The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

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Abstract

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1 h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+ h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.

Introduction

Opioids, including morphine, are critical for pain management but are highly rewarding and for some individuals their use can lead to a lifelong cycle of addiction, withdrawal, and relapse. Opioid abuse is an increasing problem worldwide and the reinforcing effects of opioid analgesics makes them susceptible to diversion and illicit use and abuse (Compton and Volkow, 2006). Although the traditional view of opioid actions is that they are neurally-mediated, recent research has suggested an important modulatory role for glia (astrocytes and microglia) in opioid actions, particularly in the areas of analgesia, tolerance, and dependence (Hutchinson et al., 2007). Moreover, glia may be involved in reward. A key finding in this regard was that of Narita et al. (2006) who demonstrated that microinjection of astrocyte conditioned media in the anterior cingulate cortex and the nucleus accumbens (NAc), but not the caudate putamen, enhanced morphine conditioned place preference (CPP), a well characterized measure of the motivational effects of various drugs (Tzschentke, 2007).

The importance of both microglia (Banati, 2002) and astrocytes (Araque et al., 1999) in modulating plasticity has been increasingly appreciated and current thinking about addiction embraces the notion of addiction as a form of experience-dependent plasticity (Hyman et al., 2006). Work in our laboratory has shown that a repeated, escalating regimen of morphine induces the activation of both microglia and astrocytes in regions associated with reward including the ventral tegmental area (VTA), prefrontal cortex, and NAc (Hutchinson et al., 2007). Furthermore, the morphine-induced activation of both microglia and astrocytes that was observed in the VTA, the source of dopamine (DA) cells that project to the prefrontal cortex and NAc, was potently inhibited by the coadministration with morphine of the glial activation inhibitor AV411 (ibudilast) (Hutchinson et al., 2007). Moreover, AV411 also reduced somatic signs of precipitated withdrawal using the same dosing regimen (Ledeboer et al., 2007). AV411 is a blood–brain barrier permeable nonspecific phosphodiesterase (PDE) inhibitor that has been used in Japan for asthma and post-stroke dizziness (Ledeboer et al., 2007) and may be an effective treatment for addiction if reward processes are attenuated. Activated glia release excitatory substances including proinflammatory cytokines (Streit et al., 1999), nitric oxide (NO) (Sparrow, 1994), prostaglandins (Tzeng et al., 2005), and excitatory amino acids (Araque et al., 1998) that could enhance the excitability of VTA dopamine neurons. This glial release of excitatory products might increase dopamine release in projection regions such as the NAc. AV411 is known to decrease or inhibit glial production of proinflammatory cytokines, chemokines and growth factors as well as NO (Ledeboer et al., 2007), and may thus reduce VTA excitability.

The goals of the current studies were to determine if AV411 coadministered with morphine would impact nucleus accumbens dopamine (DA) and whether this would be related to withdrawal signs. First, we measured DA in the NAc shell in morphine-dependent rats treated with AV411 or vehicle. It is generally accepted that the rewarding properties of addictive drugs is due to increased DA in the NAc (see Di Chiara and Bassareo, 2007 for review), and NAc DA has also been implicated in opioid withdrawal (Harris and Aston-Jones, 1994). Dependence was induced using an escalating morphine regimen, and dependence was confirmed by measuring somatic signs of naloxone-precipitated withdrawal. Microdialysis was performed during both the morphine challenge as well as naloxone treatment, in animals receiving either AV411 or vehicle. In a separate experiment, the persistence of morphine-induced dopamine release in the NAc shell was measured in AV411- or vehicle-treated rats.

Section snippets

Animals

Adult, male Sprague–Dawley rats (Harlan, Inc., Indianapolis, IN) weighing 275–350 g were pair-housed in standard Plexiglas cages with food and water freely available. Rats were maintained in a climate-controlled colony at 21° C on a 12 h light–dark cycle. All experiments were conducted during the light phase. Rats acclimated to the colony for 2 weeks prior to any procedures. All procedures were in accordance with protocols approved by the University of Colorado Institutional Animal Care and Use

Experiment 1: AV411 attenuated morphine-induced NAc DA and naloxone-precipitated withdrawal behaviors

Morphine produced an increase in NAc DA efflux, and this increase was reduced by AV411 (Fig. 2A). Naloxone precipitated potent withdrawal, and this was blunted by AV411 (Fig. 2B). Finally, there was a relationship between peak DA levels and magnitude of somatic withdrawal (Fig. 2C). With regard to extracellular DA, ANOVA revealed a significant drug group × time interaction, F(11, 110) = 2.31, p = .01. Post hoc tests indicated that DA levels were greater in vehicle-treated rats at 20, 40, and 60 min

Discussion

Products of glial activation can modulate diverse effects of opioids (Watkins et al., 2005, Watkins et al., 2007), and it has previously been reported that the glial activation and PDE inhibitor AV411 (ibudilast) reduced the somatic signs of withdrawal (Ledeboer et al., 2007). The present results show that AV411 attenuates neurochemical and behavioral indicators of both morphine dependence and reward. A novel finding here is that morphine-induced DA release in the NAc shell is reduced by

Acknowledgments

Supported by Avigen, Inc., NIH Grants DA013159 (S.F.M.), DA015642 (L.R.W.), and DE017782 (L.R.W.), and NARSAD (S.T.B.). We wish to thank Christina Zarza and Jacob Beckley for excellent technical assistance.

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