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Acute and chronic effects of desipramine administration to rhesus monkeys
Abstract:
Rhesus monkeys were studied for changes in noradrenergic functioning before and after chronic oral administration (28 days) of the tricyclic antidepressant desipramine (DMI). Decreases in cerebrospinal fluid concentration of the norepinephrine metabolite MHPG were evident following the first dose (5.0 mg/kg) of DMI, but not after chronic administration of the drug. The alpha 2-adrenoceptor agonist clonidine reduced plasma norepinephrine prior to DMI treatment, but not after 28 days of treatment with DMI. These adaptive changes in noradrenergic function were evident in spite of very low plasma levels of DMI due to rapid metabolism of the drug in the rhesus monkey. The development of changes compatible with alpha 2-adrenoceptor subsensitivity in the presence of plasma levels of the drug that are well below those considered therapeutic in the treatment of depression suggests that such a receptor change may be dissociated from the drug's antidepressant effect.
Insights
Tricyclic antidepressant desipramine (DMI) alters noradrenergic function in rhesus monkeys. Chronic DMI treatment leads to adaptive changes, suggesting alpha 2-adrenoceptor subsensitivity may be separate from antidepressant effects.
Area of Science:
- Neuropharmacology
- Psychiatry
- Animal Models
Background:
- Noradrenergic pathways are crucial targets for antidepressant medications.
- Tricyclic antidepressants like desipramine (DMI) modulate norepinephrine levels.
- Understanding adaptive changes in noradrenergic function is key to elucidating antidepressant mechanisms.
Purpose of the Study:
- To investigate the effects of chronic oral desipramine (DMI) administration on noradrenergic functioning in rhesus monkeys.
- To examine adaptive changes in alpha 2-adrenoceptor sensitivity following DMI treatment.
- To explore the relationship between receptor sensitivity changes and therapeutic antidepressant effects.
Main Methods:
- Rhesus monkeys received daily oral doses of desipramine (DMI) for 28 days.
- Cerebrospinal fluid (CSF) levels of MHPG, a norepinephrine metabolite, were measured.
- The effect of the alpha 2-adrenoceptor agonist clonidine on plasma norepinephrine was assessed before and after DMI treatment.
Main Results:
- A single dose of DMI initially decreased MHPG levels, but this effect diminished with chronic administration.
- Clonidine's ability to reduce plasma norepinephrine was impaired after 28 days of DMI treatment.
- These adaptive changes occurred despite low plasma DMI levels due to rapid metabolism in rhesus monkeys.
Conclusions:
- Chronic desipramine (DMI) administration induces adaptive changes in noradrenergic function, including potential alpha 2-adrenoceptor subsensitivity.
- These receptor changes can occur at sub-therapeutic drug concentrations.
- Alpha 2-adrenoceptor subsensitivity may be dissociable from the antidepressant efficacy of DMI.