A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Abstract

We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABA A receptor, SH-053-2 0 F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2 0 F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the a5GABA A R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following a5GABA A R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following a5GABA A R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

“…In the MAM rodent model of schizophrenia, augmented dopamine system function (measured by directly recording spontaneous dopamine neuron activity in the VTA) and aberrant behaviors, such as the hyper-responsivity to psychomotor stimulants and deficits in cognitive flexibility, are mediated by increased hippocampal activity (Gill et al, 2011;Lodge and Grace, 2007;Perez et al, 2013). Similarly, schizophrenia patients exhibit enhanced baseline hippocampal activity that is correlated with the severity of positive symptoms (Schobel et al, 2009).…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…These fast firing interneurons are known to maintain the oscillatory activity of excitatory glutamatergic pyramidal neurons through perisomatic targeting (Lewis et al, 2005;Lodge et al, 2009). Moreover, studies have further shown that attenuation of hyperactivity of neurons in the ventral hippocampus via drug treatment or deep brain stimulation can normalize the enhanced dopamine neuron activity, thereby reversing an augmented locomotor response to amphetamine seen in animal models of schizophrenia (Gill et al, 2011;. Thus, the concept of GABAergic interneuron transplantation into the hippocampus as a therapy for schizophrenia stems from the observation that persistent hippocampus hyperactivity promotes dopamine hyperfunction and that addition of new GABA-ergic interneurons into the hippocampus circuitry would restrain this hyperactivity.…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…The DNA-methylating agent, methylaxozymethanol acetate (MAM), induces a developmental model of schizophrenia whereby affected animals exhibit both the structural and behavioral abnormalities that are normally seen in schizophrenia [31]. These animals were found to exhibit an increase in dopaminergic activity within the ventral tegmental area (VTA) that was thought to be due to hippocampal hyperactivity [32].…”

“…This was investigated by monitoring of VTA neurons in MAM rats in the presence of SH-053-2'F-R-CH3 ( Table 1, 2), a benzodiazepine α 5 -selective positive modulator [31]. This compound successfully diminished the number of spontaneously active dopaminergic neurons in the VTA in addition to reversing the heightened locomotor response to low dose of D-amphetamine in MAM but not in control rats [31], supporting the possible use of a similar treatment in schizophrenia. Given that inhibition of α 5 GABA A Rs enhances learning and memory [14,34], it is feasible that an enhancer like SH-053-2'F-R-CH3 could produce anterograde memory impairment; however, no such memory impairment has been observed [35].…”

“…Hence, it was proposed that reducing hippocampal hyperactivity by using an α 5 GABA A R-selective positive modulator could be a novel therapeutic approach for schizophrenia [33]. This was investigated by monitoring of VTA neurons in MAM rats in the presence of SH-053-2'F-R-CH3 ( Table 1, 2), a benzodiazepine α 5 -selective positive modulator [31]. This compound successfully diminished the number of spontaneously active dopaminergic neurons in the VTA in addition to reversing the heightened locomotor response to low dose of D-amphetamine in MAM but not in control rats [31], supporting the possible use of a similar treatment in schizophrenia.…”