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Modulation of fear-related behaviors by prefrontal cortical GABAergic transmission and its relevance to schizophrenia Piantadosi, Patrick Thomas


Individuals with schizophrenia are hypothesized to have a “noisy” prefrontal cortex (PFC), resulting from deficient gamma-aminobutyric acid (GABA) inhibitory neurotransmission. Given that the PFC regulates emotional functioning, it is possible that neuropathological alterations in PFC GABA function contribute to deficits in affective functioning in schizophrenia. In particular, schizophrenic patients have been suggested to apply aberrant motivational salience to cues, often being hyporesponsive to cues that predict reinforcement, and hyperresponsive to cues that do not predict reward. These types of deficits can be assessed in non-human animals using discriminative Pavlovian fear conditioning and latent inhibition paradigms. In the present study, experiments were conducted to elucidate the role of PFC GABAergic transmission in the allocation of motivational salience to conditioned stimuli. Animals were trained to lever press for sucrose reward, after which fear was assessed (using conditioned suppression of lever pressing) on one of the two aversive conditioning paradigms conducted. Saline infused control animals showed normal application of motivational salience, characterized by adaptive discrimination between aversive (CS+) and neutral cues (CS-) during discriminative Pavlovian fear conditioning, and acquired irrelevance to a stimuli that was preexposed during latent inhibition. Pharmacological blockade of GABAA-receptors prior to the conditioning or test phase of the discriminative fear task eliminiated the ability to behaviorally discriminate between a CS+ and CS-. Interestingly, only pre-conditioning infusions resulted in elevated fear to the CS-, suggesting that abnormal hyperresponsivity to a neutral cue is related to deficient GABA function during acquisition, but not recall. Blockade of GABAA-receptors prior to conditioning had no effect on latent inhibition, but did enhance fear in animals that were non-preexposed to the conditioned stimulus. In contrast, latent inhibition was abolished following GABA-blockade prior to the test phase of the task. Taken together, these deficits suggest that PFC GABA transmission is critical for adaptive behavior following aversive conditioning. Such deficits observed in schizophrenia may be causally related to PFC GABA deficiency, predisposing these individuals to aberrant attributions of motivational salience to environmental stimuli.

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