Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2007; 27(42):11424-30. DOI: 10.1523/JNEUROSCI.2847-07.2007
Source: PubMed


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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Available from: Anthony Grace, Oct 06, 2015
    • "Another version, sPAL, is identical to dPAL except that the two stimuli displayed in each trial are identical. We used the dPAL version of the task because it is more sensitive to pharmacological manipulations of the hippocampus (Talpos et al. 2009), an area implicated in schizophrenia pathology (Wood et al. 2002; Lodge and Grace 2007; Jodo 2013). In dPAL, rats are presented with two of the three images in each trial in a pseudorandom order. "
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    ABSTRACT: Rationale: New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder. Objective: The objective of the present studies was to test the effects of the D- and L-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound. Methods: MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), D- and L-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers. Results: Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. L-Govadine (1.0 mg/kg), but not D-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of L-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes. Conclusion: L-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of L-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.
    Psychopharmacology 09/2015; 232(23). DOI:10.1007/s00213-015-4064-1 · 3.88 Impact Factor
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    • "chizophrenia ( Moore et al . 2006 ; Lodge and Grace . 2009 ) . Changes in the hippocampus include volume reduction , aberrant neuronal or - ganisation and excitability , deficits in synaptic transmission and synaptic plasticity , and abnormal neuronal oscillatory ac - tivity ( Gourevitch et al . 2004 ; Moore et al . 2006 ; Penschuck et al . 2006 ; Lodge and Grace . 2007 ; Matricon et al . 2010 ; Chin et al . 2011 ; Hradetzky et al . 2012 ; Phillips et al . 2012a , b ; Sanderson et al . 2012 ; Snyder et al . 2013 ) . Alongside these robust anatomical and physiological alterations , a number of studies have looked at the effects of MAM E17 treatment in behavioural paradigms assessing hippocampus - depend"
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    ABSTRACT: Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.
    Psychopharmacology 01/2015; DOI:10.1007/s00213-014-3862-1 · 3.88 Impact Factor
    • "Accordingly, some animal models of schizophrenia that induce dysfunction in the GABAergic neurons in the PFC and hippocampus also show amphetamine-or novelty-induced hyperlocomotion [40] [104] [107], but not others [27]. The lack of amphetamine-induced psychomotor effects that we describe here versus those previously shown with developmental MK-801 treatment [107], suggests either crucial differences in the mechanisms of action between MK-801 and ketamine, or that ketamine blockade of NMDARs on corticolimbic GABAergic neurons during early postnatal development may permanently induce a brain state akin to that of amphetamine-sensitized mice, thereby resulting in the occlusion of amphetamine-induced hyperlocomotion (cf. "
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    ABSTRACT: Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia. Copyright © 2015. Published by Elsevier B.V.
    Behavioural Brain Research 01/2015; 282. DOI:10.1016/j.bbr.2015.01.010 · 3.03 Impact Factor
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