Effects of short- and long-term aripiprazole treatment on Group I mGluRs in the nucleus accumbens: Comparison with haloperidol

Abstract

The D2 receptor partial agonist, aripiprazole, has shown increased therapeutic efficacy for schizophrenia, autism and Tourette's syndrome compared to traditional antipsychotics such as the D2 receptor antagonist, haloperidol. Recent evidence suggests this superior profile may be associated with downstream effects on glutamatergic synapses. Group 1 metabotropic glutamate receptors (mGluRs) and their endogenous modulators, Norbin and Homer1, are regulated by D2 receptor activity, particularly within the nucleus accumbens (NAc), a target region of aripiprazole and haloperidol. This study sought to evaluate the effects of aripiprazole on Group 1 mGluRs, Norbin and Homer1 in the NAc, in comparison to haloperidol. Sprague-Dawley rats were orally administered daily doses of aripiprazole (2.25mg/kg), haloperidol (0.3mg/kg) or vehicle for 1 or 10-weeks. Immunoblot analyses revealed Group 1 mGluR protein levels were not altered following 1-week and 10-week aripiprazole or haloperidol treatment, compared to vehicle treated rodents. However, 1-week aripiprazole and haloperidol treatment significantly elevated Homer1a and Norbin protein expression, respectively. After 10 weeks of treatment, aripiprazole, but not haloperidol, significantly increased Norbin expression. These findings indicate the antipsychotics, aripiprazole and haloperidol, exert differential temporal effects on Norbin and Homer1 expression that may have consequences on synaptic glutamatergic transmission underlying their therapeutic profile.

The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

“…Hence, acute variations in subcortical Homer1a mRNA have been proposed by our group as predictors of the typical or atypical character of the antipsychotic molecules [10,48]. These observations comply with previous reports [11,20,49,50]. From a clinical point of view, it may reflect the propensity of typical compounds to provoke extrapyramidal symptoms in humans, as discussed below in more detail.…”

“…Moreover, Homer has been per se considered a candidate gene in schizophrenia and other psychiatric diseases [14][15][16][17][18] and has been demonstrated to be involved in animal models of behavioral disorders, including schizophrenia [19][20][21][22][23][24][25]. The Homer1a gene codes for the truncated isoform of the long Homer1 protein.…”

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model

“…We administered aripiprazole intraperitoneally and 45 min before initiating the ASSR at a commonly used dose of 3 mg/kg because these settings were previously shown to induce behavioral and electrophysiological effects in similar rodent models of SZ [31][32][33]. Of note, this dose of 3 mg/kg in rats corresponds to ~30 mg in humans, which is within the therapeutic dose range used in clinical studies [34][35][36][37]. As shown in Figure 3, an acute administration of MK-801 was again able Following these results, we decided to select one NMDAr antagonist for the next set of experiments aiming to characterize the effects of aripiprazole on the electrophysiological and behavioral features of the model.…”

“…We administered aripiprazole intraperitoneally and 45 min before initiating the ASSR at a commonly used dose of 3 mg/kg because these settings were previously shown to induce behavioral and electrophysiological effects in similar rodent models of SZ [31][32][33]. Of note, this dose of 3 mg/kg in rats corresponds to ~30 mg in humans, which is within the therapeutic dose range used in clinical studies [34][35][36][37]. As shown in Figure 3, an acute administration of MK-801 was again able to elicit a strong deficit of ~50% in the PLF of the ASSR on both the global cortex and auditory cortex channel (48.2 ± 6.8 (p = 0.0048) and 51.2 ± 6.8% of the vehicle-treated group (p = 0.0239) for global and auditory cortex, respectively (Figure 3B,C)).…”