Delayed behavioral response to antidepressant drugs following selective damage to the hippocampal noradrenergic innervation in rats.

The present study was undertaken to investigate in rats the role of the noradrenergic innervation of the hippocampus in the reversal by antidepressant drugs of escape failures caused by previous exposure to inescapable shocks (learned helplessness design). Rats were either sham-operated or given a bilateral infusion of 6-hydroxydopamine (6-OHDA, 8.1 micrograms of free base in 0.8 microliter saline containing 0.02% ascorbic acid) into the dorsal hippocampus. Three weeks later, sham and lesioned rats were exposed (experimental rats) or not exposed (control rats) to 60 randomized, inescapable footshocks (0.8 mA, 15 s duration) and, 48 h later, experimental and control rats were subjected to daily consecutive shuttle-box sessions (30 trials/day; intertrial interval = 30 s). Separate groups of experimental animals were given twice daily injection (i.p.) of clomipramine (total daily dose: 16 or 32 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg), nialamide (16 mg/kg) or saline. After behavioral testing, animals were sacrificed and [3H]noradrenaline uptake was assayed in synaptosomal preparations from the hippocampus, the cerebral cortex and the septum, [3H]serotonin uptake being assessed in hippocampal synaptosomes. We found that hippocampal 6-OHDA infusion resulted in a mean 70% reduction in local [3H]noradrenaline uptake and a marked delay in the response to antidepressants (reversal of escape failures over consecutive shuttle-box sessions). The 6-OHDA infusion was found not to alter hippocampal [3H]serotonin uptake but to decrease (30%) [3H]noradrenaline uptake in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)