The alpha5 subunit of the GABA(A) receptor is localized mainly to the hippocampus of the mammalian brain. The significance of this rather distinct localization and the function of alpha5-containing GABA(A) receptors has been explored by targeted disruption of the alpha5 gene in mice. The alpha5 -/- mice showed a significantly improved performance in a water maze model of spatial learning, whereas the performance in non-hippocampal-dependent learning and in anxiety tasks were unaltered in comparison with wild-type controls. In the CA1 region of hippocampal brain slices from alpha5 -/- mice, the amplitude of the IPSCs was decreased, and paired-pulse facilitation of field EPSP (fEPSP) amplitudes was enhanced. These data suggest that alpha5-containing GABA(A) receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus.

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First developed in the 1980s by Trevor Robbins in Cambridge to investigate attentional function in rats, the 5-choice serial reaction time task involves continuous scanning by the subject across a spatial array of visual stimuli. On detecting a brief stimulus at one of five locations, the subject must make a nose poke in order to collect a reward. The task has also been conducted successfully in several strains of mice, including transgenic models. This unit presents the procedures required to run the task in mice, outlining the expected results at each stage of training and presenting examples of the most common manipulations used to dissociate behavior further.

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It has been suggested that the increased reinforcement rate on a differential-reinforcement-of-low-rate of responding (DRL) schedule observed following acute antidepressant administration in the rat is due to an improvement in timing accuracy. The aim of the present work was to evaluate the effects of antidepressants in another schedule that requires accurate estimation of time intervals, the peak procedure. Three antidepressant drugs were tested, the tricyclic antidepressant imipramine (1.0-10.0 mg/kg, i.p.) and the 5-HT reuptake inhibitors, zimelidine (10.0-40.0 mg/kg, i.p.) and clomipramine (1.0-10.0 mg/kg, i.p.). For reference, the full benzodiazepine receptor agonist, diazepam (1.0-5.0 mg/kg, i.p.) and the psychomotor stimulant, d-amphetamine (0.5-1.5 mg/kg, s.c.) were also tested. All doses of d-amphetamine tested significantly increased lever-pressing rates, whereas all the other compounds induced significant decreases in lever-pressing rates. Overall, the time at which the maximal lever-pressing rate occurred was not altered by any of the compounds, suggesting that timing accuracy was not significantly affected by any of the compounds administered. The only exception was zimelidine (40.0 mg/kg), which reduced the time at which the maximal lever-pressing rate occurred, although lever-pressing rates were also significantly reduced at this dose. These data suggest that previously reported antidepressant-induced improvement in performance on the DRL schedule may not have been due to improved timing accuracy per se but may have been due to a decrease in lever-pressing rates.