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

Abstract

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.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…This distribution is respected in SCZ, while a variety of DR β-arrestin mediated intracellular signaling show clear alterations in SCZ disease models. Some developmental and connectivity aspects of DR distribution are maintained across species and useful for the definition of SCZ as a developmental disease across circuits ( Sonnenschein and Grace, 2020 ).…”

“…Impact of DA on posttranslational control (Kos et al, 2018) Developmental Netrin1/DCC on DA neuronal dev./MAM model. (Grace and Gomes, 2019;Sonnenschein and Grace, 2020;Vosberg et al, 2020)…”

“…The dopaminergic system undergoes a delayed maturation in the brain, suggesting important stabilizing and integrating functions on neural circuits (Grace, 2016;Ohira, 2020). Schizophrenia (SCZ) is associated with dopamine (DA) neurotransmission alterations during puberty and adult life causing deficits in motivation, cognition and sensory functions (Simpson and Kellendonk, 2017;Abi-Dargham, 2018;Grace and Gomes, 2019;Sonnenschein and Grace, 2020). DA release measures in SCZ clinical studies and in preclinical models have clearly documented a fronto-cortical DA hypoactivity and a striatal (mainly dorsal) DA hyperactivity, associated with the occurrence of different SCZ symptoms (Terrillion et al, 2017;McCutcheon et al, 2019;Rao et al, 2019;Li et al, 2020).…”

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness

“…The additional cell types that appear to be targeted by the Der1 mutation: dopaminergic neurons, oxytocin/vasopressin-expressing neurons and astrocytes/ependymocytes, were not implicated in schizophrenia by the genomic EWCE analysis. However, dopamine signalling is heavily implicated in schizophrenia, in part because all antipsychotic drugs in clinical use target the dopamine D2 receptor 68 , while DRD2 is located at a genetic locus repeatedly found to associate with schizophrenia 1 , 2 and also with depression 6 . The neuropeptides oxytocin and vasopressin regulate many processes, including social behaviour and anxiety 69 , and are widely implicated in psychiatric disorders 70 .…”

Is Cannabidiol During Neurodevelopment a Promising Therapy for Schizophrenia and Autism Spectrum Disorders?

“…This section will discuss the long-lasting impact of CBD treatment during earlier periods of development (peripubertal/adolescence) on schizophrenia-like phenotypes in adulthood. Three different schizophrenia animal models were used in these studies: maternal immune activation (MIA) through polyinosinic:polycytidylic acid (poly I:C) administration during the gestational period ( Meyer and Feldon, 2012 ; Haddad et al, 2020 ), the late gestational antimitotic administration of methylazoxymethanol acetate (MAM) ( Lodge and Grace, 2009 ; Sonnenschein and Grace, 2020 ), and the spontaneous development of schizophrenia-like behaviors in the Spontaneously Hypertensive Rat (SHR) strain ( Calzavara et al, 2009 ; Calzavara et al, 2011a ; Calzavara et al, 2011b ; Levin et al, 2011 ). Chronic administration of CBD during periadolescence presented several benefits regarding the emergence of a schizophrenic-like phenotype in all studies ( Peres et al, 2016a ; Peres et al, 2018a ; Stark et al, 2019 ; Stark et al, 2020 ).…”