Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice.
OBJECTIVE
Amphetamine-induced sensitization is thought to involve dopamine D(1) receptors. Using mice lacking dopamine D(1) receptors (D (1) (-/-) ), we found that they exhibited blunted sensitization to low doses of amphetamine, while others using different treatment and testing regimens reported inconsistent results. We investigated whether experimental variables, alteration in gene expression or cholinergic input played a role in amphetamine-induced responses.


METHODS
D (1) (-/-) and wild-type (D (1) (+/+) ) mice pretreated with amphetamine (1 mg/kg, 3-7 days) or various doses of nicotine (chronically but intermittently) were challenged with amphetamine (0.7 and/or 1 mg/kg) after short and long abstinence periods. Expression of brain-derived neurotrophic factor (BDNF) and phosphorylated c-AMP response element binding protein (p-CREB) genes were measured under basal conditions and after acute or repeated amphetamine treatments.


RESULTS
D (1) (-/-) mice failed to exhibit amphetamine-induced sensitization following short-term treatments and long abstinence periods, but expressed sensitization following prolonged amphetamine treatment or a shorter abstinence period. Basal expression of p-CREB (but not BDNF) was higher in D (1) (-/-) than D (1) (+/+) mice and was reduced after amphetamine treatment. Prolonged nicotine pretreatment augmented locomotor responses to amphetamine in both genotypes and restored sensitization in D (1) (-/-) mice.


CONCLUSIONS
D(1) receptors were necessary for induction, but may not be necessary for expression of amphetamine-induced sensitization at low doses. The manifestation of amphetamine sensitization depended on the duration of treatment and length of the withdrawal period. Cholinergic-nicotinic stimulation restored amphetamine-induced sensitization in D (1) (-/-) mice. Enhanced basal expression of p-CREB in D (1) (-/-) mice may represent an adaptive mechanism related to lack of D(1) receptors.
El-Ghundi
Mufida B
MB
Department of Pharmacology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada.
Fan
Theresa
T
Karasinska
Joanna M
JM
Yeung
John
J
Zhou
Millee
M
O'Dowd
Brian F
BF
George
Susan R
SR
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D015259:Dopamine Agents; D018722:Nicotinic Agonists; D017447:Receptors, Dopamine D1; D009538:Nicotine; D000661:Amphetamine