Select a psychoactive drug that is of pharmacological interest to you, but not one you will review as part of your Critical Review. For this paper, you may choose drugs of abuse; however, the paper mu

doi: 10.1111/j.1472-8206.2008.00605.x ORIGINAL ARTICLE Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor Ashish Dhir, S.K. Kulkarni* Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India INTRODUCTION Dopaminergic system is known to play an important role in the pathophysiology of depression and the dopamine receptors are considered as one of the potential targets for the actions of antidepressants. The agents that modulate dopamine function (precursors, agonists and reuptake inhibitors) in the brain are reported to possess antidepressant property [1,2]. Monoamine oxidase inhib- itors, such as tranylcypromine, which enhance cate- cholamine levels, including dopamine are known to reverse immobility period in animals [3]. Bupropion [(±)- a-t-butylamino-3-chloropropiophenone], a selective and potent dopamine transporter blocker is used as an antidepressant in man. [1,4]. Bupropion has only a weak noradrenaline reuptake inhibiting property in synaptosomal preparations of the rat brain comparedwith potencies of the tricyclic antidepressants [4].

Bupropion also improves chronic fatigue syndrome in humans [5]. Besides, the drug is under clinical use for the treatment of obesity [6] and drug addiction [7]. One of our earlier studies has shown that bupropion could reverse the withdrawal effects from benzodiazepine tolerance [8]. Recently, we have demonstrated the involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in mediating its antidepressant action in the forced swim test (FST) [1]. It was suggested that nitric oxide synthase (NOS) inhibitors when admin- istered prior to bupropion treatment enhance its anti- depressant-like action [1].

Sigma receptors have recently been the target of drug development in psychiatric disorders, including schizo- phrenia, depression and Alzheimer’s disease [9,10]. Of the established two subtypes of sigma receptors (sigma-1 Keywords bupropion, depression, forced swim test, sigma-1 receptors Received 25 December 2007; revised 25 February 2008; accepted 25 April 2008 *Correspondence and reprints:

[email protected] ABSTRACT 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-af nity 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 antag- onist, 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 effectper seon locomotor activity except bupropion which at a higher dose (15–40 mg/kg, i.p.) signi cantly increased the locomotor activity.

The results for the rst time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion. ª2008 The Authors Journal compilationª2008 Blackwell Publishing Ltd.Fundamental & Clinical Pharmacology22(2008) 387–394387 and sigma-2), sigma-1 receptors are known to be involved in learning and memory, response to stress and depression, psychostimulant-induced sensitization, vulnerability to addiction and pain perception [11].

Sigma-1 receptor agonists modulate the release of serotonin and dopamine in the brain [12,13]. Further, sigma-1 receptors alleviated behavioural despair in both the FST [14] and tail suspension test (TST) [15]. Sigma receptors may play, in some way, a role in the antidepressant actions of selective serotonin reuptake inhibitors such as uoxetine, uvoxamine or escitalop- ram [16]. Some of the earlier studies from our laboratory have indicated the involvement of sigma-1 receptors in modulating the antidepressant-like effect of neuro- steroids in mouse FST and TST [17,18]. More recently, we have shown the sigma modulatory activity of ropinirole, a dopamine D2/D3 receptor agonist in mice [19].

Therefore, it has been hypothesized that sigma receptor modulation may be involved in the antidepressant action of drugs such as bupropion. The present study explores the possible involvement of central sigma-1 receptors in the anti-immobility effect of bupropion in mouse FST.

(+)-Pentazocine (a sigma-1 receptor agonist), proge- sterone (a sigma-1 receptor antagonist neurosteroid), rimcazole (another sigma-1 receptor antagonist) or BD 1047 (a novel sigma-1 receptor antagonist) was used in the study to examine the involvement of these receptors.

MATERIALS AND METHODS Animals Male albino mice (Laca strain) weighing 22–30 g bred in Central Animal House (CAH) facility of the Panjab University, Chandigarh, were used. The animals were housed at constant room temperature (24 ± 1 C) and relative humidity (60 ± 5%) in groups of six per cage (polycarbonate cage size: 29·22·14 cm 3) under standard laboratory conditions and maintained on natural light and dark cycle of 12 h each (lights on at 06:00 hours), and had free access to food and water. Animals were acclimatized to laboratory condi- tions before the experiment. Each animal was used only once. All the experiments were carried out between 09:00 and 15:00 hours. The experimental protocols were approved by the Institutional Animal Ethics Com- mittee (IAEC) and conducted according to the Indian National Science Academy Guidelines (INSA) for the use and care of experimental animals.Experimental protocol Forced swim test The test procedure was carried out according to the previously standardized and validated animal model in our laboratory [1,9,19–22]. In brief, mice were individ- ually forced to swim inside a rectangular glass jar (25·12·25 cm 3) containing 15 cm of water main- tained at 23–25 C; the total duration of immobility during a 6-min test was recorded with the help of stopwatch [1,9,19–22].Each mouse was judged to be immobile when it ceased struggling and remained oating motionless in water, making only those move- ments necessary to keep its head above water.

Measurement of locomotor activity Locomotor activity (ambulations) was measured by using a computerized actophotometer (IMCORP, Ambala, India). An array of 16 infrared emitter–detector pairs measured animal activity along a single axis of motion, the digital data being displayed on the front panel meters as ambulatory movements. Mice were allowed to accli- matize to the observation chamber for a period of 2 min.

Locomotion was expressed in terms of total photobeams counts per 5 min per animal [23].

Drugs and treatment The following drugs were used: bupropion (GlaxoSmith- Kline Beecham, Pennsylvania, PA, USA), (+)-pentazocine (Ranbaxy Co., Gurgaon, India), progesterone (Sigma- Aldrich Co., USA), BD 1047 (Tocris Co., Ellisville, MO, USA), rimcazole (Sigma-Aldrich Co., St. Louis, MO, USA).

All the drugs except progesterone were dissolved in distilled water and different doses were administered intraperitoneally in a xed volume of 0.1 ml per 10 g of body weight. Progesterone was dissolved in vegetable oil and administered subcutaneously. Bupropion was administered 30 min before challenging the animals to the FST. In case of interaction studies, various agonists or antagonists were given 15 min before administering bupropion. The experimental protocol comprised of various groups, each consisting of six to eight animals.

Different set of animals were used for measuring the locomotor activity. All the doses were chosen according to the literature available [24] and the previous studies carried out in our laboratory [1,9,17–19].

Statistical analysis Results expressed as mean ± SEM and the signi cance of the difference in the responses of treatment groups in comparison to the control was determined by a one-way 388 A. Dhir & S.K. Kulkarni ª2008 The Authors Journal compilationª2008 Blackwell Publishing Ltd.Fundamental & Clinical Pharmacology22(2008) 387–394 analysis of variance ( ANOVA ) followed by Tukey’s test. A value ofP< 0.05 was considered statistically signi cant.

An ED 50 value was calculated by using the Litch eld and Wilcoxon method [25]. Chi-squared test is used for checking the homogenous distribution of the data. The slope followed by the ED 50 limits for 19/20 probability was calculated according to the Litch eld and Wilcoxon method [25].

RESULTS Effect of pretreatment of bupropion on forced swim test Bupropion (20 mg/kg, i.p.) time dependently decreased the immobility period in the FST with maximum effect observed at 30 min of its administration; this effect was declining at 60 and 120 min (observations not shown).

Therefore, the latency period for bupropion was kept as 30 min.

Bupropion dose dependently (10, 15, 20 and 40 mg/kg, i.p.) decreased immobility period (in sec- onds) when compared with vehicle control group (F= 22.358,P< 0.001) in the FST (Table I;Figure 1).

The ED 50 value was found to be 18.5 mg/kg, i.p.

(7.34–46.6) (Figure 1.). Bupropion (15, 20 and 40 mg/kg, i.p.) treatment increased locomotor activity.

Both ambulatory (F= 31.041,P< 0.001) and rearing movements (F= 61.843,P< 0.001) were increased (Table I.). The lower dose of bupropion (10 mg/kg, i.p.) did not affect the locomotor activity of mice. An effective dose (20 mg/kg i.p.), and an ineffective dose(10 mg/kg i.p.), were chosen to perform drug interac- tion studies.

Effect of various sigma receptor modulators on the action of bupropion in FST The subeffective dose of (+)-pentazocine (2.5 mg/kg i.p.) enhanced the anti-immobility effect of subeffective dose of bupropion (10 mg/kg, i.p.,F= 5.260,P< 0.05, Figure 2A.).

Pretreatment with a subeffective dose of progesterone (10 mg/kg, s.c.,F= 30.352,P< 0.001,Figure 2B), rimcazole (5 mg/kg, i.p.,F= 17.375,P< 0.001, Figure 2C) or BD 1047 (1 mg/kg, i.p.,F= 13.049, P< 0.001,Figure 2D), reversed the anti-immobility action of bupropion (20 mg/kg, i.p.) as shown by an increase in immobility period compared with bupropion (20 mg/kg, i.p.)per segroup.

Combination of bupropion with various agonists or antagonists of sigma-1 receptors did not affect the locomotor activity when compared with the effectper se.

DISCUSSION Bupropion (15–40 mg/kg, i.p.) exhibited anti-immobility activity in the FST. Co-administration of sigma-1 recep- tor agonist potentiated the effects of subeffective dose of bupropion, while the sigma receptor antagonists partic- ularly the sigma-1 subtype reversed the anti-immobility Table IEffect of different doses of bupropion (10, 15, 20 and 40 mg/kg) on the mean immobility period (seconds) in forced swim test and on the locomotor activity.

Treatment DoseMean immobility periodED 50value in decreasing immobility period in mouse FSTTotal ambulatory movements Vehicle – 222.6 ± 19.65 18.5 (7.34–46.6) 125 ± 10.2 Bupropion 10 198.0 ± 33.47 120 ± 8.22 15 97.80 ± 5.64 b 167 ± 12.5 a,b 20 70.33 ± 14.52 b,c 180 ± 18.6 a,b 40 7.0 ± 7.67 b,c,d 195 ± 25.1 a,b a P< 0.05 when compared with vehicle-treated group.bP< 0.05 when compared with bupropion (10 mg/kg, i.p.).cP< 0.05 when compared with bupropion (15 mg/kg, i.p.).dP< 0.05 when compared with bupropion (20 mg/kg, i.p.). 0 10 20 30 40 50 60 70 80 90 100 110 0 5 10 20 30 4015 25 35 45 Treatment (mg/kg) % decrease in immobility time w.r.t vehicle control ED50 = 18.5 (7.34–46.6) mg/kg/i.p. (11.05 %) (56.06 %)(68.4 %)(96.86 %) Figure 1Modi cation by bupropion (10, 15, 20 and 40 mg/kg, i.p) on percentage decrease in immobility time with respect to vehicle control during the 6-min test in forced swim test and calculation of its corresponding ED 50values. Data were analysed by a one-way analysis of variance ( ANOVA ) followed by Tukey’s test (n= 6–8). Bupropion and sigma-1 receptors 389 ª2008 The Authors Journal compilationª2008 Blackwell Publishing Ltd.Fundamental & Clinical Pharmacology22(2008) 387–394 action of bupropion, thereby demonstrating the involve- ment of sigma-1 receptor modulation in mediating the anti-immobility (antidepressant-like) effect of bupropion for the rst time.

The FST is considered as major and recognized para- digm in animals for screening of antidepressant drugs [1,9,20,22,26,27]. The paradigm is based on the observation that rats or mice when forced to swim in a restricted space from which there is no possibility of an escape, eventually cease to struggle, surrendering themselves (despair or helplessness) to the experimental conditions. This is considered as a state of depression [27]. Both rst and second generations of antidepres- sant drugs are known to reverse this state of despair in animals.

The monoamine hypothesis of depression initially based on noradrenaline and serotonin de ciency, isnow extended to dopamine de ciency as well [2,28–30].

Immobility in the swim test is reversed not only by antidepressants, but also by dopamine D2/D3 receptor agonists [19,31,32] administered systemically or applied directly in the nucleus accumbens. Conversely, a num- ber of studies have reported that antidepressant effects in the swim test were reversed by dopamine antagonist sulpiride when applied directly in the nucleus accum- bens, but not in the dorsal striatum [33].

Bupropion [(±)-a-t-butylamino-3-chloropropiophen- one], a selective dopamine reuptake inhibitor [33], is clinically used as an antidepressant and also in the withdrawal therapy of nicotine [34]. The primary action mode of bupropion involves dopaminergic and noradrenergic neurotransmissions rather than seroto- nergic mechanisms [35]. Bupropion is known to increase the extracellular contents of dopamine in 0 50 100 150 200 250 300 (a) (c)(b) (d) Immobility time (s) (Mean ± SEM) (F = 5.260; P < 0.05) (F = 9.348; P < 0.05) (F = 4.281; P < 0.05) (F = 6.643; P < 0.05) (F = 7.736; P < 0.05) (F = 11.896; P < 0.05) (F = 5.299; P < 0.05) Pentazocine (2.5) – ––++–+ + – ––++–+ +– ––++–+ + – ––++–+ + Bupropion (10) ** 0 50 100 150 200 250 300 * Progesterone (10) Bupropion (20) 0 50 100 150 200 250 300 Immobility time (s) (Mean ± SEM) Rimcazole (5) Bupropion (20) *** 0 50 100 150 200 250 300 Immobility time (s) (Mean ± SEM) Immobility time (s) (Mean ± SEM) BD 1047 (1) Bupropion (20) *** Figure 2Effect of bupropion and its modulation by (a) (+)-pentazocine (2.5 mg/kg, i.p.) (b) progesterone (10 mg/kg, s.c.) (c) rimcazole (5 mg/kg, i.p.) or (d) BD 1047 (1 mg/kg, i.p.) on the immobility period (seconds) induced by the FST. Various sigma receptor modulators were administered 15 min before bupropion and 30 min after bupropion injection, mice were challenged to FST. Data were analysed by a one-way analysis of variance ( ANOVA ) followed by Tukey’s test. *P< 0.05 when compared with vehicle-treated group, **P< 0.05 when compared with corresponding bupropion-treated group. 390 A. Dhir & S.K. Kulkarni ª2008 The Authors Journal compilationª2008 Blackwell Publishing Ltd.Fundamental & Clinical Pharmacology22(2008) 387–394 the nucleus accumbens region of the brain [36].

Bupropion showed antidepressant-like effects in all the age groups of mice [37]. It also reduced the ring rates of noradrenergic and dopaminergic neurons but not that of serotonergic neurons in the dorsal raphe nucleus [36]. However, bupropion is reported to potentiate the release of dopamine and noradrenaline in hypothalamus and nucleus accumbens regions of the brain when co-administered with uoxetine and may show better and rapid onset of antidepressant actions [35]. Recently, the involvement of 5HT 2A and 5HT 6serotonin receptors in the antidepressant-like effect of bupropion in mouse FST has also been demonstrated [38,39]. Bupropion is effective in reducing the symptoms of nicotine with- drawal [40] and thus may be useful in smoking cessa- tion, possibly by blocking the nicotinic acetylcholine receptors [41].

Animal studies suggested that some of the other antidepressants not belonging to the category of dopa- mine reuptake inhibitors also enhance dopamine neuro- transmission in mesolimbic system [42]. Fluoxetine (a selective serotonin re-uptake inhibitor) or desipramine (a potent inhibitor of the noradrenaline re-uptake carrier) is also reported to increase the extracellular dopamine concentration in the prefrontal cortex [43].

This indicates the involvement of dopamine to a signif- icant extent in mediating the activity of standard antidepressant agents.

In the present study, bupropion increased the loco- motor activity in mice. Our results are similar to the ndings by Redolat et al., who have also demonstrated an increase in locomotor activity in mice following acute administration of bupropion [44]. However, bupropion is devoid of any other autonomic actions which differen- tiated this compound from amphetamine-like com- pounds and dopamine uptake blockade seems to be one of the major mechanisms of its antidepressant action [4].

Sigma receptors, non-opioid, non-phencyclidine sensi- tive, are of two subtypes: sigma-1 and sigma-2 receptors.

Sigma-1 receptors are expressed in speci c regions of the brain such as layers of the cortex, hippocampus, hypothalamic nuclei, substantia nigra and purkinje cells in the cerebellum [45,46] and have recently been the target of drug development of anti-schizophrenic and antidepressant drugs [10]. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. Sigma-1 receptors modulate the release of various neurotransmitters [47], such as serotonin [12], dopamine [13] or glutamate [48], and are known to alleviate the symptoms of depression. Sigma-1 agonistshave then been tested in various behavioural tests classi- cally used to predict an antidepressant activity. SA 4503, (+)-pentazocine, DTG, JO-1784 and SKF-10,047 (all sigma-1 receptor agonist) dose dependently decrease immobility in the FST [24,49,50]. These effects were blocked by the sigma-1 receptor antagonist NE-100 or BD1047. Further, SA 4503 and (+)-pentazocine (both sigma-1 receptor agonists) also decreased immobility period in the tail-suspension test, an effect also antag- onized by NE-100 [15].

Although, various studies have reported the involve- ment of sigma receptors in the action of antidepressants, none of them have explored the involvement of this receptor system in the antidepressant outcome of bupropion. Many antidepressant drugs interact with sigma receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans [26]. Antidepressants, such as uvoxamine, uoxetine, citalopram, sertraline, clorgy- line and imipramine, possess moderate to high af nity for sigma-1 sites [12] and it has been proposed that certain differences in the clinical effects of the anti- depressants may, in part, be explained on their distinct in uence on cerebral sigma receptors. For example, uovoxamine is known to have high af nities for sigma- 1 receptors, while tricyclic antidepressants have less [16,51,52]; the effect can be antagonized by the admin- istration of progesterone or BD 1047 (a sigma-1 receptor antagonist) [53]. The sigma ligands are hypothesized to increase the ring activity of dorsal raphe nucleus.

Treatment with sigma ligands may rapidly modulate N-methyl- D-aspartate (NMDA) receptor-mediated trans- mission in the hippocampus, and potentially other forebrain regions, which in turn would lead to a modulation of serotonin neurotransmission in the dorsal raphe nucleus via feedback loops [12]. Combined treat- ment with sigma ligands and amantadine or memantine (NMDA receptor antagonist) may be an alternative in the treatment of antidepressant-resistant depressive patients in future [14].

To elucidate the interaction of bupropion with sigma receptors, we have used (+)-pentazocine, a selective sigma-1 receptor agonist and found that pretreatment with subeffective dose (the dose which did not affect the immobility period in the FST) potentiated the antidepres- sant activity of subeffective dose of bupropion. Further, the antidepressant effect of effective dose of bupropion was antagonized by progesterone, a sigma-1 receptor antagonist neurosteroid, rimcazole, a sigma-1 receptor antagonist antipsychotic agent, or BD 1047, a novel Bupropion and sigma-1 receptors 391 ª2008 The Authors Journal compilationª2008 Blackwell Publishing Ltd.Fundamental & Clinical Pharmacology22(2008) 387–394 selective sigma-1 receptor antagonist respectively. Fur- ther, there were no alterations in the locomotor activity when bupropion was combined with various agonists or antagonists. This implies that the antidepressant-like effect in the FST is independent of locomotor activity of bupropion.

Many brain regions have been implicated in regulating emotions and there is increasing recognition of the role played by particular subcortical structures in depression such as nucleus accumbens [54,55]. These areas have been found to play a critical role in domains which are prominently affected in most depressed patients such as regulation of motivation, sleep and response to pleasur- able and aversive stimuli [54]. Bupropion is known to increase extracellular dopamine and noradrenaline con- centrations in several mesocorticolimbic areas including nucleus accumbens which may have an impact on bupropion’s antidepressant actions [35].In vivobrain microdialysis studies demonstrate that administration of bupropion enhances the increases in extracellular dopa- mine in the nucleus accumbens [36]. Sigma-1 receptors are known to modulate the dopamine release in the nucleus accumbens region of the brain as systemic administration of JO-1784, (+)-pentazocine, both selec- tive sigma-1 receptor ligand, and di-tolyl-guanidine (20 microg/i.v.), a non-selective sigma receptor ligand is known to produce a signi cant increase ofN-methyl- D-aspartate (NMDA)-induced dopaminergic neuronal activation [56]. In the present study, it is hypothesized that sigma receptors may modulate the bupropion- induced dopaminergic release in the nucleus accumbens region; thus displaying anti-immobility action in the FST.

In conclusion, these ndings suggest that sigma receptors (sigma-1 site) may play a role in the anti-immobility effect of bupropion in mice in despair paradigm.

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