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Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia - PubMed

Comparative Study

Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia

Kathryn M Gill et al. Schizophr Bull. 2014 Mar.

Abstract

Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.

Keywords: GABA receptor positive allosteric modulator; dopamine supersensitivity; haloperidol; schizophrenia; ventral tegmental area; withdrawal.

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Figures

Fig. 1.
Fig. 1.

Schematic representation of cannula sites in ventral hippocampus with representative tissue (modified from Paxinos and Watson).

Fig. 2.
Fig. 2.

In methylazoxymethanol acetate (MAM) and saline (SAL) rats, α5 gamma-aminobutyric acid (GABAA) receptor positive allosteric modulator (α5PAM) treatment decreased the number of spontaneously active dopamine (DA) neurons. (A) Following 1wk withdrawal from repeated haloperidol (HAL) treatment, the number of spontaneously active DA neurons in both SAL and MAM rats injected with vehicle was reduced. In contrast, following 1wk withdrawal from repeated HAL, treatment with the α5PAM reversed the HAL-induced reduction in cells per track in SAL, but not in MAM, rats. (B) Repeated HAL treatment had no effect on the firing rate of DA neurons recorded in SAL or MAM rats treated with vehicle. However, the α5PAM increased the firing rate of DA neurons in withdrawn HAL-treated SAL rats. (C) Repeated HAL treatment, as well as α5PAM injection, had no impact on the percentage of spikes occurring in bursts for DA neurons recorded in SAL and MAM rats (*P < 0.05).

Fig. 3.
Fig. 3.

Following 1wk withdrawal from repeated haloperidol (HAL) treatment, the number of spontaneously active dopamine (DA) neurons in both saline (SAL) and methylazoxymethanol acetate (MAM) rats microinfused with vehicle in the ventral hippocampus (vHPC) was reduced compared with that in untreated control animals. (A) Infusion of tetrodotoxin (TTX) in the vHPC reversed the HAL-induced reduction in DA cells per track in SAL, but not in MAM, rats. (B) Repeated HAL treatment had no effect on the firing rate of DA neurons recorded in SAL or MAM rats infused with vehicle or TTX in the vHPC. (C) Repeated HAL treatment had no effect on the percentage of spikes occurring in bursts for DA neurons recorded in SAL or MAM rats infused with vehicle or TTX in the vHPC (*P < 0.05).

Fig. 4.
Fig. 4.

Administration of apomorphine increased the number of spontaneously active dopamine (DA) neurons in saline (SAL) rats withdrawn from repeated haloperidol (HAL) treatment, presumably by reversal of DA neuron depolarization block, while having no effect on the number of active DA neurons in HAL-withdrawn methylazoxymethanol acetate (MAM) rats (*P < 0.05).

Fig. 5.
Fig. 5.

Repeated haloperidol (HAL) treatment enhanced the locomotor response to D-amphetamine in saline (SAL) animals, (A) which was reduced by pretreatment with the α5 gamma-aminobutyric acid (GABAA) receptor positive allosteric modulator (α5PAM). Methylazoxymethanol acetate (MAM) rats treated repeatedly with HAL exhibited a locomotor response following D-amphetamine similar to untreated MAM rats. (B) However, repeated HAL treatment blocks the effect of α5PAM pretreatment in decreasing the locomotor response in MAM rats (*P < 0.05).

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