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Abstract
5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based
learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating
which is often affected in schizophrenic patients, we tested whether Ro 4368554, a
5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse
inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro
4368554 altered fear conditioning using fear potentiated startle, a model for emotional
learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg)
when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine
(0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption
was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly
ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or
Ro 4368554 were administered before two daily fear conditioning sessions; rats were
tested on the following day. Rats that received scopolamine displayed no fear potentiated
startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped
Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased
Fos expression in the central nucleus of the amygdala and this was attenuated by Ro
4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating
sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related
disorders.