Aberrant Dopamine D2-Like Receptor Function in a Rodent Model of Schizophrenia

Abstract

Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAMtreated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcriptionpolymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia

“…(B,C)]. It should be noted that dopamine D4 receptor expression was below the limits of detection, consistent with our previous observations (Perez and Lodge, ). Furthermore, NAc expression of TH (adult: NAc: 8.05 ± 0.43 cf.…”

“…To examine dopamine‐related molecular mechanisms that may underlie the different behavioral responses between preadolescent and adult rats, quantitative RT‐PCR was performed using probes for the dopamine D1, D2, D3, D4, D5 receptors, as well as the DAT, tyrosine hydroxylase and dopamine receptor signaling molecules RGS2, RGS9 and GIRK2. We have previously reported that adult, MAM‐treated rats display significant increases in D3 receptor expression throughout the NAc (Perez and Lodge, ). Here we demonstrate, that preadolescent rats do not display significant differences in the expression of a number of dopaminergic markers throughout either the NAc or VTA [three‐way ANOVA; F 1,180(Region) = 0.256, F 1,180(Age) = 2.032, F 8,180(Gene) = 1.738, F 1,180(Region × Age) = 0.580, F 8,180(Region × Gene) = 0.395, F 8,180(Age × Gene) = 1.054, F 8,180(Region × Age × Gene) = 0.518, all p > 0.05; Fig.…”

A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia

“…Consistent with the pharmacological studies detailed above, rats with selective vHipp PV knockdown display increases in the number of spontaneously active VTA dopamine neurons, without overt changes in firing rate or bursting pattern. This neurophysiological phenotype is consistent with that observed in rodent models of schizophrenia, such as the MAM-treated rat (Lodge and Grace, 2007; Perez and Lodge, 2012, 2013; Perez et al, 2013). Interestingly, while the increase in dopamine neuron activity is qualitatively similar to that of the MAM-treated rat, it appears to be of a smaller magnitude.…”

“…This can be directly examined in rodent models by recording the electrophysiological activity of midbrain dopamine neurons (Lodge and Grace, 2007; Perez and Lodge, 2012, 2013). Such studies have suggested that the increase in dopamine system function is associated with changes in the number of spontaneously active neurons in the absence of changes in firing rate or bursting pattern (Lodge and Grace, 2007; Perez and Lodge, 2012, 2013). Under control conditions, it is thought that about 50% of the midbrain dopamine neurons are quiescent due to a tonic GABAergic drive from the ventral pallidum (VP) (Grace et al, 2007).…”

The Effect of ANKK1 Taq1A Polymorphism on Cognition in Recent-Onset Psychosis: A Controlled Study

“…The dopaminergic neurotransmitter system (DAS) has been implicated in the etiopathogenesis of schizophrenia since antipsychotics were found to reduce psychotic symptoms by blocking D2/D3 dopamine receptors [1].Findings from both animal [2] and human in vivo and postmortem studies [3 -4] have provided further evidence for structural and functional abnormalities in the DAS in schizophrenia. Since its first description, it is an ongoing reformulation of the dopamine hypothesis of schizophrenia [5].…”