Dysregulation of the dopamine system is central to many models of the pathophysiology of psychosis in schizophrenia. However, emerging evidence suggests that this dysregulation is driven by the disruption of upstream circuits that provide afferent control of midbrain dopamine neurons. Furthermore, stress can profoundly disrupt this regulatory circuit, particularly when it is presented at critical vulnerable prepubertal time points. This review will discuss the dopamine system and the circuits that regulate it, focusing on the hippocampus, medial prefrontal cortex, thalamic nuclei, and medial septum, and the impact of stress. A greater understanding of the regulation of the dopamine system and its disruption in schizophrenia may provide a more complete neurobiological framework to interpret clinical findings and develop novel treatments.

Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D receptors to normalize both hyperdopaminergic and hypodopaminergic states. Traditional D antagonist antipsychotic drugs have been shown previously to reduce dopamine neuron activity through action on D autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces dopamine neuron activity via inhibition or, as seen following D antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperdopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active dopamine neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100-200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of dopamine neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperdopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.

Current antipsychotic drugs (APDs) act on D 2 receptors, and preclinical studies demonstrate that repeated D 2 antagonist administration downregulates spontaneously active DA neurons by producing overexcitation-induced inactivation of firing (depolarization block). Animal models of schizophrenia based on the gestational MAM administration produces offspring with adult phenotypes consistent with schizophrenia, including ventral hippocampal hyperactivity and a DA neuron overactivity. The MAM model reveals that APDs act differently in a hyperdopamineregic system compared to a normal one, including rapid onset of depolarization block in response to acute D 2 antagonist administration and downregulation of DA neuron population activity following acute and repeated D 2 partial agonist administration, none of which are observed in normal rats. Novel target compounds have been developed based on the theory that glutamatergic dysfunction is central to schizophrenia pathology. Despite showing promise in preclinical research, none of the novel drugs succeeded in clinical trials. However, preclinical research is generally performed in normal, drug-naïve rats, whereas models with disease-relevant pathology and prior APD exposure may improve the predictive validity of preclinical research. Indeed, in MAM rats, chronic D 2 antagonist treatment leads to persistent DA supersensitivity that interferes with the response to drugs that target upstream pathology. Moreover, MAM rats revealed that the peripubertal period is a stress-sensitive window that can be targeted to prevent the development of MAM pathology in adulthood. Neurodevelopmental models, such as the MAM model, can thus be used to test potential pharmacotherapies that may be able to treat schizophrenia in early stages of the disease.

The group 2 metabotropic glutamate receptor (mGluR2/3) agonist, pomaglumetad methionil (POM), showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations. Although previous studies have shown that mGluR2/3 agonists have no effect on dopamine (DA) in wild type rats, we used the methylzoxymethanol acetate (MAM) model to determine whether POM may indirectly normalize DA neuron activity in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to SAL rats, using in vivo, anesthetized, electrophysiological recordings. POM dose-dependently reduced the number of spontaneously active DA neurons in the VTA of MAM rats to control levels without affecting DA firing in SAL rats, which persisted following 14d repeated treatment with POM. In female MAM rats, POM significantly reduced DA neuron population activity only during proestrous and estrous stages. MAM rats also demonstrated dose-dependent improvement in novel object recognition following acute POM, which was not observed in SAL rats. Similar to the MAM rats, DA neuron population activity was increased in a hippocampal-dependent manner following acute restraint stress. Administration of POM prior to 2 h restraint stress prevented the restraint-induced increase in DA neuron population activity, and this effect was blocked by pretreatment with an mGluR2/3 antagonist. Thus, the ability of POM to reduce the hyperdopaminergic activity in both MAM rats and in wild type rats following restraint stress suggests that it can indirectly regulate DA neuron activity, which may underlie its potential therapeutic effects.

Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31–40. In either late adolescence (PD 47–56) or adulthood (PD 83–96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats.