Some effects of chronic antidepressant treatments on rat brain monoaminergic systems

A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha 2-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days. Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO4 were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied. Central alpha 2-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25 mg/kg i.p.) to decrease rat brain MHPG-SO4 content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective. The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex 3H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. CHronic, but not acute, pargyline decreased 3H-clonidine binding and this was due to a diminished number of binding sites. The induction of subsensitive presynaptic alpha 2-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical 3H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha 2-adrenoceptors.