There is substantial evidence that early life events influence brain development and subsequent adult behavior and play an important role in the causation of certain psychiatric disorders including schizophrenia and depression. The underlying mechanism of the effects of these early environmental factors is still not understood. It is a challenge to attempt to model early environmental factors in animals to gain understanding of the basic mechanisms that underlie the long-term effects. This paper reviews the effects of rearing rats from weaning in social isolation and reports some recent results indicating hippocampal dysfunction. Isolation rearing in rats from weaning produces a range of persistent behavioral changes in the young adult, including hyperactivity in response to novelty and amphetamine and altered responses to conditioning. These are associated with alterations in the central aminergic neurotransmitter functions in the mesolimbic areas and other brain regions. Isolation-reared rats have enhanced presynaptic dopamine (DA) and 5-HT function in the nucleus accumbens (NAC) associated with decreased presynaptic 5-HT function in the frontal cortex and hippocampus. Isolation-reared rats have reduced presynaptic noradrenergic function in the hippocampus, but have enhanced presynaptic DA function in the amygdala. These neurochemical imbalances may contribute to the exaggerated response of the isolated rat to a novel stimulus or to stimuli predictive of danger, and isolation-induced behavioral changes. These changes have neuroanatomical correlates, changes which seem to parallel to a certain degree those seen in human schizophrenia. A greater understanding of the processes that underlie these changes should improve our knowledge of how environmental events may alter brain development and function, and play a role in the development of neuropsychiatric disorders.

Intracerebral microdialysis in conjunction with HPLC coupled to electrochemical detection was used to investigate the effect of isolation-rearing in the rat on extracellular dopamine (DA) and its metabolites in vivo, in the shell region of the nucleus accumbens, in response to footshock and in relation to a conditioned emotional response. Male Lister hooded rats were reared from weaning for 6-8 weeks in either social isolation or groups of five. In the training phase, rats were exposed to a novel environment for 10 mm where they experienced mild footshock. Footshock caused an immediate increase in basal extracellular DA levels in both rearing groups relative to control rats. However, the increase in extracellular DA was prolonged in the case of the isolation-reared rats and significantly greater than in group-reared rats. Exposure to the novel environment without shock (control groups) did not significantly alter basal extracellular DA in the nucleus accumbens shell; 140 mm later rats were returned to the testing box (contextual stimulus) without receiving footshock. The contextual stimulus increased basal extracellular DA in the nucleus accumbens of both groups of rats with respect to controls; however, this increase was significantly greater and more prolonged in isolates. Extracellular levels of the metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid did not differ between isolation-and group-reared rats, and they were not significantly affected by either footshock or the contexual stimulus. These results suggest that exposure to footshock and a contextual stimulus are associated with increases in basal extracellular DA levels in the nucleus accumbens shell. The results also support evidence in favour of an isolation-induced enhancement in dopaminer~ic activity in the nucleus accumbens, which probably underlies aspects of the behavioural syndrome associated with isolation. Key Words: Isolation-rearing-Microdialysis-Dopamine-Conditioned emotional response -Nucleus accumbens-Rat. J. Neurochem. 70, 384-390 (1998).taneous activity when exposed to a novel environment (Sahakian et al., 1975;Fulford et al., 1994), an altered locomotor response to d-amphetamine administration (Jones et a!., 1992), impairments in psychoactive drug reinforcement (Phillips et al., 1994), and deficits in prepulse inhibition of an acoustic startle (Geyer et al., 1993;Wilkinson et al., 1994;Varty and Higgins, 1995). Neurochemical measurements made using intracerebral microdialysis have shown that isolation causes greater increases in extracellular levels of dopamine (DA) in the nucleus accumbens (NAcc) and caudate putamen after d-amphetamine administration (Jones et a!., 1992), suggesting that isolation may enhance dopaminergic activity in the NAcc and caudate putamen. The deficits in prepulse inhibition of acoustic startle, characteristic of isolation-reared rats, are thought to result from overactivity of DA neurones of the mesolimbic system. It is noteworthy that similar sensorimotor gating deficits are seen in h...

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