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Dopamine Problems? Blame the Hippocampus

13 November 2007. The dopamine hypothesis of schizophrenia, which proposes that dysfunction in the brain’s dopamine (DA) system causes some of the symptoms of schizophrenia, is one of the most venerable and influential biological theories of the disease (see Current Hypothesis by A. Abi-Dargham). In recent years it has been proposed that the dysregulation of the DA system observed in schizophrenia is due not to abnormalities in the system itself, but is the result of aberrant regulation of the system by other networks (see e.g., Grace, 2000; Abi-Dargham, 2004). In a new study employing a rat model of schizophrenia, Anthony Grace and Daniel Lodge at the University of Pittsburgh provide electrophysiological and behavioral evidence that disruptions in the ventral hippocampus can cause abnormal signaling in DA pathways that ascend from the ventral tegmental area (VTA) to subcortical and cortical targets in the forebrain. The subcortical (mesolimbic) and cortical (mesocortical) DA pathways have each been implicated in symptoms of schizophrenia.

MAM to dams
Grace’s group has argued that hippocampal dysfunction, which has been reported in schizophrenia, could impact dopamine neurotransmission via a multisynaptic pathway from the output center of the hippocampus—the ventral hippocampus (vHipp), or subiculum—to the VTA. (The full pathway is vHipp to nucleus accumbens to ventral pallidum to VTA.) In a report in the October 17 issue of The Journal of Neuroscience, the researchers examine this circuit in the methylazoxymethanol acetate (MAM) model of schizophrenia, in which a DNA methylating agent is administered to pregnant rat dams on the seventeenth day of gestation. As reviewed by Lodge and Grace, this technique has been shown to cause anatomical, behavioral, and electrophysiological abnormalities in adult offspring that are reminiscent of those seen in human patients with schizophrenia.

When Lodge and Grace made in vivo extracellular recordings from DA neurons in the ventral tegmental area (VTA), the adult rats that had been exposed to MAM in utero showed almost twice as much spontaneous neural activity as control rats. In parallel, the authors indeed found that the average firing rate in neurons of the vHipp of MAM-treated rats was more than twice as high as that seen in controls. When they chemically inactivated the vHipp with tetrodotoxin (TTX), the researchers found that they had abolished the increased spontaneous VTA activity in MAM-treated rats. The TTX treatment had no effect on DA neuron activity in control animals. These results were supported by experiments in which the rats were injected with D-amphetamine, an indirect dopamine agonist that is known to cause abnormally large responses in animal models of schizophrenia and in human schizophrenia patients. The MAM-treated rats showed considerably more locomotor activity than controls after amphetamine treatment, but their behavior fell within normal range after TTX inactivation of the vHipp.

Taken together, Lodge and Grace write, these results indicate that the baseline activity of dopaminergic neurons in the VTA are regulated by the ventral hippocampus, and that the disruptions in dopamine signaling associated with schizophrenia may be caused by the hippocampal abnormalities reported in the disease. The authors are circumspect about the limitations of the animal model they used in these experiments. “Nonetheless,” they write, “we posit that at the core of this disorder is a disruption of systems interactions that can be modeled in animals, but when placed in the context of complex human brain and behavioral patterns, yields the complex pattern of psychopathology recognized as schizophrenia.”—Peter Farley.

Reference:
Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007 Oct 17;27(42):11424-30. Abstract

 
Comments on News and Primary Papers
Comment by:  Anissa Abi-Dargham
Submitted 29 November 2007 Posted 29 November 2007

What struck me most about the paper of Lodge and Grace is the overall consistency of the body of work between the preclinical and clinical observations, even down to the effect size for the dopaminergic alteration. Dopamine release in schizophrenia is at least double that in controls; whether measured after amphetamine (on average 17 percent displacement of the benzamide radiotracer versus 7 percent in controls) (Laruelle et al., 1999) or at baseline (19 percent D2 occupancy by dopamine in patients versus 9 percent in controls) (Abi-Dargham et al., 2000), the increase in dopamine activity in VTA of the MAM rats reported here is also a doubling of what is measured in saline-treated rats.

This work presents an important contribution to the field because it clarifies the role of the hippocampus in one of the cardinal features of the disorder as modeled in MAM rats. The fact that MAM treatment is one of the most valid animal models of schizophrenia—it replicates many of the...  Read more


View all comments by Anissa Abi-Dargham

Comment by:  Elizabeth Tunbridge
Submitted 20 December 2007 Posted 20 December 2007
  I recommend the Primary Papers

In their recent paper Lodge and Grace elegantly demonstrate that hyperactivity of the ventral hippocampus underlies the elevated number of spontaneously active ventral tegmental dopamine neurons, and the concomitant increase in amphetamine-induced locomotor activity, found in MAM-treated rats. Since neonatal MAM treatment recapitulates some of the neurochemical, anatomical, and behavioral abnormalities associated with schizophrenia, these findings raise the possibility that the abnormal subcortical dopamine function associated with this disorder might also result from hippocampal dysfunction.

These findings are consistent with a wealth of evidence suggesting that the hippocampus is a prominent site of dysfunction in the schizophrenic brain (reviewed in Harrison, 2004), and it will be exciting to see the results of the clinical studies described by Anissa Abi-Dargham above.

In the future, it will be important to try to integrate these findings with other models aiming to explain the subcortical dopaminergic hyperactivity...  Read more


View all comments by Elizabeth Tunbridge
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