Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum.
Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. The present study assessed the effects of neonatal VH (nVH) lesion and amphetamine treatment on the expression of NGFI-B mRNA in pre- and post-pubertal rats. Sprague-Dawley rat pups received bilateral injection of ibotenic acid or phosphate buffered saline in VH at postnatal (PD) 7. At PD35 and PD56, groups of sham and lesioned animals were administered with D-amphetamine (1.5 mg/kg) or saline and killed 20 min later. In situ hybridization analyses showed that the basal level of NGFI-B mRNA in saline-treated lesioned rats was significantly reduced in the medial PFC (mPFC) and cingulate cortex (CC) only at post-pubertal (PD56) age. No significant difference in NGFI-B mRNA levels was seen in the dorsal striatum or nucleus accumbens (NAcc). Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.
Bhardwaj
S K
SK
Douglas Hospital Research Centre, Department of Psychiatry, McGill University, 6875 LaSalle Boulevard, Verdun, Quebec, Canada H4H 1R3.
Beaudry
G
G
Quirion
R
R
Levesque
D
D
Srivastava
L K
LK
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D007051:Ibotenic Acid / Q000633:toxicity; D017403:In Situ Hybridization; D008297:Male; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D007051:Ibotenic Acid; D000661:Amphetamine