Figure 4.

To examine whether enhanced noradrenergic neurotransmission was necessary for the persistent antidepressant-like effect in the forced-swim test, α-methyl-p-tyrosine (AMPT), an inhibitor of tyrosine hydroxylase, was administered 2 days after the end of the chronic desipramine treatment regimen. AMPT reversed the antidepressant-like effect in the forced-swim test, even at a dose where it did not affect behavior on its own (a). The changes in noradrenergic neurotransmission after acute and chronic desipramine treatment are demonstrated in this diagram (b). The membrane NE transporter (NET) is blocked by acute desipramine treatment, resulting in an increased synaptic NE concentration. Two days after completion of chronic desipramine treatment, when the plasma and brain concentrations of desipramine and its major active metabolite are not detectable, the membrane NET is downregulated. Under this condition, the increase of synaptic NE and antidepressant effect on behavior result not only from the direct blocking of NET by the desipramine, but also from reduced NET expression and function. Inhibition of NE synthesis with AMPT reverses the increase in neurotransmission, resulting in a loss of antidepressant efficacy, even though the NET is downregulated. Data shown are means ± SEM of 5–7 rats per group. *p < 0.05, ***p < 0.001 vs control; ###p < 0.001 vs desipramine alone.