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Volume 16, Number 22, Issue of November 15, 1996 pp. 7366-7375
Copyright ©1996 Society for Neuroscience

Enhanced Amphetamine Sensitivity and Increased Expression of Dopamine D2 Receptors in Postpubertal Rats after Neonatal Excitotoxic Lesions of the Medial Prefrontal Cortex

Received July 10, 1996; revised Aug. 28, 1996; accepted Sept. 3, 1996.

Gonzalo Flores, Graham K. Wood, Jin-Jun Liang, Remi Quirion, and Lalit K. Srivastava

Douglas Hospital Research Center, Departments of Psychiatry and Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada H4H 1R3

Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty or d-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and after d-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD39 and PD60. The levels of DA D2 receptors, measured using [³H]-YM-09151-2 binding, and its mRNA by in situ hybridization, were observed to be significantly increased at PD60 in striatal and limbic areas of lesioned rats. Levels of other DA receptor subtypes were not significantly affected at any time points. Lesioned rats at PD39 show a small increase in DA transporter level in the shell of nucleus accumbens; however, this effect seems to wear off at PD60. The data suggest that neonatal MPFC lesions may alter the functional development and maturation of mesolimbic/nigrostriatal DA systems in that neonatally lesioned rats grow into a behavioral/neurochemical deficit.

Key words: prefrontal cortex; schizophrenia; animal model; nucleus accumbens; ibotenic acid; dopamine receptors; neurodevelopment

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