Ketamine Suppresses the Ventral Striatal Response to Reward Anticipation: A Cross-Species Translational Neuroimaging Study.

Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.

Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats.

Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.