Action Of Bupropion Research Articles

Influence of the endocannabinoid system on the antidepressant activity of bupropion and moclobemide in the behavioural tests in mice

BackgroundThough there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase.MethodsThe mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants.ResultsAn intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals.ConclusionThe outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.

Adolescent and adult mice display differential sensitivity to the effects of bupropion on the acquisition of a water maze task.

Adolescence is characterized by major neurobiological changes, and the effects of some psychoactive drugs seem to differ between adolescents and adults. Bupropion, an antidepressant that is also used to treat nicotine addiction, induces behavioral actions in both adolescent and adult rodents. However, the effects of this drug on spatial ability have not been compared in animals at different stages of their development. The present study was conducted to assess the effects of bupropion on spatial learning and memory in adolescent and adult mice. Adolescent (post-natal day: PND35-36) and adult (PND >65) NMRI mice received bupropion (10, 20 and 40mg/kg) or saline during the acquisition (4 trials/day on 5 consecutive days) of a Morris water maze (MWM) task. Retention was evaluated with a probe trial performed after the acquisition phase. Data showed that age did not affect performance of the task. However, the factor Drug treatment reached statistical significance, with high doses of bupropion (40 and 20mg/kg) impairing acquisition of the MWM test in adolescents. The drug did not induce detrimental effects on the acquisition or retention of the task in adults. Bupropion impairs acquisition of the spatial task in adolescent but not in adult mice. It does not seem to alter retrieval of previously acquired spatial information in either adolescents or adults. Our findings suggest that, during the adolescent period, mice are more vulnerable to the actions of bupropion on spatial learning.

Stereoselective Metabolism of Bupropion to OH-bupropion, Threohydrobupropion, Erythrohydrobupropion, and 4'-OH-bupropion in vitro.

Bupropion is a widely used antidepressant, smoking cessation aid, and weight-loss therapy. It is administered as a racemic mixture, but the pharmacokinetics and activity of bupropion are stereoselective. The activity and side effects of bupropion are attributed to bupropion and its metabolites S,S- and R,R-OH-bupropion, threohydrobupropion, and erythrohydrobupropion. Yet the stereoselective metabolism in vitro and the enzymes contributing to the stereoselective disposition of bupropion have not been characterized. In humans, the fraction of bupropion metabolized (fm) to the CYP2B6 probe metabolite OH-bupropion is 5–16%, but ticlopidine increases bupropion exposure by 61%, suggesting a 40% CYP2B6 and/or CYP2C19 fm for bupropion. Yet, the CYP2C19 contribution to bupropion clearance has not been defined, and the enzymes contributing to overall bupropion metabolite formation have not been fully characterized. The aim of this study was to characterize the stereoselective metabolism of bupropion in vitro to explain the stereoselective pharmacokinetics and the effect of drug-drug interactions (DDIs) and CYP2C19 pharmacogenetics on bupropion exposure. The data predict that threohydrobupropion accounts for 50 and 82%, OH-bupropion for 34 and 12%, erythrohydrobupropion for 8 and 4%, and 4′-OH-bupropion for 8 and 2% of overall R- and S-bupropion clearance, respectively. The fm,CYP2B6 was predicted to be 21%, and the fm,CYP2C19, 6% for racemic bupropion. Importantly, ticlopidine was found to inhibit all metabolic pathways of bupropion in vitro, including threohydrobupropion, erythrohydrobupropion, and 4′OH-bupropion formation, explaining the in vivo DDI. The stereoselective pharmacokinetics of bupropion were quantitatively explained by the in vitro metabolic clearances and in vivo interconversion between bupropion stereoisomers.

Effects of Acute Intracerebroventricular Microinfusions of Bupropion on Background Spike Activity of Locus Coeruleus Neurons in Rats

Considering that noradrenergic (NAE) neurons of the locus coeruleus (LC) play significant roles in the formation of biological rhythms, pain, addictions, and mood disorders, we tested the effects of acute intracerebroventricular microinfusions of bupropion, an inhibitor of NA reuptake used in clinics as an antidepressant, on background spike activity on LC neurons in chloral hydrate anesthetized rats. Ten microliters of the solutions containing 0.001, 0.01, 0.1, 1.0, or 10.0 μmol bupropion were infused during 3 min; spike activity of single LC neurons identified according to the known characteristics was recorded extracellularly by glass microelectrodes. Microinfusions of 0.01 to 10.0 μmol bupropion suppressed background spiking of the above neurons in a dose-dependent manner. The normalized mean intensities and durations of inhibition were 17.3, 19.4, 26.3, and 41.1% and 1.4, 7.1, 12.4, and 18.3 min, respectively. The smallest dose (0.001 μmol) was ineffective. It is assumed that bupropion increases the NA level in proximity to NAE LC neurons. The actions of bupropion on other cerebral neuromodulatory systems need further examination. Inhibition of LC neuronal activity by bupropion can help to explain some acute, chronic, and side effects of this agent used in clinics for correction of mood disorders.

Bupropion effects on high-fat diet-induced steatohepatitis and endothelial dysfunction in rats: role of tumour necrosis factor-alpha

This study aimed to elucidate the effect of bupropion (BUP) on high-fat diet (HFD)-treated rats that is to say the action of BUP on diabetes and hyperlipidemia with its consequences on liver and endothelial function. Male Wistar rats were fed HFD or normal chow for 15 weeks then given either BUP (50 mg/kg) or distilled water by gavage for 4 weeks. The effect of BUP on diabetes, hyperlipidemia, hepatic and vascular functions as well as tumour necrosis factor-alpha (TNF)-α were assessed. The intima-media thickness of the aorta was evaluated. BUP significantly decreased serum lipid, liver enzyme, homeostasis model assessment for insulin resistance (HOMA-IR), serum TNF-α and the impaired glucose tolerance. Liver from rats with non-alcoholic steatohepatitis (NASH) demonstrated significant higher TNF-α level, inflammatory cell infiltration, ballooning and steatosis which significantly ameliorated by BUP treatment. Neither intima/media ratio nor vascular reactivity to acetylcholine is improved by BUP treatment. NASH induced by a HFD was associated with hyperlipidemia, insulin resistance, endothelial dysfunction and increase in liver TNF-α. All of these may contribute to the pathogenesis of NASH. BUP has potential role in improving metabolic and hepatic function with negative vascular effect. Since BUP is a well-known antidepressant, it will be a candidate drug in treatment of depression in hepatic diseased or metabolic disturbed patients.

Possible involvement of sigma‐1 receptors in the anti‐immobility action of bupropion, a dopamine reuptake inhibitor

Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a dopamine reuptake inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10-40 mg/kg, i.p.) reduction in immobility period and the ED(50) value was found to be 18.5 (7.34-46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15-40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.

Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment.

Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be elucidated. Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical condition than utilizing acute injections. When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80%) which was reversed by the alpha 2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter bupropion treatment. Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic alpha 2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting profound alterations of the firing activity of NE and 5-HT neurons.

Regulation of Dopamine Receptors by Bupropion: Comparison with Antidepressants and CNS Stimulants

Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.

Antidepressant Profile of Bupropion and three Metabolites in Mice

Bupropion is a novel antidepressant, distinct from tricyclic antidepressants both neurochemically and behaviorally. Bupropion forms several metabolites in both rodents and humans. Three chemically different molecules - BW 306, BW 494, and BW 287 - were selected. Comparative assessment of antidepressant activity of bupropion and its metabolites in mice, and pharmacological analysis of possible mechanisms of action of the parent drug and its metabolites (using interaction studies with pimozide, D,L-propranolol, and prazosin) were carried out. The results obtained show that: bupropion has a pharmacological spectrum in various animal models which predicts both antidepressant and stimulatory activity in man. BW 306 is the most active of the metabolites studied and, compared to bupropion, seems more "antidepressant" and less stimulant. BW 494, compared to bupropion or BW 306, has a lower degree of activity in various tests used to evaluate antidepressants. BW 287 has no effect in any of the tests used in this study. The interaction studies with pimozide, D,L-propranolol, and prazosin in the various tests have shown that: the stimulatory effect of bupropion, BW 306, and BW 494 is antagonized by both pimozide and prazosin. in the behavioral despair test, the reduction in the duration of immobility by bupropion and BW 494 is antagonized by pimozide, but not by prazosin or D,L-propranolol. the antagonism of reserpine-induced hypothermia by bupropion and BW 306 is significantly decreased by prazosin and D,L-propranolol, but not by pimozide. These data suggest that the clinical antidepressant profile (without a major stimulatory effect) observed in man after administration of bupropion is related to metabolite BW 306 and possibly to BW 494, rather than to bupropion itself.

Dependence on Benzodiazepines

Bupropion, a specific dopamine reuptake inhibitor, was compared to amitriptyline in two multicenter studies involving 183 depressed outpatients and inpatients. Initial results from these ongoing studies provide additional evidence of the antidepressant activity of bupropion. At the end of the treatment periods (6 weeks for inpatients and 13 weeks for outpatients), bupropion appeared to be at least as effective as amitriptyline. However, bupropion exerted a slightly but nonsignificantly smaller overall therapeutic effect than amitriptyline during the first 4 weeks of drug treatment. Slight weight loss and dopaminergic side effects, such as insomnia, nausea/vomiting, and anorexia, were somewhat more common among bupropion-treated patients. Compared to bupropion, amitriptyline induced more weight gain and had more anticholinergic, antihistaminic, and antiadrenergic side effects. In view of its numerous sites of action, amitriptyline does not appear to be the ideal antidepressant. It remains to be demonstrated whether bupropion has any advantage over secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.