Elsevier

Neuropharmacology

Volume 62, Issue 3, March 2012, Pages 1342-1348
Neuropharmacology

Invited review
Dopamine system dysregulation by the hippocampus: Implications for the pathophysiology and treatment of schizophrenia

https://doi.org/10.1016/j.neuropharm.2011.05.011Get rights and content

Abstract

For decades, the predominant hypothesis of schizophrenia centered on dysfunctions of the dopamine system. However, recent evidence now suggests that the dopamine system may be “normal” in its configuration, but instead is regulated abnormally by modulatory processes. Convergent studies in animals and in humans have now focused on the hippocampus as a central component in the generation of psychosis and possibly other symptom states in schizophrenia. Thus, activity in the ventral hippocampus has been shown to regulate dopamine neuron responsivity by controlling the number of dopamine neurons that can be phasically activated by stimuli. In this way, this structure determines the gain of the dopamine signal in response to stimuli. However, in schizophrenia, the hippocampus appears to be hyper-active, possibly due to attenuation of function of inhibitory interneurons. As a result, the dopamine system is driven into an overly responsive state. Current medications have focused on blockade of overstimulated dopamine receptors; however, this now appears to be several synapses downstream from the pathological antecedent. Therapeutic approaches that focus on normalizing hippocampal function may prove to be more effective treatment avenues for the schizophrenia patient.

This article is part of a Special Issue entitled ‘Schizophrenia’.

Highlights

► The hippocampus has been identified as a site of pathology in schizophrenia. ► Parvalbumin interneuron loss in hippocampus alters the dopamine system. ► Restoring GABA tone in the hippocampus can be achieved by a novel GABA drug.

Section snippets

The dopamine hypothesis of schizophrenia

The high morbidity associated with schizophrenia coupled with the comparatively less effective treatments available compared to other psychiatric disorders has generated a substantial amount of research into the pathophysology of this devastating disorder. Nonetheless, the basic neurobiological constructs that lead to the disruptions associated with schizophrenia are comparatively poorly understood. For a number of years, the dopamine (DA) hypothesis has driven the primary line of inquiry into

Dopamine neuron activity states

Dopamine neurons are known to exist in several activity states. In the control state, dopamine neurons are either spontaneously firing or are in an inhibited, nonfiring state (Bunney and Grace, 1978, Grace and Bunney, 1984). Approximately half of the dopamine neurons are firing in the control rat; a parameter known as population activity. Since dopamine neurons are driven by a pacemaker conductance, the nonfiring state must be maintained by an active inhibitory input. One of the most potent

Dopamine system overdrive and schizophrenia

What about in the case of schizophrenia? As reviewed above, there is substantial evidence that the dopamine system is hyper-responsive in schizophrenia patients; in particular, there is abnormally high amphetamine-induced dopamine release that correlates with exacerbation of psychosis (Laruelle and Abi-Dargham, 1999). Moreover, there is also increased baseline D2 stimulation in terms of D2 occupancy in the schizophrenia patient. This is consistent with what has been observed in a developmental

Stress and the pathophysiology of schizophrenia

Taking together data from animal studies and human imaging, an explanation for the pathophysiology of schizophrenia points to a dysfunction of hippocampal interneurons leading to overdrive of tonic dopamine neuron population activity; this results in an abnormally amplified dopamine response to stimuli. However, what is the origin of the hippocampal dysfunction that leads to the delayed emergence of psychosis? Although direct evidence for this model does not exist, evidence gleaned from other

Treatment

Schizophrenia is modeled above as a hippocampal pathology leading to an overdrive of the DA system. The treatment of schizophrenia for the past half century has focused almost exclusively on blocking overactivity within the DA system by blocking DA D2 receptors. However, whether simple receptor blockade is and adequate explanation for the efficacy of antipsychotic drugs remains in doubt. Thus, simple D2 blockade would be expected to induce several compensatory processes, such as increased DA

Summary

Schizophrenia is a disorder that has been resistant to precise definition and treatment. Part of this may be due to the somewhat inappropriate focus on the DA system. However, recent studies suggest that this disorder may result from a pathology within the ventral hippocampus that leads to an overdrive of the DA system. By targeting treatments at the site of pathology rather than at the DA receptor, more effective pharmacotherapeutic approaches may be developed. There is also a major concern

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