Effects of chronic antidepressant treatment of β-adrenoceptor subtype binding in the rat cerebral cortex and cerebellum

Abstract

The effects of desipramine, tranylcypromine, and phenelzine on beta-adrenoceptor subtype binding were measured in rat cerebral cortex and cerebellum. The drugs were administered to male Sprague Dawley rats for 28 d sc via 2ML4 Alzet osmotic minipumps (desipramine HCl 10, tranylcypromine HCl 1, phenelzine sulfate 5, 10 mg kg-1/d). Binding of [3H]CGP 12177 was measured to determine total beta-adrenoceptor density in each brain region. The relative densities of beta 1- and beta 2-adrenoceptors were directly calculated from competition analysis using ICI 89406 to displace [3H]CGP 12177. beta 1-Adrenoceptor density was decreased in cortical tissue following each antidepressant treatment, but no effects on beta 2-adrenoceptor density were evident. With cerebellar tissue, despite a higher density of beta 2-adrenoceptors in this area, no effects of antidepressants on beta 2-adrenoceptor density were evident. The present data confirm and extend previous reports of beta 1- but not beta 2-adrenoceptor downregulation in brain following chronic antidepressant drug treatment.

Postsynaptic α-2 Adrenergic Receptors are Critical for the Antidepressant-Like Effects of Desipramine on Behavior

“…Activation of presynaptic β-2 autoreceptors increases NE release (Murugaiah and O’Donnell, 1995); this has been suggested to contribute in the regulation of antidepressant actions of desipramine. In addition, β-1 adrenergic receptors may also contribute to the antidepressant-like effect of desipramine, given that repeated treatment with desipramine reduces the density of this subtype in the brain (Daws et al , 1998; Paetsch and Greenshaw, 1993). Consistent with this, it has been found that desipramine and related drugs produce β-1 adrenergic receptor-mediated discriminative stimulus effects (Crissman et al , 2001; Crissman and O’Donnell, 2002).…”

“…In addition, desipramine and other NE reuptake inhibitors substitute for the β-adrenergic agonist isoproterenol in a drug discrimination task, indicating that β-adrenergic receptors play a role in mediating the effects of desipramine, as well as other NE reuptake inhibitors (Crissman et al , 2001; Crissman and O’Donnell, 2002). Further, repeated treatment with desipramine downregulates β-1, but not β-2, adrenergic receptors in the brain (Paetsch and Greenshaw, 1993). Consistent with this, downregulation of β-2 adrenergic receptors does not alter the antidepressant-like effect of desipramine (O’Donnell, 1990).…”

Effects of Repeated Antidepressant Treatment on Type 4A Phosphodiesterase (PDE4A) in Rat Brain

“…Several hypotheses have been proposed, often involving the downregulation of postsynaptic receptors, including ␤-adrenergic and serotonergic receptors. There are numerous reports indicating that repeated treatments with norepinephrine reuptake inhibitors, MAO inhibitors, and some serotonin reuptake inhibitors decrease the density of ␤-adrenergic receptors (Ordway et al, 1991;Paetsch and Greenshaw, 1993;Goodnough and Baker, 1994;Palvimaki et al, 1994). However, not all antidepressants down-regulate ␤-adrenergic receptors.…”

Perturbations in brain monoamine systems during stress

“…In suicide victims, the number of beta 1 -ARs in temporal and frontal cortex was significantly lower than in matched controls (Depaermentier et al 1993;Little et al 1993). However, the psychotropic role of beta-AR downregulation is still unknown since also the antidepressant desmethylimipramine downregulated brain beta-ARs (Wolfe et al 1978;Ordway et al 1988;Paetsch and Greenshaw 1993). In contrast, treatments of rats with the selective serotonin reuptake inhibitors citalopram and fluoxetine increased binding of the antagonist radioligand 125 I-iodocyanopindolol to beta 1 -ARs in frontal cortex and striatum (Palvimaki et al 1994).…”