Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia

Abstract

Background: The hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity.

Methods: Here we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats).

Results: Aberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats.

Conclusion: Taken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.

Keywords: Schizophrenia; dopamine; orexins; paraventricular nucleus of the thalamus.

Figure 1.

Schematic representation of the polysynaptic circuit involved in the regulation of dopamine neuron population activity, which includes the ventral hippocampus (vHipp), paraventricular nucleus of the thalamus (PVT), nucleus accumbens (NAc), ventral pallidum (VP), and ventral tegmental area (VTA). Under “normal” conditions, GABAergic projections from the VP provide a tonic suppression of VTA activity (left). Methylazoxymethanol acetate-treated rats model schizophrenia, whereby aberrant glutamatergic inputs to the NAc from the vHipp drive a downstream hyperfunction of the dopamine system (center). Aberrant dopamine neuron activity can be reversed by blocking orexin 1 and 2 receptors (OX_1/2R) in the PVT, resulting in a decreased glutamatergic transmission to the NAc (right). Adapted from (Grace et al., 2007).

Figure 2.

Administration of the dual orexin receptor antagonist, TCS 1102, restores normal dopamine system function in the MAM rodent model of schizophrenia (A). MAM-treated vehicle rats display a significant increase in ventral tegmental area (VTA) dopamine neuron activity compared with saline-treated vehicle rats. *P < .001. Further, TCS 1102 administration restores normal dopamine system function in MAM-treated rats. ^#P = .01 denotes significance from MAM-treated vehicle rats. The average firing rate of VTA dopamine neurons is attenuated by TCS 1102 administration (B). *P = .002 denotes significance from MAM-treated vehicle rats. ^#P = .01 denotes significance from saline-treated rats administered TCS 1102. No differences were observed in the average percent bursting between any groups (C). Representative dopamine recording and action potential from a saline-treated vehicle (D), MAM-treated vehicle (E), saline-treated TCS 1102 (F), and MAM-treated TCS 1102 (G) rats.

Figure 3.

Intracranial microinjection of exogenous orexin A (OXA) or orexin B (OXB) peptides into the paraventricular nucleus of the thalamus (PVT) causes a significant increase in ventral tegmental area (VTA) dopamine neuron activity (A). *P < .001 denotes significance from vehicle control. No differences were observed in the average firing rates (C) or average percent bursting between any groups (D). B depicts a representative brain slice (left) with a canula track indicated by an arrow in the PVT and corresponding schematic of the brain section (right). Representative dopamine recording and action potential from a control saline (E), OXA (F), and OXA (G) microinjected rats.

Figure 4.

Intracranial microinjection of the dual orexin antagonist, TCS 1102, into the paraventricular nucleus of the thalamus (PVT), restored normal dopamine system function in MAM-treated rats (A). *P < .001 denotes significance from saline-treated vehicle. ^#P < .001 denotes significance from MAM-treated vehicle. TCS 1102 administration attenuated the average firing rate (B) and average percent bursting (C) in MAM-treated vehicle rats. *P < .05 denotes significance from saline-treated vehicle. ^#P < .05 denotes significance from MAM-treated vehicle. Representative dopamine recording and action potential from a saline-treated TCS 1102 (D) and MAM-treated TCS 1102 (E) rats.