State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia

Abstract

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.

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

“…Hallucinations and delusions tend to co-occur and are thus proposed to manifest due to a common pathophysiological mechanism (6,9). Psychotic symptoms can be attenuated by D 2 receptor blocking drugs (10,11) that reduce the abnormal increased DA neuron activity (12)(13)(14), but the underlying cognitive processes likely involve complex connections between numerous brain regions that remain dysfunctional. This article will discuss some of the circuits that regulate DA neuron activity and how dysfunction in these upstream circuits may influence the DA system in schizophrenia.…”

Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin1A receptor neurotransmission in the hippocampus

“…It is interesting to note that an increase in population activity of DA neurons had also been documented in our laboratory with asenapine, a drug approved for the treatment of psychosis that has subnanomolar affinities for a variety of monoaminergic receptors (Oosterhof et al, 2014). In contrast, no significant change of this parameter has been reported using quetiapine, aripiprazole and brexpiprazole (Moreines et al, 2017; Oosterhof et al, 2016; Sonnenschein et al, 2018). In the case of clozapine, olanzapine and risperidone, it was initially hypothesized that they exert an antipsychotic action primarily by a depolarization block which, by blocking D 2 receptors on DA cell body, induces an over-excitation of DA neurons resulting in their cessation of firing following repeated administration (Grace and Bunney, 1984; Grace et al, 1997).…”

Effects of Atypical Antipsychotics on Neuroactive Vitamins in Patients With Schizophrenia

“…Aripiprazole, an atypical antipsychotic drug, performed its beneficial functions to improve schizophrenic symptom via partial agonist activity at D 2 receptors to normalize both hyperdopaminergic and hypodopaminergic states. 38 Compared with first-generation agents, aripiprazole resulted in less extrapyramidal symptoms and tardive dyskinesia. 7 According to our results, in addition to those conventional functions, aripiprazole may have accessional positive effects on schizophrenic patients through elevating vitamin D concentrations and ameliorating vitamin D deficiency.…”