The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice

doi:10.1016/j.pbb.2004.03.004

Pharmacology Biochemistry and Behavior

Volume 78, Issue 1, May 2004, Pages 135-141

https://doi.org/10.1016/j.pbb.2004.03.004 Get rights and content

Abstract

It has been shown that the alpha-adrenergic system is involved in some effects of opioids, including analgesia and reward. Gender differences also exist between males and females in response to alpha-adrenergic agents. This study was designed to determine the effects of alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) in female mice. The experiments showed that subcutaneous injections of morphine (0.5–8 mg/kg) induced CPP in a dose-dependent manner in mice. Intrapritoneal administration of the alpha-1-adrenoceptor agonist, phenylephrine (0.03, 0.1 and 0.3 mg/kg), and alpha-2 adrenoceptor agonist, clonidine (0.0001, 0.0005 and 0.001 mg/kg), as well as alpha-1-adrenoceptor antagonist, prazosin (0.01, 0.05 and 0.1 mg/kg) or alpha-2 adrenoceptor antagonist, yohimbine (0.005, 0.01 and 0.05 mg/kg) did not induce motivational effects and also did not alter locomotor activity in the animals. In the second set of experiments, the drugs were used before testing on Day 5, to test their effects on the expression of morphine-induced CPP. Intrapritoneal administration of phenylephrine and clonidine decreased the expression of morphine-induced CPP. In contrast, after application of prazosin or yohimbine, the expression of morphine-induced CPP was increased. Administration of lower (0.03 mg/kg) and higher doses of phenylephrine (0.1 and 0.3 mg/kg) during acquisition of morphine CPP decreased and increased the morphine CPP, respectively. Similarly, the administration of prazosin and clonidine decreased while yohimbine increased the morphine CPP. It may be concluded that alpha-adrenoceptor mechanism(s) influence morphine-induced CPP in female mice.

Introduction

Several studies have shown that the alpha-adrenergic and opioid systems can interact in a complex manner. For example, opioids have been shown to inhibit noradrenergic activity in the hippocampus (Matsumoto et al., 1994), cortex (Werling et al., 1987) and the locus ceruleus of the rat (Sklair-Tavron et al., 1994), and also cynomolgus monkeys (Aston-Jons et al., 1992). Morphine also tends to inhibit noradrenaline release from human neuroblastoma cells (Atcheson et al., 1994). There are also reports showing that opioids increase the turnover of norepinephrine (Brazell et al., 1991).

The noradrenergic and opioid systems have been shown to be involved in the development and expression of opioid dependence (for review, see Maldoado, 1997). The rats tolerant to the antinociceptive effects of morphine show cross-tolerance to the effect of norepinepherine (Milne et al., 1985) and alpha-2 adrenoceptor agonist, clonidine (Solomon and Gebhart, 1988). Furthermore, rats tolerant to the antinociceptive effect of clonidine show cross-tolerance to the effects of morphine (Paalzow, 1978). Clonidine also attenuates some of the signs of morphine withdrawal in rats (Kosten, 1994) as well as the signs of morphine withdrawal in humans (Gold et al., 1987). Acute administration of the adrenoceptor antagonist, yohimbine, increases the physical effects of morphine withdrawal in rats (Dwoskin et al., 1983), suggesting that alpha-2 adrenoceptors are involved in the development of physical dependence upon opioids (Iglesias et al., 1992). It has also been shown that signs of discriminative-stimulus (Hughes et al., 1996) and development of conditioned opiate withdrawal effects of morphine (Schulteis et al., 1998) may be enhanced by clonidine.

The conditioned place preference (CPP) paradigm has been widely used as a model for studying the reinforcing effects of drugs of dependence and addiction McBride et al., 1999, Tzschentke, 1998. Considerable evidence indicates that alpha-2 adrenergic agonists and antagonists can induce CPP or conditioned place aversion (CPA; see review, Tzschentke, 1998). Morphine-induced CPP may be related to dopaminergic mechanism(s) (Rezayof et al., 2002). Several studies in mice and rats revealed the existence of interactions between adrenergic and dopaminergic systems Lategan et al., 1990, Shi et al., 2000, Drouin et al., 2002. It has been also postulated that there is a difference between male and female animals in response to morphine (Cicero et al., 2000) and alpha-adrenergic agents Luzier et al., 1998, Turner et al., 1999; therefore, in the present study, the effects of alpha-1 and alpha-2 adrenoceptors on the expression and acquisition of morphine CPP in female mice has been studied.

Section snippets

Animals

Experiments were carried out on female Swiss–Webster mice (n=8 per group) weighing 20–30 g (Pasture Institute, Tehran, Iran). The animals were group housed (eight per cage) at a constant temperature of 22–24 °C, on a 12:12-h light/dark cycle (light period 0700–1900 h). Standard laboratory mouse chow and water were available at all times except during experimentation. The animal Ethics Committee of the Baghyatallah (a.s.) University of Medical Sciences Research Department approved all of the

Effects of morphine and alpha-adrenoceptor drugs on behavior in the CPP paradigm

The effects of morphine, phenylephrine, prazosin, clonidine and yohimbine have been shown in Fig. 1. Injection of different doses of morphine sulphate (1.0, 2.0, 4.0 and 8.0 mg/kg) to mice caused a significant increase in time spent in the drug-paired compartment compared to that spent in the saline-paired compartment [F(4,35)=5.5, P<.002]. Subcutaneous injection of saline to the animals (saline control group) in the conditioning compartments did not produce any preference or aversion for

Discussion

In the present study, morphine administration to female mice induced CPP in a dose-related manner. Because the method used is not state-dependent learning (see review, Tzschentke, 1998), all the animals were tested in drug-free state. These results are in agreement with those obtained by others in both male and female mice (see review, Tzschentke, 1998, Zarrindast et al., 2002, Zarrindast et al., 2003). It is likely that dopamine mesocorticolimbic systems and μ-opioid receptors in these regions

Acknowledgements

This work was supported by the grant from Department of Research, Baghyatallah (a.s.) University of Medical Sciences, and Behavioral Science Research Center (BSRC). The authors thank J. Nichols for his collaboration in the preparation of this manuscript.

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The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α₁ adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α₁ adrenoceptor antagonist, was microinjected into the VLO. The expression of α₁ adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α₁ adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α₁ adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.
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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].
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.
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Importantly, the attenuation of CPP elicited by the disruption of NE signaling does not appear to be related to generalized failures in learning given DBH knockout mice are capable of expressing CPP for food and conditioned taste aversion to lithium chloride (Weinshenker et al., 2000; Olson et al., 2006; Schank et al., 2006). In contrast to the effects of NE disruption, enhanced NE signaling in NET knockouts or via α2-antagonist treatment increases CPP for psychostimulants and opiates (Xu et al., 2000; Zarrindast et al., 2002; Sahraei et al., 2004). Despite this evidence, several other studies indicate that disruptions to NE signaling fail to alter cocaine or ethanol self-administration (Roberts et al., 1977; Richardson and Novakovski, 1978; Wee et al., 2006).
Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α₁- and β-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse.
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Second, given the suppression of LC firing produced by autocrine release of galanin discussed earlier, one might predict that NE depletion would phenocopy increased galanin transmission; indeed, this is the case in many instances. For example, like transgenic galanin overexpression or galanin receptor agonist administration, selective suppression of NE transmission via knockout of α1-adrenergic receptors or the NE biosynthetic enzyme dopamine β-hydroxylase, 6-OHDA lesions, or the administration of adrenergic receptor antagonists can attenuate the rewarding effects of morphine and withdrawal symptoms (Drouin et al., 2002; Maldonado, 1997; Mazei-Robison and Nestler, 2012; Olson et al., 2006; Sahraei et al., 2004; Ventura et al., 2005; Weinshenker and Schroeder, 2007; Zarrindast et al., 2002). Similar to manipulations of galanin itself, suppression of NE transmission has no effect for the most part on operant psychostimulant self-administration, but we and others have shown that psychostimulant conditioned place preference and reinstatement are also reduced upon blockade of NE signaling (Leri et al., 2002; Mantsch et al., 2010; Schroeder et al., 2010, 2013; Smith and Aston-Jones, 2011; Ventura et al., 2007; Vranjkovic et al., 2014; Wee et al., 2008; Weinshenker and Schroeder, 2007; Zhang and Kosten, 2005, 2007) (our unpublished data).
Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer׳s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively.
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For example, clonidine, tizanidine and xylazine, alpha-2 adrenergic agonists, have been proposed to decrease morphine-induced CPP in mice [26]. In another study, it was shown that phenylephrine, a selective alpha-1 antagonist, and clonidine decreased morphine-induced CPP and that prazosin and yohimbine, selective alpha-1 and alpha-2 antagonists respectively, increased morphine-induced CPP in mice [27]. Thus, the contribution of alpha-2 receptors to CPP is still being debated.
Dexmedetomidine (DEX) is an alpha-2 adrenergic agonist drug recently introduced to anesthesia practice. Certain agents used in anesthesia practice have been associated with abuse and addiction problems; however, few studies have investigated the role of DEX on addictive processes. Here, the effects and possible mechanisms of action of DEX on conditioned place preference (CPP), a model used for measuring the rewarding effects of drug abuse in rats, was investigated. The CPP apparatus was considered “biased” as the animals preferred the grid side to the mesh side. Male Wistar albino rats weighing 250–300 g were divided into several groups, including control (saline), morphine (10 mg/kg), DEX (2.5–20 μg/kg), naloxone alone (0.5 mg/kg) and a combination (0.5 mg/kg naloxone plus 20 μg/kg DEX) (n = 7–8 for each group). The CPP effects of morphine, DEX, saline and the combination were evaluated. All the drug and saline administrations except naloxone were performed by intraperitoneal (ip) injections. Naloxone was injected subcutaneously (sc) when given alone or in combination with DEX. Morphine (10 mg/kg) and DEX (5–20 μg/kg) produced CPP that were statistically significant relative to saline-injected rats. DEX-induced CPP was significantly reversed by pretreatment with naloxone, an opioid antagonist. Naloxone alone treatment did not cause any significant effect on CPP. Our results suggest that DEX produces CPP effects similar to morphine in rats and that opioidergic mechanism may be responsible for DEX-induced CPP. Thus, DEX might have the potential to be addictive, and this possibility should be considered during clinical application of this drug.
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Previous studies have demonstrated that α2-adrenoceptor agonists produce dose dependent analgesia in animals (Fairbanks et al., 2002; Pertovaara, 1993). Clonidine, an α2-adrenoceptor agonist, produces analgesia (Congedo et al., 2009) that can be blocked by yohimbine, a selective α2-adrenoceptor antagonist (Gulati et al., 2009; Sahraei et al., 2004). In addition, studies have shown, that clonidine potentiates the antinociceptive effect produced by morphine and oxycodone in rats (Gulati et al., 2009).
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The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice

Abstract

Introduction

Section snippets

Animals

Effects of morphine and alpha-adrenoceptor drugs on behavior in the CPP paradigm

Discussion

Acknowledgements

Br. J, Anaesth.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res. Rev.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Behav. Brain Res.

Pain

Pharmacol. Biochem. Behav.

Neuropsychopharmacology

Prog. Neurobiol.

Neurophramacology

Pharmacol. Biochem. Behav.