A study of the sensitivity of rat brain alpha2-adrenoceptors during chronic antidepressant treatments

Summary Two experimental approaches were used to study the effect of chronic antidepressant treatments on the functioning of central alpha₂-adrenoceptors. In one, the effect of antidepressant treatment on the ability of a low dose of clonidine (25 g/kg) to lower rat brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO₄) levels was studied. In the other, potential treatment-induced alterations in rat frontal cortex ³H-clonidine binding were determined. The same cortical tissue was also studied in parallel for ³H-dihydroalprenolol binding.Of the tricyclics imipramine, amitriptyline and nortriptyline, only chronic imipramine (10 mg/kg b.i.d. for 14 days) attenuated the clonidine-induced reduction in brain MHPG-SO₄ levels. Repeated electroconvulsive shock therapy (100 mA for 1 s once daily for 10 days), but not chronically administered pargyline, also antagonized the neurochemical response to clonidine.The following long-term antidepressant treatments were investigated for their effect on rat frontal cortex ³H-clonidine and ³H-dihydroalprenolol binding: desipramine, imipramine, nortriptyline, amitriptyline, mianserin, iprindole, nisoxetine, pargyline and electroconvulsive shock therapy. Only chronic pargyline (25 mg/kg once daily for 14 days) altered cortical ³H-clonidine binding. Scatchard analysis revealed that the drug-induced decrease was due to a reduction in the number of recognition sites with no change in affinity. With the exceptions of mianserin and nisoxetine, all other seven forms of antidepressant treatment decreased cortical ³H-dihydroprenolol binding, Scatchard analysis revealing a diminution in the number of recognition sites.The results of this, and previous studies, indicate that under the dosage regimens employed only some forms of long-term antidepressant treatments induce a down-regulation in the functioning of rat brain presynaptic alpha₂-adrenoceptors, as assessed by the clonidine-MHPG-SO₄ model. No correlation was found between treatment-induced alterations in the characteristics of cortical ³H-clonidine recognition sites and the effect of identical treatment on the clonidine-induced reduction in rat brain MHPG-SO₄ levels.To unequivocally assume that drug-induced changes in central ³H-clonidine recognition sites reflect alterations in the functioning of central presynaptic alpha₂-adrenoceptors may be open to question.