Evidences for the agmatine involvement in antidepressant like effect of bupropion in mouse forced swim test.

Although bupropion has been widely used in the treatment of depression, the precise mechanism of its therapeutic actions is not fully understood. The present study investigated the role of agmatine in an antidepressant like effect of bupropion in mouse forced swim test. The antidepressant like effect of bupropion was potentiated by pretreatment with agmatine (10-20mg/kg, ip) and by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine (40 µg/mouse, icv), an agmatine biosynthetic precursor, ornithine decarboxylase inhibitor, dl-α-difluoromethyl ornithine hydrochloride, DFMO (12.5 µg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 µg/mouse, icv) and agmatinase inhibitor, arcaine (50 µg/mouse, icv) as well as imidazoline I1 receptor agonists, moxonidine (0.25mg/kg, ip) and clonidine (0.015 mg/kg, ip) and imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline hydrochloride, 2-BFI (5mg/kg, ip). Conversely, prior administration of I1 receptor antagonist, efaroxan (1mg/kg, ip) and I2 receptor antagonist, idazoxan (0.25mg/kg, ip) blocked the antidepressant like effect of bupropion and its synergistic combination with agmatine. These results demonstrate involvement of agmatine in the antidepressant like effect of bupropion and suggest agmatine and imidazoline receptors as a potential therapeutic target for the treatment of depressive disorders.

Tratamiento de la depresión con bupropión en monoterapia / No disponible

No disponible

Tolerancia y perfil de efectos secundarios de bupropión / No disponible

No disponible

Involvement of dopamine receptors in the anti-immobility effects of dopamine re-uptake inhibitors in the forced swimming test.

The effects of dopamine re-uptake inhibitors, bupropion and nomifensine on immobility in the forced swimming test were studied in mice. Bupropion and nomifensine reduced immobility time dose-dependently. Both drugs significantly displayed anti-immobility effects at doses without altering locomotor activity. Anti-immobility effects of bupropion and nomifensine were inhibited by the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH 23390) and the dopamine D2 receptor antagonist sulpiride. These findings suggest that dopamine may be related to depression and dopamine D1 and dopamine D2 receptors play a role in the effects of dopamine re-uptake inhibitors.

Bupropion inhibits nicotine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine.

Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Recently, bupropion has been reported to noncompetitively inhibit alpha3beta2, alpha3beta4, and alpha4beta2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native alpha3beta2* and alpha3beta4* nAChRs using functional neurotransmitter release assays, nicotine-evoked [(3)H]overflow from superfused rat striatal slices preloaded with [(3)H]dopamine ([(3)H]DA), and nicotine-evoked [(3)H]overflow from hippocampal slices preloaded with [(3)H]norepinephrine ([(3)H]NE). The mechanism of inhibition was evaluated using Schild analysis. To eliminate the interaction of bupropion with DAT or NET, nomifensine or desipramine, respectively, was included in the superfusion buffer. A high bupropion concentration (100 microM) elicited intrinsic activity in the [(3)H]DA release assay. However, none of the concentrations (1 nM-100 microM) examined evoked [(3)H]NE overflow and, thus, were without intrinsic activity in this assay. Moreover, bupropion inhibited both nicotine-evoked [(3)H]DA overflow (IC(50) = 1.27 microM) and nicotine-evoked [(3)H]NE overflow (IC(50) = 323 nM) at bupropion concentrations well below those eliciting intrinsic activity. Results from Schild analyses suggest that bupropion competitively inhibits nicotine-evoked [(3)H]DA overflow, whereas evidence for receptor reserve was obtained upon assessment of bupropion inhibition of nicotine-evoked [(3)H]NE overflow. Thus, bupropion acts as an antagonist at alpha3beta2* and alpha3beta4* nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function. The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.

Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine; however, nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effects through a different mechanism than nicotine. Given bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission.