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Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia - PubMed

  • ️Mon Jan 01 2007

Comparative Study

Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia

Daniel J Lodge et al. J Neurosci. 2007.

Abstract

Evidence supports a dysregulation of subcortical dopamine (DA) system function as a common etiology of psychosis; however, the factors responsible for this aberrant DA system responsivity have not been delineated. Here, we demonstrate in an animal model of schizophrenia that a pathologically enhanced drive from the ventral hippocampus (vHipp) can result in aberrant dopamine neuron signaling. Adult rats in which development was disrupted by prenatal methylazoxymethanol acetate (MAM) administration display a significantly greater number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity because, in MAM-treated rats, vHipp inactivation completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior. These data provide a direct link between hippocampal dysfunction and the hyper-responsivity of the DA system that is believed to underlie the augmented response to amphetamine in animal models and psychosis in schizophrenia patients.

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Figures

Figure 1.
Figure 1.

A, Representative section demonstrating the localization of bilateral cannulas placements in the ventral hippocampus. The injection sites are denoted by arrows. B, Schematic illustrating the target injection sites within the ventral hippocampus (shaded area). Plate adapted from Paxinos and Watson (1986).

Figure 2.
Figure 2.

A, C, Afferent modulation of DA neuron activity states in MAM- and SAL-treated rats. In control rats (white bars), the simultaneous NMDA-induced activation of the vHipp and PPTg (patterned bars) resulted in a significant increase in DA neuron population activity (A) attributable to vHipp activation (Lodge and Grace, 2006a); and a significant increase in average burst firing (C) attributable to PPTg activation (Lodge and Grace, 2006a). In contrast, in MAM-treated rats (dark bars), vHipp activation failed to further increase DA neuron population activity (A), whereas PPTg afferent-induced burst firing (C) remained intact. B, The effect of NMDA-induced afferent activation on average firing rate. An asterisk represents a statistically significant difference from control (p < 0.05, one-way ANOVA, Student–Newman–Keuls post hoc or, if data failed tests for normality and/or equal variance, a Kruskal–Wallis one-way ANOVA on Ranks, Dunn's post hoc; n = 5 rats/group). SAL, Saline-treated.

Figure 3.
Figure 3.

A–C, Inactivation of the vHipp by TTX (1 μ

m

; patterned bars) normalizes the aberrant increase in DA neuron population activity in MAM rats (A), although has no observable effect in control rats (white bars; A–C) or on any other DA neuron activity state in MAM rats (dark bars; B, C). An asterisk represents a significant difference between vehicle and vHipp inactivated rats (p < 0.05, one-way ANOVA, Student–Newman–Keuls post hoc or, if data failed tests for normality and/or equal variance, a Kruskal–Wallis one-way ANOVA on Ranks, Dunn's post hoc; n = 5 rats/group). SAL, Saline-treated.

Figure 4.
Figure 4.

Bilateral vHipp inactivation by TTX (1 μ

m

) normalizes the aberrant locomotor response to

d

-amphetamine (0.5 mg/kg i.p.) observed in MAM rats. A, MAM-treated rats display an increased response to

d

-amphetamine administration compared with saline-treated rats. B, C, Inactivation of the vHipp by TTX significantly attenuates the locomotor response to

d

-amphetamine in MAM rats (C) although has no significant effect on psychostimulant-induced locomotion in saline-treated (SAL) rats (B). †Significant difference from control (p < 0.05, two-way ANOVA, Tukey's post hoc; n = 9–17 rats/group).

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