A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice.
BACKGROUND
We previously reported that mice lacking dopamine D3 receptors (D3R) were resistant to behavioural sensitization to ethanol (EtOH). Since knockout mice have permanent receptor inactivation, we investigated how temporary pharmacological blockade and activation of D3Rs affected the induction or expression of EtOH sensitization.


METHODS
In induction studies, DBA/2 mice received 0, 10 or 75 mg/kg, subcutaneous (s.c.) of the D3R antagonist, U99194A ,before each of seven EtOH (2.2 g/kg, intraperitoneal) or saline injections. Locomotor activity (LMA) was assessed in activity chambers. In expression studies, mice received seven injections of EtOH or saline, followed 14 days later with U99194A or vehicle immediately before a test dose of EtOH (1.8 g/kg). In separate experiments, the effects of the D3R agonist PD128907 (0.01 mg/kg, s.c.) were similarly examined during and after EtOH sensitization.


RESULTS
Chronic co-administration of low-dose U99194A blocked the induction of EtOH sensitization, while acute U99194A had no effect in mice that were already sensitized. Chronic co-administration of PD128907 resulted in decreased LMA but this effect was also seen in saline-treated mice, suggesting a simple subtractive effect. In previously sensitized mice, acute PD128907 significantly attenuated the expression of EtOH sensitization, indicating an enhanced response to the drug.


CONCLUSIONS
Results suggest a modulatory role for the D3R in behavioural sensitization to EtOH, where D3R blockade is associated with induction and D3R stimulation is associated with expression of EtOH sensitization. A model is suggested to account for these complementary functions of the D3R at different stages of EtOH sensitization.
Harrison
Sarah Jane
SJ
Psychology Department, University of Toronto, Toronto, ON, Canada.
Nobrega
José N
JN
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D000431:Ethanol / Q000009:adverse effects*; D007189:Indans / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000502:physiology*
D001578:Benzopyrans; D002492:Central Nervous System Depressants; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004338:Drug Combinations; D007189:Indans; D010078:Oxazines; D050637:Receptors, Dopamine D3; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; D000431:Ethanol