Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats

Physiology & Behavior 180 (2017) 137–145

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Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats

MARK

Susana Barbosa-Méndez, Maura Matus-Ortega, Alberto Salazar-Juárez⁎ Subdirección de Investigaciones Clínicas, Laboratorio de Neurofarmacología Conductual, Microcirugía y Terapéutica Experimental, Instituto Nacional de Psiquiatría, Ciudad de México 14370. Mexico

A R T I C L E I N F O

A B S T R A C T

Keywords: Mirtazapine Cocaine Pharmacotherapy Locomotor sensitization Drug-addiction 5-HT receptors Alpha receptors

Cocaine abuse and dependence are a global public health problem. To date, no effective therapy has been established to treat cocaine dependence but mirtazapine—as well as prazosin used in preclinical and clinical trials—has been shown to decrease cocaine behavioral effects. Therefore, our hypothesis was that the effectiveness of mirtazapine might improve when used in combination with prazosin. This study investigated the combined effect of mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. We found that chronic treatment with the mirtazapine-prazosin combination significantly improved the effect of single mirtazapine dosing on cocaine-induced locomotor activity and on the induction and expression of cocaine sensitization. These results suggest that the combined use of mirtazapine and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine.

1. Introduction Cocaine abuse and dependence, both chronic brain disorders, have become a global public health problem [1]. Despite significant progress in our understanding of neurobiological changes associated with substance abuse and dependence during the last decade, few pharmacological interventions have proven to successfully treat cocaine dependence [2]. Mirtazapine (MSD REMERON, Schering-Plough-Organon, USA) is an effective noradrenergic and a specific serotoninergic antidepressant with pronounced early-anxiolytic effects in patients with moderate to severe depression [3,4]. Several studies have found that mirtazapine mitigates various behavioral alterations induced by drugs of abuse [5,6]. At the preclinical level, mirtazapine decreases symptom severity during morphine and methamphetamine withdrawal, reduces morphine-induced rewarding effects, inhibits the acquisition of morphine dependence, and attenuates the establishment of conditioned place preference to morphine and methamphetamine in rats [7–11]. Other studies show that mirtazapine has proven to be effective in reducing the reinstatement of methamphetamine self-administration [12] and decreasing the expression of methamphetamine-induced locomotor sensitization [9–11]. In addition, we recently reported that daily dosing of mirtazapine (30 mg/Kg, i.p.) for 30 days during drug-extinction significantly attenuates the induction and expression of locomotor

⁎

Corresponding author. E-mail address: [email protected] (A. Salazar-Juárez).

http://dx.doi.org/10.1016/j.physbeh.2017.08.017 Received 19 April 2017; Received in revised form 21 August 2017; Accepted 23 August 2017 Available online 24 August 2017 0031-9384/ © 2017 Elsevier Inc. All rights reserved.

sensitization to cocaine and nicotine, decreases the duration of the cocaine- and nicotine-induced locomotor effect [13–15] and reduce the reacquisition of cocaine self-administration [16]. Human studies have shown that mirtazapine administration reduces benzodiazepine, cocaine, and methamphetamine abuse [5,17]. Double blind, placebocontrolled clinical trials report that mirtazapine significantly improves symptoms of depression, anxiety, and insomnia, minimizing physical and subjective discomfort and dysphoric symptoms during benzodiazepine, methamphetamine, alcohol, and cocaine withdrawal [6,18,19,20], as well as reducing craving [6]. Furthermore, preclinical and clinical trials have found that alpha-1 adrenergic receptors contribute significantly to the behavioral effects of cocaine [21–24]. Prazosin, an antagonist of alpha-1 adrenergic receptors, blocks the acquisition of morphine- or cocaine-induced place preference; reverses tolerance to morphine analgesia; attenuates morphine-withdrawal symptoms in mice; and reduces the reinstatement of cocaine or heroin self-administration in rats [25–29]. Pretreatment with prazosin blocks the acute locomotor response and the development of behavioral sensitization to cocaine and methamphetamine, and significantly reduces hypophagia, locomotor hyperactivity, and Fos expression in the striatum induced by cocaine or amphetamine in rats [23,24,30,31]. In addition, 1 mg/kg doxazosin, another alpha-1 antagonist, blocks the development and expression of cocaine-induced behavioral sensitization in rats [32]. In some clinical trials, doxazosin

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activity [13] or produce sedation, nor does it induce weight gain [41,42], in rats. Additionally, preclinical and clinical trials have reported that 30 mg/Kg mirtazapine decreases cocaine-induced locomotor activity [13], attenuates morphine-induced place preference [7], and reduces morphine and methamphetamine withdrawal symptoms, in rats and humans. Other authors have shown that 1 mg/Kg prazosin is the optimal dose to decrease behavioral effects caused by cocaine [24,29]. Further, 0.5 mg/kg oxymetazoline has proven to be the optimal dose to decrease the effect of alpha-1 adrenergic antagonists, such as prazosin [37,38].

has proven effective to reduce cocaine use and alleviate some of the positive subjective effects of cocaine in cocaine-dependent individuals [33,34]. Some double blind, placebo-controlled studies have found that mirtazapine is not better than placebo at reducing cocaine use in cocaine-dependent patients and that it increases anxiety in patients who are in acute methamphetamine withdrawal [18,35]. Moreover, as shown by preclinical and clinical trials, prazosin significantly reduces cocaine-induced behavioral effects [29,33,36]. Therefore, our research hypothesis was that mirtazapine effectiveness might improve when used in combination with prazosin. This study explored the potential additive or synergistic effects of co-administering mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. In addition, in order to determine if the behavioral effect of the combination with mirtazapine and prazosin was the result of the pharmacological action of prazosin on mirtazapine, we administered oxymetazoline, an alpha-1 adrenergic agonist, which has demonstrated the ability to reverse the effects induced by prazosin [37,38]. Locomotor sensitization is considering a critical physiological mechanism that reflects the establishing of some of the persistent features of drug abuse and facilitates the expression of drug craving and compulsive drug-seeking behavior [39]. Moreover, the drug-sensitization induces an increase in the salience that result in an increased vulnerability to drug-relapse [40]. Our results indicate that co-administration of mirtazapine and prazosin significantly enhanced the effect of mirtazapine on cocaine-induced locomotor activity during the induction and expression of behavioral sensitization.

2.3. Behavioral sensitization procedure 2.3.1. Apparatuses/devices For each animal, locomotor activity was assessed in transparent Plexiglas cages (50 × 50 × 30 cm) set in activity chambers linked to a PC. Each activity chamber was surrounded by an array of photocell beams (16 × 16) located 3 cm from the floor surface to scan locomotor activity (OMNIALVA, Instruments, Mexico). Interruptions of the photobeams were automatically quantified with OABiomed software (1.1) and then analyzed. Locomotor activity was defined as consecutive beam breaks (OMNIALVA, Mexico). 2.4. Methodology

2. Materials and methods

To estimate spontaneous locomotor activity, the study used a standard protocol [13]. Habituation of the rats to the activity chambers took place during three 30-min sessions. The animals were then randomly assigned to different pharmacological treatment groups. Locomotor activity was recorded for 30 min, and the rats were returned to their home cages after each experimental session had been completed.

2.1. Animals

2.5. Experimental procedures

The study used male Wistar rats weighing 250–280 g at the onset of the experiments. They were housed four per cage in standard plastic rodent cages (57 cm × 35 cm × 20 cm) in a colony room maintained at 21 ± 2 °C and at 40–50% humidity under a 12-h light/dark cycle (lights on at 7:00 AM). The animals had free access to water and rodent chow pellets, except during experimental sessions. All the experiments were conducted during the light phase, between 9:00 AM and 3:00 PM. The study procedures were approved by the Committees on Bioethics and Institutional Laboratory Animal Care and Use, in strict compliance with the Guide for the Care and Use of Laboratory Animals issued by the National Institutes of Health.

The study used 144 male Wistar rats divided into three groups, with each group undergoing a different experiment. For experiments 1 and 2, we used 56 animals further divided into seven experimental groups (n = 8); for experiment 3, we used 32 animals assigned to four groups (n = 8). Each experimental group received a different pharmacological treatment. 2.6. Experiment 1 To determine if chronic co-administration of mirtazapine (30 mg/ Kg) and prazosin (1 mg/Kg) prior to daily exposure to cocaine attenuated induction of locomotor sensitization to cocaine, this experiment was divided into three pharmacological phases: phase I, the pre-induction phase, which lasted 30 consecutive days; phase II, induction of locomotor sensitization to cocaine, which lasted 25 days; and phase III, post-induction, which lasted 15 consecutive days (Fig. 1-A). After a three-day habituation period, the saline (SAL), the prazosin (PRZ), and the mirtazapine (MIR) groups received saline solution (0.9% NaCl, i.p.), prazosin (1 mg/Kg, i.p.), and mirtazapine (30 mg/kg, i.p.), respectively, during the three aforementioned phases. The rats in the cocaine group (COC) received saline in the pre-induction phase and cocaine (10 mg/kg, i.p.) in both the cocaine-induction and the cocainepost-induction phases 30 min before saline administration. In contrast, the rats in the PRZini + COC and the MIRini + COC groups received prazosin (1 mg/Kg, i.p.) or mirtazapine (30 mg/kg, i.p.) during both the pre-induction and the induction phases, 15 and 30 min, respectively, before receiving either saline or cocaine. The PRZini + MIRini + COC group received prazosin 15 min before mirtazapine and mirtazapine 30 min before receiving either saline or cocaine in the pre-induction and the induction phases. During post-induction, prazosin and mirtazapine were withdrawn and the three groups received cocaine only. After administration of each treatment, locomotor activity for each

2.2. Drugs Cocaine hydrochloride (purity > 98%) was kindly donated by the Mexican government under strict regulatory controls. All the drugs used in experimental animals were kept under official surveillance (COFEPRIS- LC-0004-2003). Cocaine hydrochloride, prazosin (Minipres, Pfizer), mirtazapine (REMERON, Schering-Plough-Organon), and oxymetazoline (Sigma-Aldrich) were dissolved in sterile saline solution (0.9% NaCl, Sigma Aldrich). The solutions were freshly prepared and maintained at − 20 °C before intraperitoneal (i.p.) administration. Saline (0.9% NaCl) was used as control in all experiments. To determine if co-administration of prazosin and mirtazapine could prevent the locomotor effects of cocaine, mirtazapine was administered 15 min after prazosin and 30 min before cocaine (or saline). The volume injected into each animal depended on its body weight (BW): BW (g)/100 ml. 2.2.1. Dose selection For this study, the optimal mirtazapine dose (30 mg/kg) was determined in accordance with previous reports. They showed that ≥ 30 mg/Kg mirtazapine does not affect spontaneous locomotor 138

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Fig. 1. Co-administration of mirtazapine and prazosin modified the induction of locomotor sensitization to cocaine. A) Experiment timeline. After habituation (Ha), the SAL, the MIR, the PRZ, MIR + PRZ, and the COC groups received saline, mirtazapine, prazosin, and cocaine, respectively. During pre-induction and induction, the MIRini + COC and the PRZini + COC groups received either prazosin or mirtazapine for 15 or 30 min, respectively, before either saline or cocaine administration. The PRZini + MIRini + COC group received prazosin 15 min before mirtazapine and mirtazapine 30 min before receiving either saline or cocaine in the pre-induction and the induction phases. Mirtazapine, prazosin, and the combined administration of mirtazapine and prazosin for 30 days before cocaine administration attenuated the induction of locomotor sensitization to cocaine (B). Mean locomotor activity ( ± S.E.M.) by group (n = 8 animals per group) during the induction (C) and the post-induction phases of locomotor sensitization (D). *p < 0.01: significant effects of the cocaine treatment on locomotor activity compared to the SAL, the PRZ, the MIR, and the MIR + PRZ groups. **p < 0.01: significant effects of mirtazapine, prazosin, and the combined administration of mirtazapine and prazosin on locomotor activity compared to the COC group. #p < 0.01: significant effects of the co-administration of mirtazapine and prazosin on locomotor activity compared to the COCini and the PRZini groups, as determined by a one-way ANOVA followed by Tukey's tests.

group received daily saline only. The cocaine + mirtazapine (COC + MIR), the cocaine + prazosin (COC + PRZ), and the cocaine + prazosin + mirtazapine (COC + PRZ + MIR) groups received cocaine daily during induction. In the extinction and the cocaine-expression phases, the COC + PRZ and the COC + MIR received prazosin or mirtazapine 15 and 30 min, respectively, before administration of either saline or cocaine (10 mg/ kg, i.p.). In contrast, the COC + PRZ + MIR group received15 min before mirtazapine and mirtazapine 30 min before administration of either saline or cocaine (10 mg/kg, i.p.). In the post-expression phase, prazosin and mirtazapine were withdrawn and the group received cocaine only. After each administration, locomotor activity for each animal was recorded for 30 min (Fig. 2-A).

animal was recorded for a total of 30 min (Fig. 1-A).

2.7. Experiment 2 This experiment consisted of four experimental phases: phase I, cocaine-induction phase, which lasted 15 days; phase II, the cocaineextinction phase, which lasted 30 days; phase III, for cocaine expression, which lasted 25 days; and phase IV or the post-expression phase that lasted 20 days (Fig. 2-A). To determine if the chronic co-administration of prazosin and mirtazapine during the extinction phase attenuated the expression of cocaine-induced locomotor sensitization, the SAL, the PRZ, and the MIR groups received saline solution (0.9% NaCl, i.p.), prazosin (1 mg/Kg, i.p.), and mirtazapine (30 mg/kg, i.p.), respectively, during the four abovementioned phases. The cocaine group (COC) received cocaine (10 mg/kg, i.p.) during the induction, the expression, and the post-expression phases. During extinction, cocaine was withdrawn and the

2.8. Experiment 3 This experiment evaluated the effect of oxymetazoline (α1 receptor 139

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Fig. 2. Co-administration of mirtazapine and prazosin modified the expression of cocaine sensitization. Experiment timeline. After habituation (Ha), the SAL, the MIR, the PRZ, MIR + PRZ, and the COC groups received saline, mirtazapine, prazosin, and cocaine, respectively. The MIR + COC and the PRZ + COC groups received cocaine during the induction and the post-expression phases. During extinction and cocaine expression, they received either prazosin or mirtazapine before saline or cocaine administration. The PRZ + MIR + COC group received prazosin before mirtazapine and mirtazapine before receiving either saline or cocaine in the extinction and the cocaine-expression phases (A). Mirtazapine (30 mg/Kg i.p.), prazosin (1 mg/Kg), and co-administration of mirtazapine and prazosin for 30 days during cocaine extinction led to long-term attenuation of the expression of cocaine-induced locomotor sensitization (B). Mean locomotor activity ( ± S.E.M.) by group (n = 8 animals per group) during induction (C) and expression (D) of locomotor sensitization and the post-expression phase (E). *p < 0.01: significant effects of cocaine treatment on locomotor activity compared to the SAL, the PRZ, the MIR and the MIR + PRZ groups. **p < 0.01: significant effects of mirtazapine, prazosin, and the combined administration of mirtazapine and prazosin on locomotor activity compared to the COC group. #p < 0.01: significant effects of the coadministration of mirtazapine and prazosin on locomotor activity compared to the COC and the PRZ groups, as determined by a one-way ANOVA followed by Tukey's tests.

slowed down and then plateaued at ± 20% of the locomotor activity value obtained during habituation. The statistical significance level was set at p < 0.05.

agonist) on the combined administration of mirtazapine and prazosin, as per the protocol described in the above experiment. The COC + PRZ, the COC + MIR, and the two COC + PRZ + MIR groups were administered the treatments described in experiment 2 (Fig. 3-A). During the agonist phase, one of the COC + PRZ + MIR groups oxymetazoline (0.5 mg/Kg, i.p.) 15 min before prazosin and prazosin (1 mg/Kg, i.p.) 15 minutes before mirtazapine and mirtazapine (30 mg/Kg, i.p.) 30 min before administration of cocaine (10 mg/kg, i.p.).

3. Results 3.1. Experiment 1: co-administration of mirtazapine and prazosin modified the induction of locomotor sensitization to cocaine The SAL, the PRZ, the MIR and the MIR + PRZ groups had no significant increases in locomotor activity (Tukey's test, N.S. p = 0.96). As shown in Fig. 1-B-C, cocaine (10 mg/kg) produced a significant increase in locomotor activity during the induction (one-way ANOVA; F = (7.1180) 323.76 p < 0.0001) and the post-induction (one-way ANOVA; F = (7.722) 390.62 p < 0.0001) phases, compared to the SAL (Tukey's test p < 0.002), the PRZ (Tukey's test p < 0.004), the MIR (Tukey's test p < 0.002), and the MIR + PRZ (Tukey's test

2.9. Statistical analysis Data were expressed as mean ± S.E.M. Locomotor activity was measured by counting beam breaks during the testing session. During the experimental phase, the results for locomotor activity in each group were analyzed with a one-way analysis of variance (ANOVA) followed by a Tukey's HSD test for post hoc comparisons. The extinction procedure was considered effective when cocaine-induced locomotor activity 140

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Fig. 3. Acute dosing of oxymetazoline disrupted the effect of the co-administration of prazosin and mirtazapine on the expression of cocaine sensitization. Experiment timeline. After habituation (Ha), the COC + PRZ, the COC + MIR, and the COC + PRZ + MIR groups received cocaine in the induction and the expression phases. During agonist, one of the COC + PRZ + MIR groups received oxymetazoline (0.5 mg/Kg, i.p.) before prazosin; prazosin (1 mg/Kg, i.p.) before mirtazapine; and mirtazapine (30 mg/Kg, i.p.) before cocaine (10 mg/kg, i.p.) (A). Oxymetazoline decreased the effect of the co-administration of prazosin and mirtazapine (B). Mean locomotor activity ( ± S.E.M.) by group (n = 8 animals per group) during agonist (C). *p < 0.01: significant effects of the oxymetazoline treatment on locomotor activity compared to the COC + PRZ, the COC + MIR, and the COC + PRZ + MIR groups.

p < 0.003), and the MIR + PRZ (Tukey's test, p < 0.002) groups. Upon withdrawal of mirtazapine and prazosin, the rats in the MIRini + COC, the PRZini + COC, and the PRZini + MIRini + COC groups showed a gradual increase in locomotor activity. Tukey's test revealed significant differences in locomotor activity in the MIRini + COC, the PRZini + COC, and the PRZini + MIRini + COC groups, compared to the SAL (Tukey's test, p < 0.002), the PRZ (Tukey's test, p < 0.004), the MIR (Tukey's test p < 0.003), the MIR + PRZ (Tukey's test p < 0.004), and the COC (Tukey's test, p < 0,001) groups (Fig. 1-D). These findings suggest that chronic co-treatment with mirtazapine and prazosin improved the persistent attenuation of cocaine-induced locomotor sensitization produced by either mirtazapine or prazosin alone.

p < 0.003) groups. Treatment with prazosin or mirtazapine during the pre-induction and the induction phases produced a long-term attenuation in cocaineinduced locomotor activity, compared to the COC group (Tukey's test, p < 0.002) (Fig. 1-C). In addition, the post hoc test found differences in locomotor activity in the MIRini + COC and the PRZini + COC groups, compared to the SAL (Tukey's test, p < 0.002), the PRZ (Tukey's test p < 0.004), MIR (Tukey's test p < 0.002), and the MIR + PRZ (Tukey's test p < 0.003) groups. Finally, significant differences were found between the MIRini + COC and the PRZini + COC (Tukey's test, p < 0.005) groups. In contrast, chronic co-administration of prazosin and mirtazapine during the pre-induction and the induction phases produced a sustained decrease in cocaine-induced locomotor activity, compared to the COC (Tukey's test, p < 0.001), the PRZini + COC (Tukey's test, p < 0.002), and the MIRini + COC (Tukey's test, p < 0.005) groups. In addition, the statistical analysis found differences between the PRZini + MIRini + COC group compared to the SAL (Tukey's test, p < 0.002), the PRZ (Tukey's test, p < 0.004), MIR (Tukey's test,

3.2. Experiment 2: co-administration of mirtazapine and prazosin modified the expression of cocaine sensitization As shown in the above experiment, 10 mg/kg cocaine significantly 141

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increased locomotor activity during the induction (one-way ANOVA; F = (7943) 413.31 p < 0.0001) and the expression (one-way ANOVA; F = (7,1457) 608.64, p < 0.0001) phases, compared to the SAL (Tukey's test, p < 0.0002), the PRZ (Tukey's test, p < 0.0003), MIR (Tukey's test, p < 0.0002), and the MIR + PRZ (Tukey's test, p < 0.0003) groups (Fig. 2-B). A post hoc test, however, found no differences between the COC and the COC + MIR (Tukey's test; N.S. p = 0.99), the COC + PRZ (Tukey's test; N.S. p = 0.96), and the COC + PRZ + MIR (Tukey's test; N.S. p = 0.45) groups (Fig. 2-C). In contrast, during the expression phase, cocaine given daily to rats previously dosed with either mirtazapine or prazosin did not increase significantly locomotor activity. A statistical analysis revealed major significant differences between the mean locomotor activity in the COC + MIR and the COC + PRZ groups, compared to the SAL (Tukey's test, p < 0.001), the PRZ (Tukey's test, p < 0.003), the MIR (Tukey's test, p < 0.002), the MIR + PRZ (Tukey's test, p < 0.003), and the COC (Tukey's test, p < 0.0001) groups (Fig. 2-D). Additionally, chronic co-treatment with mirtazapine and prazosin given to the rats in the COC + PRZ + MIR group significantly decreased cocaine-induced locomotor activity compared to the COC (Tukey's test, p < 0.0002), the COC + MIR (Tukey's test, p < 0.0003), and the COC + PRZ (Tukey's test, p < 0.0002) groups. Upon withdrawal of mirtazapine or prazosin, cocaine given daily to animals previously treated with mirtazapine, prazosin or mirtazapine + prazosin gradually increased locomotor activity (one-way ANOVA; F = (7908) 506.93 p < 0.00001). A Tukey's post hoc test revealed significant differences in mean locomotor activity in the COC + MIR, the COC + PRZ, and the COC + PRZ + MIR groups, compared to the SAL (Tukey's test, p < 0.0002), the PRZ (Tukey's test, p < 0.0003), the MIR (Tukey's test, p < 0.0001), the MIR + PRZ (Tukey's test, p < 0.0003), and the COC (Tukey's test, p < 0.0001) groups (Fig. 2B). This finding suggests that chronic co-administration of mirtazapine and prazosin during the extinction phase enhances the persistent attenuation of the expression of cocaine-induced locomotor sensitization.

Our results are also consistent with those of other rodent studies. These studies reveal that antagonism of the 5-HT2A and the 5-HT3 receptors reduces hyperactivity induced by cocaine; decreases the expression of some cocaine-induced genes; and attenuates induction of cocaine sensitization [44–46]. According to authors elsewhere, prazosin pretreatment blocks the acute locomotor response and the development of behavioral sensitization to ethanol, cocaine, or methamphetamine, while significantly reducing hypophagia, locomotor hyperactivity, and Fos expression in the striatum induced by cocaine or amphetamine, in rats [23,24,25,29,30,31,47]. Moreover, 1 mg/kg doxazosin, another alpha-1 antagonist, blocks the development and expression of cocaine-induced behavioral sensitization in rats [32]. Nevertheless, with regard to the effect of prazosin, our results differed from those reported by other researchers. Prazosin did not affect the induction of locomotor sensitization to morphine, amphetamines, or cocaine [48]. Compared to the decrease induced by either mirtazapine or prazosin alone, co-administration of mirtazapine and prazosin significantly reduced the locomotor stimulant effects of cocaine. These results are in line with previous reports that indicated that the combined administration of serotonin (PRX-07034 or ritanserin) and adrenergic receptor antagonists (including prazosin) significantly decreased the characteristic hyperlocomotion of patients with schizophrenia [49]. Still other pre-clinical studies have found that prazosin used in combination with such drugs as propranolol, a β-adrenergic receptor antagonist, or naltrexone, an opioid receptor antagonist, decreases alcohol drinking more effectively than either drug alone [50–53]. All of the above suggests that the combined use of serotonergic and adrenergic antagonists—mainly the 5-HT2 and the 5-HT3 subtypes and alpha-1 receptors— effectively produce a reduction in alterations in locomotor activity associated with drugs of abuse.

3.3. Experiment 3: acute dosing of oxymetazoline disrupted the effect of the co-administration of prazosin and mirtazapine on the expression of cocaine sensitization

The role of the serotonin and the adrenergic systems in the expression of drug-induced locomotor sensitization responses has been well documented [54,55]. The literature shows that 5-HT2A/C, 5-HT3, and alfa-1 receptors may be potential targets to treat some aspects of cocaine abuse [56,57]. In this study, we found that 30-day dosing of mirtazapine or prazosin during cocaine-withdrawal significantly attenuated the expression of cocaine-induced locomotor sensitization. This result is consistent with those of earlier mirtazapine studies: acute (30-min pretreatment) or repeated (15 daily sessions) mirtazapine administration during methamphetamine withdrawal decreased the expression of methamphetamine-induced locomotor sensitization [8,43] methamphetamine-induced place preference, and cue-induced reinstatement of methamphetamine self-administration [9–12]. We have also found that mirtazapine (30 mg/Kg) given for 30 days during the extinction phase produced a significant long-term attenuation of locomotor activity and expression of cocaine- and nicotine-induced behavioral sensitization in rats [13–15]. In addition, there are reports that treatment with 5-HT2A (ketanserin) and 5-HT3 (ondansetron) receptor antagonists for several days during drug withdrawal significantly attenuates the locomotor-stimulant effects of cocaine and the conditioned place preference. It also blocks the expression of cocaine-induced behavioral sensitization in rodents [58–63]. Prazosin or doxazosin—an antagonist of alpha1-adrenergic receptors—has proven to block the expression of behavioral sensitization to ethanol, morphine, and cocaine and to attenuate cocaine-induced reinstatement of drug seeking in rats [24,27,29,30,47]. Recently, the combination with a α1-adrenergic and 5-HT2 receptor antagonists (ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg)) was found to block behavioral sensitization to amphetamine in C57Bl6 mice

4.2. Co-administration of mirtazapine and prazosin modified the expression of cocaine sensitization

As shown in Fig. 3B-C, acute dosing of oxymetazoline in the PRZ + COC + MIR group during the agonist phase significantly increased (one-way ANOVA; F = (3820) 192.81 p < 0.00001) cocaine-induced locomotor activity. A post hoc test found differences between the OXY, the COC + PRZ, and the COC + PRZ + MIR (Tukey's test, p < 0.0001) groups, but found no differences between the OXY and the COC + MIR (Tukey's test; N.S. p = 0.84) groups. This suggests that the enhancement in attenuation induced by the co-administration of prazosin and mirtazapine is due to the synergistic effect of prazosin on mirtazapine. 4. Discussion 4.1. Co-dosing mirtazapine and prazosin modified the induction of locomotor sensitization to cocaine This study found that the single daily dosage of mirtazapine or prazosin decreased cocaine-induced locomotor activity. Further, it showed that compared to mirtazapine or prazosin alone, daily co-administration of mirtazapine (30 mg/Kg) and prazosin (1 mg/Kg) significantly decreased cocaine-induced locomotor activity and the induction of locomotor sensitization. These results are consistent with previous reports that indicate that acute mirtazapine administration decreases cocaine-induced locomotor activity and the expression of cocaine sensitization [13]. Other authors have shown that mirtazapine also decreases locomotor activity induced by morphine and methamphetamine, in rats [6,43]. 142

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Nevertheless, the decrease in locomotor sensitization generated by the combination with mirtazapine and prazosin, a critical physiological mechanism for the establishment of compulsive drug-seeking behavior, in animals and humans [39,40], supports the future use of the combination with mirtazapine-prazosin as a potential therapeutic treatment for cocaine dependence.

and to alcohol in DBA2 mice [64]. Moreover, this combination inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference [64]. The above findings are consistent with our results. We found that co-administration of mirtazapine and prazosin for 30 days during cocaine withdrawal significantly reduced the expression of cocaine sensitization, compared to either drug alone. They differ, however, from other results that indicate that a combination of pergolide—a non-selective DA agonist—and mirtazapine in rats did not decrease methamphetamine-induced behavioral sensitization [65]. In contrast, as shown by randomized, double-blind, placebo-controlled clinical trials, a combination of some serotonin reuptake inhibitors (including escitalopram, sertraline citalopram, and desipramine) and drugs such as modafinil, gabapentin, bupropion, buprenorphine, and methadone successfully reduces the effects of drugs like cocaine and opioids [66–72]. This is consistent with our results. Lastly, the literature shows that cocaine-induced dopamine release is blocked by alpha-1-adrenergic, 5-HT2A/C, and 5-HT3 antagonists [73–75]. Thus, the decrease in locomotor activity and expression of locomotor sensitization in this study was likely due to a significant decrease in cocaine-induced dopamine release produced by the antagonism of adrenergic and serotonergic receptors.

Acknowledgements This study was carried out with the support of grants INP-2040 and CONADIC-2014, and Merck-Sharp & Dohme/Schering-Plough Mexico2007. Disclosure The authors declare that there are no conflicts of interest. Authorship contributions Participated in research design: Alberto Salazar-Juárez. Conducted experiments: Alberto Salazar-Juárez, Susana Barbosa Méndez. Performed data analysis: Alberto Salazar-Juárez. Wrote or contributed to the writing of the manuscript: Alberto Salazar-Juárez.

4.3. Acute dosing of oxymetazoline disrupted the effect of the coadministration of prazosin and mirtazapine on the expression of cocaine sensitization

References

Early studies reported that the oxymetazoline was able to displace the binding of prazosin (3H) in membranes of renal tubules [76], liver, submaxillary gland [77] and brain [78]. In addition, it has been reported that alpha-1 adrenergic receptors antagonists such as prazosin were able to reverse the antinociceptive effects induced by alpha-1 adrenergic receptors agonists such as oxymetazoline [79]. Other studies have described that alpha-1 agonist not only blocks the pharmacological action of prazosin, but it also induces an increase in motor activity [37,80]. In this study we found that the acute administration of oxymetazoline decreased the behavioral effect generated by the combination of mirtazapine and prazosin on cocaine-induced locomotor activity, which is in line with the above results and suggests that prazosin is responsible for improving mirtazapine-induced effects on the expression of cocaine sensitization.

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5. Conclusions We have reported elsewhere that mirtazapine administration decreases the expression of cocaine-induced locomotor sensitization. With this study we found that prazosin when used in combination with mirtazapine enhances the effect of mirtazapine alone, since the administration of an alpha-1 adrenergic agonist blocks the effect of prazosin. We could potentially argue, that the effect induced by the combination with mirtazapine and prazosin on cocaine sensitization and cocaine-induced locomotor activity could be due to direct pharmacodynamics effects of mirtazapine or prazosin on neural systems (i.e., noradrenergic and serotonergic) involved in modulating reinforcement and motivation for cocaine-behaviors. Thus, the combined action of mirtazapine on alpha-2 adrenergic receptors, 5-HT2 and 5-HT3 receptors and prazosin on alpha-1 adrenergic receptors expressed in the nucleus accumbens, prefrontal cortex, and the ventral tegmental area could be responsible for the decrease in locomotor activity and sensitization cocaine. However, one limitation of this study is that it lacks assessments describing the effect of co-administration of mirtazapine and prazosin at the neurochemical and histological level, which support the behavioral observations described above. 143

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