Ontogeny of dopamine agonist-induced sensitization: role of NMDA receptors.

Abstract

In contrast to adults, preweanling rats exhibit behavioral sensitization for only a few days after cessation of dopamine (DA) agonist treatment. The reasons for this ontogenetic difference are uncertain, but maturational changes in the N-methyl-D-aspartate (NMDA) receptor may be responsible, since stimulation of these receptors is necessary for the development of DA agonist-induced sensitization in adult rats. The purpose of the present study was to examine the relationship between NMDA receptor functioning and DA agonist-induced sensitization during the preweanling period. To that end, 17-day-old rats were injected (i.p.) on 4 consecutive days with saline or 0.3 mg/kg dizocilpine (a non-competitive NMDA receptor antagonist) followed, 30 min later, by an injection of saline, 2.5 mg/kg amphetamine (an indirect DA agonist), or 1.0 mg/kg NPA (a direct DA agonist). Sensitization was tested 2 days later (i.e., at 22 days of age), with rats receiving a challenge injection of saline, amphetamine, NPA, or dizocilpine. Results showed that the NMDA antagonist had adult-like effects on the behavioral sensitization of preweanling rats, as amphetamine- and NPA-induced sensitization were eliminated by dizocilpine pretreatment. When given alone, dizocilpine substantially increased the locomotor activity (i.e., line-crosses) of preweanling rats, an effect that became sensitized with repeated drug treatment. Lastly, preweanling rats already sensitized to dizocilpine did not exhibit cross-sensitization to amphetamine or NPA. Thus, with few exceptions, NMDA receptor stimulation appears to modulate sensitization in a similar fashion across ontogeny. This finding suggests that maturational differences in the NMDA receptor system are not responsible for the lack of long-term sensitization in the younger animal.