The effect of chronic antidepressant administration on β‐adrenoceptor function of the rat pineal

Abstract

1 The 1-adrenoceptor agonist, isoprenaline (1.5-3.0 mg kg-intravenously), produced a doserelated increase in rat pineal melatonin content. This increase was prevented by pretreatment with the selective PI-adrenoceptor antagonist, atenolol (2mgkg 1), but not by the P2-adrenoceptor antagonist, butoxamine (2 mg kg-1). The P2-adrenoceptor agonist, terbutaline (5.0mg kg-1), produced a moderate increase in pineal melatonin content. 2 Repeated daily administration of desmethylimipramine (10mg kg-for 10 days) and maprotiline (10mg kg-for 10 days), antidepressants predominantly inhibiting noradrenaline (NA) uptake, reduced the isoprenaline-induced increase in pineal melatonin content. Amitriptyline (20 mg kg-I for 14 days), a drug which inhibits both NA and 5-hydroxytryptamine (5-HT) uptake, had a similar effect. The P-adrenoceptor agonist, clenbuterol (5 mg kg-for 14 days), also attenuated the increase in pineal melatonin produced by isoprenaline. 3 In contrast, chronic administration of the selective 5-HT uptake inhibitor, fluoxetine (10mg kg-for 10 days), or the antidepressants, iprindole and mianserin (both 20mg kg1 for 14 days), which do not inhibit monoamine uptake, failed to reduce the increase in pineal melatonin following isoprenaline. Repeated electroconvulsive shock was similarly without effect. 4 Ten hours after the final dose of desmethylimipramine (10mg kg-1) once daily for 10 days there was no change in the usual dark phase increase in pineal melatonin. 5 The data suggest that repeated administration of certain antidepressant drugs results in reduced pineal P-adrenoceptor sensitivity. However the lack of change in the dark phase increase in pineal melatonin following repeated desmethylimipramine, implies that the reduced B-adrenoceptor sensitivity may be part of an adaptive process which maintains normal pineal function. Therefore the decrease in 1-adrenoceptor number in the brain reported after chronic antidepressant administration may not be associated with a change in overall synaptic function.

Neuroimmune endocrine effects of antidepressants

“…A similar effect was found with venlafaxine (a serotonin-norepinephrine reuptake inhibitor) on acute treatment 146. However, melatonin levels were attenuated by subchronic treatment, possibly because of adaptive desensitization of the pinealocyte β-adrenoceptors that maintain normal pineal function after modification of overall pineal synaptic function 145,146. Another study showed that fluoxetine (a selective serotonin reuptake inhibitor) had a positive effect on AA-NAT gene expression in the hippocampus and striatum, indicating a possible pathway via antidepressants which modulate melatonin synthesis 147.…”

“…Studies on isolated rat pineal glands incubated with desipramine (a tricyclic antidepressant) showed increased levels of melatonin and increased activity of N-acetyltransferase compared with controls 144,145. A similar effect was found with venlafaxine (a serotonin-norepinephrine reuptake inhibitor) on acute treatment 146.…”

Cortical β‐ and α2‐ Adrenoceptor Binding, Hypothalamic Noradrenaline and Pineal Melatonin Concentrations Measured at Different Times of the Day after Repeated Treatment of Rats with Imipramine, Zimeldine, Alaproclate and Amiflamine

“…Down-regulation of P-adrenoceptors has also been demonstrated in the pineal gland after chronic antidepressant treatment by monitoring the melatonin response to j3-adrenergic agonists (Cowen et al 1983). These authors found that repeated treatment of rats with the serotonin reuptake inhibitor fluoxetine did not affect either basal or isoprenaline-stimulated pineal melatonin concentrations, whereas desipramine and maprotiline (which exert their actions preferentially on noradrenaline uptake) reduced both basal and isoprenaline-stimulated melatonin levels (Cowen et al 1983). Repeated desipramine treatment has also been shown to reduce the night-time increase in melatonin content without affecting the daytime content, despite a similar degree of down-Pineal melatonin 20.00 02.00 08.00 11.00 14.00 25 1 1 Fig The number of rats in each group is indicated in the abscissa.…”

Neuropharmacology of venlafaxine

“…Chronic antidepressant treatment has also been shown to desensitize the βAR-AC system and downregulate β-adrenergic receptors in the rat pineal gland [Moyer et al, 1979;Moyer et al, 1981;Cowen et al, 1983]. Pineal melatonin synthesis is under the control of NE released onto pineal adrenergic receptors [Klein et al, 1970].…”