Effect of antidepressant agents on β-adrenergic receptor and neurotransmitter regulatory systems

Abstract

The effects of established and several novel antidepressant agents on brain monoamine oxidase A and B; high affinity synaptosomal uptake of norepinephrine, dopamine and serotonin; and β-adrenergic receptor kinetics evaluated by ( 3H)-dihydroalprenolol binding to cortical membranes are described. Extremely weak in vitro inhibitory effects on rat brain mitochondrial MAO-type A or B were observed with P74-1197 (+) or (−) and HP-505, both 3-aryl-spiroisobenzofuranpiperidines, P77-2984 a 3-aryl-spirobenzothiophenepiperidine derivative, LM-5008 an indolylethylpiperidine, desipramine, nisoxetine and P76-2543 a 4-aryl-1,3 benzodiazapine. As anticipated, deprenyl showed potent substrate selective inhibition of MAO type B. LM-5008, P74-1197(+) and P77-2984 were potent selective inhibitors of serotonin synaptosomal uptake while nisoxetine, P76-2543 and P74-1197(−) appeared to preferentially inhibit reuptake of norepinephrine. The kinetics (B max and K D) of ( 3H)-dihydroalprenolol binding were also studied following chronic administration of these same drugs (10 mg/kg, b.i.d.). After 10 days of treatment, heterogeneous results were obtained in that some compounds elicited changes in receptor density and dissociation constant while others, such as nisoxetine, produced no kinetic alterations. While present biochemical antidepressant tests utilized in this study are designed to evaluate modulations of aminergic systems in terms of neurotransmitter availability, fluxes in concentration and attendant receptor recognition site sensitivities, the underlying mode(s) of action at the cellular level still require further clarification.