The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention

Abstract

Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.

Fig. 1.

Dopamine (DA) neurons exist in distinct states of activity: baseline tonic population activity (ie, proportion firing spontaneously) and rapid, salience-driven phasic burst firing. In normal rats, approximately one half are firing spontaneously, with the other half in an inhibited, nonfiring state. This inhibition is maintained by a GABAergic inhibitory input from the ventral pallidum (VP). This spontaneous tonic firing state is regulated by the ventral hippocampus (vHipp) through excitatory projections to the nucleus accumbens (NAc), which, in turn, inhibits the ventral pallidum (VP) and releases silent DA neurons from inhibition. But only active DA neurons can be driven to phasic firing by the pedunculopontine tegmentum (PPTg). Therefore, the number of neurons that are active determines the amplitude of the phasic DA response.

Fig. 2.

The hippocampus regulates DA neuron responsivity based on context. (A) The ventral hippocampus (vHipp) activates the nucleus accumbens (NAc) to inhibit the ventral pallidum (VP), driving VTA DA neuron tonic population activity. Pedunculopontine tegmentum (PPTg) input acts on tonically active DA neurons to generate phasic bursts of firing: this constitute the behaviorally salient rapid DA response. (B) If an organism is in a benign context where rapid reactions are not necessary, the number of DA neurons firing is kept low and the PPTg will only activate phasic bursting in a small population of neurons. As a result, a salient stimulus will trigger a calm orienting response. (C) In contrast, if the organism is in a threatening environment, the vHipp-NAc-VP pathway causes a large population of DA neurons to be active, increasing vigilance to the environment. Now the same salient stimulus will cause a larger phasic response, driving the organism to rapidly orient to the stimulus to prepare an appropriate response. (D) In schizophrenia, DA neuron population activity is in a constant high-activity state. Hence, most of the stimuli the organism encounters will lead to maximal dopamine output, resulting in the attribution of strong behavioral importance to stimuli, even to stimuli that should be safely ignored.

Fig. 3.

In schizophrenia, the hippocampus is proposed to be hyperactive, leading to an overdrive in the responsivity of midbrain DA neurons that project to the associative striatum. This is proposed to underlie the positive symptoms of schizophrenia. Additionally, a hyperactive, dysrhythmic limbic hippocampus can also interfere with the function of other circuits. Thus, the hippocampus-prefrontal cortex (PFC) projection would lead to disruption of PFC activity and rhythmicity, leading to cognitive disruption. Moreover, the hippocampus-basolateral amygdala (BLA) projection would interfere with the BLA-limbic cortical control of emotional responses, possibly leading to negative symptoms. Therefore, a hyperactive, dysrhythmic limbic hippocampus potentially disrupts multiple interconnected circuits, and could contribute to all 3 symptom classes of schizophrenia.

Fig. 4.

Data from preclinical models and schizophrenia imaging/postmortem findings suggest that the site of deficit in the schizophrenia brain likely involves a decreased PV interneuron inhibition of pyramidal neurons in the limbic hippocampus. Current therapeutic approaches to schizophrenia rely on blocking DA receptors in the associative striatum to attenuate the impact of DA system overdrive. However, blocking D2 receptors is acting 5 synapses downstream from where we believe the deficit driving schizophrenia is located. As a result, it is not surprising that D2 antagonist antipsychotic drugs are not as efficacious as one that targets diminished inhibition in the limbic hippocampus.