Latent Inhibition-Related Dopaminergic Responses in the Nucleus Accumbens are Disrupted Following Neonatal Transient Inactivation of the Ventral Subiculum

Abstract

Schizophrenia would result from a defective connectivity between several integrative regions as a consequence of neurodevelopmental failure. Various anomalies reminiscent of early brain development disturbances have been observed in patients' left ventral subiculum of the hippocampus (SUB). Numerous data support the hypothesis of a functional dopaminergic dysregulation in schizophrenia. The common target structure for the action of antipsychotics appears to be a subregion of the ventral striatum, the dorsomedial shell part of the nucleus accumbens. Latent inhibition, a cognitive marker of interest for schizophrenia, has been found to be disrupted in acute patients. The present study set out to investigate the consequences of a neonatal functional inactivation of the left SUB by tetrodotoxin (TTX) in 8-day-old rats for the latent inhibition-related dopaminergic responses, as monitored by in vivo voltammetry in freely moving adult animals (11 weeks) in the left core and dorsomedial shell parts of the nucleus accumbens in an olfactory aversion procedure. Results obtained during the retention session of a threestage latent inhibition protocol showed that the postnatal unilateral functional blockade of the SUB was followed in pre-exposed TTXconditioned adult rats by a disruption of the behavioral expression of latent inhibition and induced a total and a partial reversal of the latent inhibition-related dopaminergic responses in the dorsomedial shell and core parts of the nucleus accumbens, respectively. The present data suggest that neonatal inactivation of the SUB has more marked consequences for the dopaminergic responses recorded in the dorsomedial shell part, than in the core part of the nucleus accumbens. These findings may provide new insight into the pathophysiology of schizophrenia.

Early Prefrontal Functional Blockade in Rats Results in Schizophrenia-Related Anomalies in Behavior and Dopamine

“…The cannula was left in the PFC for 4 min after the end of the microinjection to allow PBS and TTX to diffuse in the targeted structure. The amount of TTX microinjected in the PFC (100 mM Â 0.3 ml), approximately 10 ng, is similar to that reported previously in the literature (Zhuravin and Bures, 1991;Peterschmitt et al, 2007;Meyer et al, 2009;Meyer and Louilot, 2011). It has been reported that the effects resulting from the TTX blockade last 24-48 h (Rothfeld et al, 1986).…”

“…Recent evidence from in vivo animal studies backs the existence of a differential involvement of dopaminergic neurons innervating the core and dorsomedial shell subregions of the nucleus accumbens in this phenomenon (Jeanblanc et al, 2002;Louilot et al, 2010). Moreover, as shown recently, unilateral neonatal functional blockade in the left hemisphere of two temporal regions linked to the PFC, the entorhinal cortex, or the ventral subiculum of the hippocampus (Jay and Witter, 1991;Hoover and Vertes, 2007) have been found to be sufficient to induce a disruption of the behavioral manifestation of latent inhibition and the latent inhibition-related dopaminergic variations in adult animals, with a differential reversal of these responses in the left core part of the nucleus accumbens (Peterschmitt et al, 2007;Meyer and Louilot, 2011).…”

“…On PND8, rat pups (weight 18.8 ± 0.2 g) were anaesthetized by gas anesthesia by vaporizing isoflurane (Forene, ABBOTT, Rungis, France; for further details see Peterschmitt et al, 2007;Meyer et al, 2009;Meyer and Louilot, 2011). A stainless steel guide cannula (30 gauge, 12.5 mm length, Small Parts, Miami) was lowered into the PFC at coordinates 1.5 mm relative to bregma (AP), 0.4 mm lateral to the midline (L), and 3.9 mm below the cortical surface (H).…”

“…The microinjection site in the PFC was identified by postmortem using Evans blue (Sigma), a vital dye added to the solutions of PBS and TTX, and reported as remaining visible in the cerebral tissue several weeks after injection (Martin and Ghez, 1999;Peterschmitt et al, 2007;Meyer et al, 2009;Brooks et al, 2011;Meyer and Louilot, 2011). Each rat pup was identified by means of small three-digit ear tags , Harvard Apparatus, Les Ulis, France).…”

“…Latent inhibition was measured in a three-stage latent inhibition paradigm involving a conditioned olfactory aversion procedure, with banana odor (amyl acetate, Prolabo, Strasbourg, France) as the conditional olfactory stimulus (CS), and LiCl-induced aversion as the unconditional stimulus, as previously reported (Jeanblanc et al, 2002;Peterschmitt et al, 2007;Louilot et al, 2010;Meyer and Louilot, 2011). All pre-exposed and non-preexposed animals were microinjected at PND8 with either PBS or TTX in the PFC as indicated before (see neonate surgery).…”