Dopamine System Dysregulation and the Pathophysiology of Schizophrenia: Insights From the Methylazoxymethanol Acetate Model

Abstract

Data from numerous studies have strongly implicated the dopamine (DA) system in the pathophysiology of schizophrenia. The data are particularly robust for the positive or the psychotic symptoms of schizophrenia, which can be mimicked by DA agonists and attenuated by D2 antagonist antipsychotic drugs. Nonetheless, there is little evidence for a major dysfunction within the DA system itself; instead, current research has focused on a disruption in the regulation of the DA system. One region in particular that has shown correlations with DA dysfunction is the limbic portion of the hippocampus, which comprises the ventralmost segment in rats analogous to the anterior aspect in humans. Thus, studies in patients with schizophrenia have shown hyperactivity in the hippocampus that correlates with psychosis as well as a loss of parvalbumin gamma-aminobutyric acid–ergic (GABAergic) inhibitory neurons (1). To examine the pathophysiology of schizophrenia, we employed a developmental disruption model that uses the mitotoxin methylazoxymethanol acetate (MAM). This drug is administered to pregnant rats at gestational day 17 to mimic the second trimester in humans, during which insults have a higher impact on inducing schizophrenia births. The offspring are then examined peripubertally for developmental changes and as adults to test for dysfunctions that correspond to schizophrenia in humans. The adult offspring of MAM-treated rats display many characteristics consistent with schizophrenia (2,3), including neuroanatomic changes (thinning of limbic cortices with an increase in cell packing density, loss of parvalbumin interneurons), behavioral deficits (prepulse inhibition of startle, reversal learning, extradimensional shift, latent inhibition, social interaction), and pharmacologic responses (hyperresponsivity to phencyclidine, increased locomotion to amphetamine). Furthermore, as in humans, there is hyperactivity in the ventral hippocampus (vHipp) and a disruption of rhythmic activity including delta and gamma rhythms (3). There was also a substantial increase in DA neuron population activity. In anesthetized and awake rats, DA neurons exhibit several activity states that are regulated by different systems and differentially affect system function (Figure 1). In the basal state, DA neurons discharge in a slow, irregular tonic firing pattern. However, if the organism is exposed to a behaviorally salient stimulus, DA neurons transition to a rapid burst-firing mode. Thus, burst firing is considered to be the behaviorally relevant phasic response to stimuli. Burst firing is driven by a glutamatergic input arising primarily from the brainstem pedunculopontine tegmentum (PPTg) acting on N-methyl-D-aspartate