Reports of prenatal ethanol (ETOH) effects on the dopamine system are inconsistent. In an attempt to clarify this issue, dams were given 35% ethanol-derived calories as the sole nutrient source in a liquid diet from the 10th through the 20th day of gestation (ETOH). Controls were pair-fed (PF) an isocaloric liquid diet or given ad libitum access to laboratory chow (LC). Prenatal exposure to both liquid diets reduced body weight of offspring relative to LC controls, more so for ETOH than for PF exposure. Prenatal ETOH also decreased litter size and viability, relative to both LC and PF control groups. On postnatal days 21-23, male and female offspring were given an injection of saline vehicle or one of eight specific dopamine receptor agonists or antagonists. Immediately after injection subjects were placed in individual observation cages, and over the following 30 min, eight behaviors (square entries, grooming, rearing, circling, sniffing, yawning, head and oral movements) were observed and quantified. No prenatal treatment effects on drug-induced behaviors were observed for dopamine D2 (Apomorphine, DPAT or Quinpirole) or D3 (PD 152255, Nafadotride, Apo or Quin effects on yawning) receptor agonists or antagonists, or for the vehicle control. In contrast, prenatal treatment effects were seen with drugs affecting the dopamine D1 receptor. Both D1 agonists (SKF 38393) and antagonists (SCH 23390 and high doses of spiperone) altered behaviors, especially oral and sniffing behaviors, in a manner which suggested enhanced dopamine D1 drug sensitivity in both ETOH and PF offspring relative to LC controls. These results suggest that at this age, both sexes experience a prenatal undernutrition-linked increase in the behavioral response to dopamine D1 agonists and antagonists, which can be intensified by gestational exposure to alcohol.

01 May 2003·Neurotoxicology and TeratologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Sonya K. Sobrian ; Barbara L. Jones ; R.Robert Holson ; Shiny Varghese

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.

01 Nov 2002·Pharmacology Biochemistry and BehaviorQ4 · PSYCHOLOGY

Reevaluation of PNU-99194A discriminative stimulus effects

Q4 · PSYCHOLOGY

Article

Author: Adam J. Prus ; Lisa E. Baker

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Behavioural disorders	Discovery	US	Parke-Davis & Co. Ltd.	-

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