PD-152255

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.

This study evaluated the relative importance of D(3) receptor antagonism in the discriminative stimulus effects of the putative D(3) receptor antagonist PNU-99194A. Eight male Sprague-Dawley rats were trained to discriminate PNU-99194A (10 mg/kg sc) from vehicle in a two-choice drug discrimination procedure under a FR 20 schedule of food reinforcement. The selective D(3) antagonists PD 152255 and S14297 were examined for stimulus generalization. The D(2) antagonist haloperidol and the D(2)/D(3) receptor agonist (+)-7-OH-DPAT were also assessed for antagonism of PNU-99194A discrimination. PD 152255 (1.0-3.0 mg/kg) engendered no generalization to PNU-99194A. Due to its markedly rate-suppressive effects, PD 152255 could not be tested at higher doses. S-14297 produced partial substitution (66%) for PNU-99194A at both 3.0 and 8.0 mg/kg. Neither haloperidol nor (+)-7-OH-DPAT blocked the discrimination of PNU-99194A and, surprisingly, actually appeared to potentiate its effects. These data, along with other recent findings, suggest that the discriminative stimulus effects of PNU-99194A appear to involve complex pharmacological actions and are not solely mediated by D(3) receptor antagonism.