Behavioral response profiles following drug challenge with dopamine receptor subtype agonists and antagonists in developing rat.

As part of an investigation into the effects of gestational ethanol (ETOH) exposure on the developing dopamine (DA) system, pregnant Sprague-Dawley rats were exposed to one of three conditions: ETOH, pair-fed (PF) to the ETOH group, or ad libitum lab chow controls (LC). In this paper we report behavioral drug challenge effects for offspring of the two control groups (PF and LC). Male and female pups between postnatal days (PNDs) 21 and 23 in age were exposed to one of three intraperitoneal/subcutaneous doses of one of eight drugs chosen to assess the functional status of the DA D(1), D(2), and D(3) receptor subtype, or a saline control. Agonists were SKF 38393, apomorphine (APO), quinpirole (QUIN), and 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin [7-OH-DPAT (DPAT)]; antagonists were spiperone (SPIP), SCH 23390, and two recently developed D(3) antagonists nafadotride (NAF) and PD 152255. Immediately following drug injection, pups were placed in observation cages, where eight behaviors (square entries, grooming, circling, rearing, sniffing, head and oral movements, and yawning) were scored at 3-min intervals for 30 min. Classic behavioral profiles were generally obtained for the high-dose mixed agonists APO, DPAT, and QUIN, which potently increased square entries, rearing, and sniffing, while reducing grooming and head movements. However, low-dose APO had no effect on behavior. The D(1) agonist, SKF 38393, had a strikingly different behavioral profile; it had no effect on square entries at any dose, while increasing grooming and sniffing at the medium dose. The D(1) antagonist, SCH 23390, profoundly decreased all behaviors except oral and head movements, especially at high doses. In contrast, the effects of the D(2) antagonist, SPIP, were limited to increasing sniffing at the medium dose. The two putative D(3) antagonists, NAF and PD 152255, presented strikingly different profiles. NAF induced a pattern of behavioral suppression that resembled the profile of high-dose SCH, while high-dose PD 152255 stimulated behavior. The failure of low-dose APO to have any effect on behavior suggests that the D(2) autoreceptor is not functional in preweanling rats. This hypothesis is further supported by the lack of behavioral suppression seen with low-dose QUIN and DPAT. Failure of NAF to produce behavioral activation at low doses and the stimulatory effects seen with PD 152255 suggests that either the D(3) autoreceptor, the postsynaptic D(3) receptor, or both are not fully functional at this age as well.