Neonatal neurosteroid administration results in development-specific alterations in prepulse inhibition and locomotor activity: neurosteroids alter prepulse inhibition and locomotor activity.
BACKGROUND
Early life exposure to stress and to GABAA receptor modulators have well-defined and persistent behavioral effects. A single neonatal injection of the GABAergic neurosteroid allopregnanolone (3alpha-hydroxy,5alpha-pregnane-20-one, 10 mg/kg, i.p.) alters the localization of prefrontal cortex (PFC) interneurons in adulthood. Such displacement could result in disinhibited behavior associated with impaired development of the mesocortical dopamine system.


OBJECTIVE
To determine if there is a critical window in which allopregnanolone levels may impact the development and mature function of the mesocorticolimbic circuitry.


METHODS
Behavioral measures, including prepulse inhibition (PPI) and total locomotor activity, after amphetamine exposure were assessed at postnatal day 20 (P20) (prepuberty), P40 (puberty), P60 (postpuberty), and P80 (adulthood) in animals previously exposed to allopregnanolone (10 mg/kg) on P2 and P5. PFC tyrosine hydroxylase immunoreactivity was stereologically measured.


RESULTS
P2 administration of allopregnanolone resulted in an increased locomotor response to amphetamine (14, 28% on P20 and P80, respectively) and reduced PPI (28, 22% on P20 and P80, respectively) at P20 and P80, whereas allopregnanolone administration on P5 increased locomotor response to amphetamine (20%) and reduced PPI (37%) at P80. Clozapine (7.5 mg/kg) pretreatment reversed the PPI deficit in P2-exposed animals. The total length of tyrosine hydroxylase immunopositive fibers in PFC was not altered by neonatal neurosteroid exposure, but more fibers were located in layers V/VI vs I-III.


CONCLUSIONS
Altering neonatal allopregnanolone levels disrupts PFC-dependent behavior, indicating that allopregnanolone might be important for normal PFC circuitry development. The temporal exposure differences (P2 vs P5) and ontological-dependent effects (P20 and P80, but not P40 or P60) suggest critical windows of vulnerability to neurosteroid insult across development.
Gizerian
Samantha S
SS
Curriculum in Neurobiology and Department of Psychiatry, University of North Carolina at Chapel Hill, 7023 Neurosciences Hospital, Chapel Hill, NC 27599, USA.
Moy
Sheryl S
SS
Lieberman
Jeffrey A
JA
Grobin
A Chistina
AC
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects
D018756:GABA Antagonists; D011280:Pregnanolone; D000661:Amphetamine; D003024:Clozapine