other psychiatric disorders. Finally, it was concluded that NMDA receptor blockade not only prevents, but also reverses many, if not all, learned behaviours, and that this phenomenon differs from the effect of antidepressants.