Postnatal functional inactivation of the ventral subiculum enhances dopaminergic responses in the core part of the nucleus accumbens following ketamine injection in adult rats

TL;DR

This study shows that early postnatal inactivation of the ventral subiculum in rats increases dopaminergic responses in the nucleus accumbens after ketamine, shedding light on neurodevelopmental aspects of schizophrenia.

Contribution

It demonstrates that neonatal inactivation of the ventral subiculum enhances adult dopaminergic responses to ketamine, linking neurodevelopmental disruption to schizophrenia-related neurochemistry.

Findings

Increased dopamine response in TTX animals after ketamine

Greater locomotor activity in TTX animals post-ketamine

Supports role of NMDA receptors in schizophrenia pathophysiology

Abstract

For almost two decades schizophrenia has been considered to be a functional disconnection disorder. This functional disconnectivity between several brain regions could have a neurodevelopmental origin. Various approaches suggest the ventral subiculum (SUB) is a particular target region for neurodevelopemental disturbances in schizophrenia. It is also commonly acknowledged that there is a striatal dopaminergic (DA) dysregulation in schizophrenia which may depend on a subiculo-striatal disconnection involving glutamatergic NMDA receptors. The present study was designed to investigate, in adult rats, the effects of the non-competitive NMDA receptor antagonist ketamine on DA responses in the ventral striatum, or, more specifically, the core part of the nucleus accumbens (Nacc), following postnatal functional inactivation of the SUB. Functional inactivation of the left SUB was carried out by local tetrodotoxin (TTX) microinjection at postnatal day 8 (PND8), i.e. at a critical point in the neurodevelopmental period. DA variations were recorded using in vivo voltammetry in freely moving adult rats (11 weeks). Locomotor activity was recorded simultaneously with the extracellular levels of DA in the core part of the Nacc. Data obtained during the present study showed that after administration of ketamine, the two indexes were higher in TTX animals than PBS animals, the suggestion being that animals microinjected with TTX in the left SUB at PND8 present greater reactivity to ketamine than animals microinjected with PBS. These findings could provide new information regarding the involvement of NMDA glutamatergic receptors in the core part of the Nacc in the pathophysiology of schizophrenia.