Augmented D1 dopamine receptor signaling and immediate-early gene induction in adult striatum after prenatal cocaine.
BACKGROUND
Prenatal exposure to cocaine can impede normal brain development, triggering a range of neuroanatomical and behavioral anomalies that are evident throughout life. Mouse models have been especially helpful in delineating neuro-teratogenic consequences after prenatal exposure to cocaine. The present study employed a mouse model to investigate alterations in D(1) dopamine receptor signaling and downstream immediate-early gene induction in the striatum of mice exposed to cocaine in utero.


METHODS
Basal, forskolin-, and D(1) receptor agonist-induced cyclic adenosine monophosphate (cAMP) levels were measured ex vivo in the adult male striatum in mice exposed to cocaine in utero. Further studies assessed cocaine-induced zif 268 and homer 1 expression in the striatum of juvenile (P15), adolescent (P36), and adult (P60) male mice.


RESULTS
The D(1) dopamine receptor agonist SKF82958 induced significantly higher levels of cAMP in adult male mice treated with cocaine in utero compared with saline control subjects. No effects of the prenatal treatment were found for cAMP formation induced by forskolin. After an acute cocaine challenge (15 mg/kg, IP), these mice showed greater induction of zif 268 and homer 1, an effect that was most robust in the medial part of the mid-level striatum and became more pronounced with increasing age.


CONCLUSIONS
Together these findings indicate abnormally enhanced D(1) receptor signal transduction in adult mice after prenatal cocaine exposure. Such changes in dopamine receptor signaling might underlie aspects of long-lasting neuro-teratogenic effects evident in some humans after in utero exposure to cocaine and identify the striatum as one target potentially vulnerable to gestational cocaine exposure.
Tropea
Thomas F
TF
Laboratory of Molecular and Developmental Neuroscience, Department of Pediatrics, Division Of Pediatric Neurology, New York Presbyterian Hospital/Weill-Cornell Medical College, New York, New York 10021, USA.
Guerriero
Réjean M
RM
Willuhn
Ingo
I
Unterwald
Ellen M
EM
Ehrlich
Michelle E
ME
Steiner
Heinz
H
Kosofsky
Barry E
BE
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000009:adverse effects*; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion / Q000502:physiology; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation
D001552:Benzazepines; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017874:Immediate-Early Proteins; D017447:Receptors, Dopamine D1; D005576:Colforsin; C071262:SK&F 82958; D000262:Adenylyl Cyclases; D003042:Cocaine