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Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia - PubMed

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Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia

Susan F Sonnenschein et al. Neuropharmacology. 2020 Feb.

Abstract

Current antipsychotic drugs (APDs) act on D2 receptors, and preclinical studies demonstrate that repeated D2 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 D2 antagonist administration and downregulation of DA neuron population activity following acute and repeated D2 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 D2 antagonist treatment leads to persistent DA supersensitivity that interferes with the response to drugs that target upstream pathology. Moreover, MAM rats revealed that the peri-pubertal 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. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Keywords: Animal model; Antipsychotic; Depolarization block; Dopamine; MAM; Schizophrenia.

Published by Elsevier Ltd.

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Conflict of interest statement

CONFLICT OF INTEREST

SFS declares no conflicts of interest.

Figures

Figure 1.
Figure 1.

Hippocampal-striatal regulation of DA neuron activity in normal and schizophrenia. A) In a normal system, the limbic hippocampus (HPC), regulates dopamine (DA) neuron population activity in the ventral tegmental area (VTA), with variable gain based on context. The HPC sends glutamatergic input to the nucleus accumbens in the ventral striatum, which sends inhibitory projections to the ventral pallidum. The ventral pallidum holds a proportion of DA neurons in an inhibited state. In response to relevant stimuli, only spontaneously active DA neurons can respond to glutamatergic input from the pedunculopontine tegmentum (PPTg), gated by the laterodorsal tegmentum (LDT), with burst firing. The DA signal to the striatum has topographic organization with DA neurons in the substantia nigra pars compacta (SNc) projections to the dorsal striatum, lateral VTA projections to the associative striatum, and medial VTA projections to the ventral striatum. B) In schizophrenia, the limbic HPC is in a pathologically hyperactive state and no longer responds appropriately to context. Increased excitatory input from HPC to the ventral striatum results in less inhibition of the ventral pallidum and fewer DA neurons held in a silent state. The increased DA signal is most prevalent in the associative striatum.

Figure 2.
Figure 2.

Antipsychotic drug modulation of DA neuron activity states. A) First generation D2 antagonist antipsychotic drugs (APDs) act on postsynaptic and presynaptic D2 receptors in the striatum to produce depolarization block of DA neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) and reduces DA neuron population activity in both regions. The DA signal is diminished to all domains of the striatum, resulting in both the antipsychotic effect and extrapyramidal side effects, including motor dysfunction. Following prolonged treatment, the system adapts by upregulating the number of D2 receptors, which can produce DA supersensitivity. B) Second generation D2 antagonist APDs only produce depolarization block of DA neurons in the ventral tegmental area (VTA), resulting in a reduced DA signal to the associative and ventral striatum without effect on the DA neurons that project to the dorsal striatum. Thus, SGAs produce an antipsychotic effect without motor side effects. However, like first generation APDs, following prolonged treatment, there is an upregulation of D2 receptors, which can produce DA supersensitivity. C) D2 partial agonists normalize DA neuron population activity by reducing hyperdopaminergic activity via DA neuron inhibition and increasing hypodopamineregic activity via postsynaptic stimulation. The downregulation of DA neuron activity does not occur through depolarization block and does not produce an upregulation of D2 receptors.

Figure 3.
Figure 3.

A proposed model for ntipsychotic drug effects on symptom domains of schizophrenia. A) In schizophrenia, a hyperactive and dysrhythmic limbic hippocampus (HPC) contributes to positive symptoms through its indirect regulation of DA activity in the ventral tegmental area (VTA), which projects to the associative striatum. It also contributes to negative and cognitive symptoms through its disruption of activity patterns with regions including the prefrontal cortex (PFC) and amygdala. All current antipsychotic drugs (APDs) act on D2 receptors in the striatum, which results in a reduction in positive symptoms, but produce minimal benefit on cognitive symptoms or negative symptoms. B) Compounds that target the site of pathology in the limbic HPC by either increasing function of parvalbumin positive interneurons (PVI) or reducing the activity of pyramidal neurons (Pyr) should normalize hippocampal output and thereby may be more beneficial in treating all symptom domains of schizophrenia.

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