Alterations of the dopaminergic and glutamatergic neurotransmission in adult rats with postnatal ibotenic acid hippocampal lesion

Abstract

In 6-week and 8-week-old rats (pre- and post-pubertally) with neonatal excitotoxic lesions of the ventral hippocampus with ibotenic acid (IBO), we have studied apomorphine-induced motor activity and glutamate and dopamine D1 and D2 binding sites in the hippocampus, striatum, nc. accumbens and frontal cortex as well as K+ -stimulated (3H)-D-aspartate release from hippocampal and frontal cortical slices. Specific glutamate binding was enhanced in the frontal cortex of 8-week-old IBO-treated animals, whereas that in other brain regions remained unchanged. Both D1 and D2 binding sites were downregulated in the striatum without changes in other brain structures. In 6-week-old rats, neither the glutamate nor the dopamine binding sites were altered. The amino acid release from hippocampal and frontal cortical slices of adult IBO treated rats was significantly decreased in comparison to controls, whereas in 6-week-old rats, no significant alterations were detectable. The additionally monitored motor activity was enhanced only in adult IBO-lesioned rats after apomorphine pretreatment. The present data are in agreement with the hypothesis of hyperactive dopamine and hypoactive glutamate systems in schizophrenia and are discussed in the light of schizophrenia-like behavioral changes in rats after postnatal hippocampal IBO lesion.

Alterations in Behavioral Responses to a Cholinergic Agonist in Post-Pubertal Rats with Neonatal Ventral Hippocampal Lesions: Relationship to Changes in Muscarinic Receptor Levels

“…This is consistent with other neurochemical and behavioral changes that are primarily seen in post-pubertal lesioned animals (Flores et al, 1996;Laplante et al, 2004a;Lipska et al, 1993Lipska et al, , 1995O'Donnell et al, 2002;Schroeder et al, 1999). Thus, these data suggest that NVH lesions result in developmental alterations in central cholinergic neurotransmission.…”

“…For example, post-pubertal NVH lesioned animals are hyper-reactive to stress and amphetamine, display deficits in prepulse inhibition (PPI) of startle and latent inhibition, and impaired social behavior and working memory Lipska et al, 1993Lipska et al, , 1995Lipska et al, , 2002Sams-Dodd et al, 1997). NVH lesions also induce a number of morphological and physiological (O'Donnell et al, 2002;Schroeder et al, 1999) changes in the prefrontal cortex (PFC) suggesting the neurodevelopmental reorganization of PFC circuitry.…”

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

“…For example, N-acetylaspartate concentrations, taken as markers of neuronal integrity (Bertolino et al 2002) and stress-induced expression of brain derived neurotrophic factor (BDNF) mRNA expression, as a mediator of synaptic plasticity, are reduced in the medial PfC of NVHL rats (Molteni et al 2001). Both major excitatory and inhibitory transmitter systems in the PfC also appear to be altered by NVHLs, as evidenced by alterations in splice variants of AMPA glutamate receptor mRNA (Stine et al 2001), increased glutamate binding (Schroeder et al 1999), decreased concentrations of the γ-aminobutyric acid (GABA) production enzyme GAD-67 mRNA (Lipska et al 2003) and decreased pyramidal cell dendritic length and spine density . Correlated with these molecular and cellular alterations are neurophysiological changes: NVHL rats show abnormal patterns and elevations of neuronal firing in medial PfC pyramidal neurons produced by VTA stimulation that is mirrored by similar abnormalities in firing in medium spiny neurons in the NAc (Goto and O'Donnell 2002).…”

To Model a Psychiatric Disorder in Animals Schizophrenia As a Reality Test

“…Another series of studies have focused on neonatal damage of restricted brain regions in rats (Lipska et al 1993;Flores et al 1996a;Chambers et al 1996;Wan et al 1996Wan et al , 1998Wan and Corbett 1997;Brake et al 1999, Black et al 1998Grecksch et al 1999;Schroeder et al 1999) and in monkeys (Beauregard and Bachevalier 1996;Bertolino et al 1997;Saunders et al 1998;Bachevalier et al 1999). The main objective of many of these studies is to disrupt development of the hippocampus, a brain area consistently implicated in human schizophrenia (Falkai and Bogerts 1986;Jeste and Lohr 1989;Bogerts et al 1990;Suddath et al 1990;Eastwood et al 1995Eastwood et al , 1997Eastwood andHarrison 1995, 1998;Weinberger 1999), and thus disrupt development of the widespread cortical and subcortical circuitry in which the hippocampus participates.…”