Increased Fear Learning Coincides with Neuronal Dysinhibition and Facilitated LTP in the Basolateral Amygdala following Benzodiazepine Withdrawal in Rats

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Abstract
Animals chronically administered with diazepam (DZM – 2 mg/kg/day i.p.) or vehicle (VEH) for 21 days were tested in a fear-conditioning paradigm 4 days after the last administration. Increased freezing was observed in DZM withdrawn rats as compared to VEH injected control rats in both associative and nonassociative context and this increase was greatest for the DZM withdrawal group in the paired context. In animals anesthetized with urethane, single pulses in the medial prefrontal cortex evoked a field potential including a population spike (PS) in the basolateral complex of the amygdala (BLA) of control animals, whereas in DZM withdrawn animals multiple PSs were evoked. In brain slices from control rats, stimulation of the external capsule evoked a field potential including a PS in the BLA, whereas in DZM withdrawn rats multiple PSs were evoked. The amplitude of the PS was smaller in slices obtained from DZM withdrawn rats than from control rats, and paired pulse inhibition was significantly less in the former. Perfusion with DZM 2 μM of slices obtained from DZM withdrawn rats eliminated repetitive spiking. GABAergic blockade with 50 μM picrotoxin in control rats resulted in the appearance of multiple secondary PSs. In slices from DZM withdrawn rats high-frequency stimulation induced a highly significant potentiation that lasted at least 2 h (LTP), whereas in control rats the same stimulation did not induce LTP. Neuronal hyperexcitability leading to facilitated LTP observed in BLA of DZM withdrawn rats could be due to depressed GABAergic activity (dysinhibition). The increased synaptic plasticity may be at the root of the increased fear learning observed in withdrawn animals.