Behavioural PharmacologyThe glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse
Introduction
Glial cells (astrocytes, microglia and oligodendrocytes) constitute the majority of cells in the central nervous system (CNS), with the remaining cells being neurons. The glia contain receptors (e.g., Fumagalli et al., 2003, Khan et al., 2001, Kukley et al., 2001, Parpura et al., 1994), secrete neurotransmitters, neurotrophic and neuroinflammatory factors (Benz et al., 2004, Bezzi et al., 1998, Kang et al., 1998, Parpura et al., 1994, Watkins et al., 2007), control clearance of neurotransmitters from synaptic clefts (Camacho and Massieu, 2006), and are involved with synaptic plasticity (e.g., Ullian et al., 2004). Given these multiple modes of controlling neurological functions, it is not surprising that glia and their secretions have been reported to modulate the effects of drugs of abuse, or these drugs have been reported to modulate glial function (e.g., Fantegrossi et al., 2004, LaVoie et al., 2004, Narita et al., 2006, Song & Zhao, 2001, Suzuki et al., 2007, Thomas et al., 2004b, Watkins et al., 2005, 2007). Particularly provocative have been reports that glial cell line-derived neurotrophic factor (GDNF), which glial cells release and for which they also serve as a target, have been reported to block conditioned place preference (CPP) induced by methamphetamine (Niwa et al., 2007c) and cocaine (Messer et al., 2000), and sensitization to methamphetamine's effects (Niwa et al., 2007c).
Phosphodiesterase (PDE) activity, which modulates cAMP levels within CNS cells including glia, can also influence the effects of abused drugs. For instance, the selective inhibitor of PDE 4, rolipram, attenuates many of methamphetamine's effects, as well as the discriminative stimulus and hyperlocomotor effects of morphine (Iyo et al., 1996Iyo et al., 1995, Mori et al., 2000, Yan et al., 2006).
AV411 (aka, ibudilast) (3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) is a non-selective PDE inhibitor preferentially targeting PDE's 3, 4, 10, and 11 (Gibson et al., 2006). AV411 modulates the activity of microglia and astroglia, suppressing the lypopolysaccharide (LPS) and interferon-gamma (IFN-γ) production of inflammatory tumor necrosis factor-alpha (TNF-α), interleukins IL-1β and IL-6, and nitric oxide (NO), while increasing the productions of nerve growth factor, GDNF, neurotrophin-4 and anti-inflammatory cytokine IL-10 (Kawanokuchi et al., 2004, Mizuno et al., 2004, Suzumura et al., 1999). Administration of AV411 attenuates several of morphine's effects including its activation of brain microglia and astrocytes, and its induction of elevated dopamine levels, CPP, tolerance and dependence (Hutchinson et al., 2007Hutchinson et al., 2009, Ledeboer et al., 2007). Because AV411 does share in these biochemical effects reported to modulate the pharmacology of methamphetamine (e.g., Iyo et al., 1996Iyo et al., 1995, Mori et al., 2000, Narita et al., 2006, Niwa et al., 2007a, Yan et al., 2006, 2007), as well as its already reported ability to modulate the effects of another drug of abuse, morphine (Hutchinson et al., 2007Hutchinson et al., 2009, Ledeboer et al., 2007), we tested whether AV411 could attenuate prime- and stress-induced reinstatement of extinguished responding in rats previously reinforced with methamphetamine.
Section snippets
Subjects
Adult male Long–Evans hooded rats (Harlan, Indianapolis, IN) weighing 275–300 g at the start of studies were acclimated to the vivarium for at least 1 week prior to catheter implantation. When not in testing, rats were individually housed in standard plastic rodent cages in a temperature-controlled (22 °C), in an American Association of Animal Laboratory Care-accredited facility in which they had ad libitum access to water. The rats were allowed ad libitum rat chow for at least 1 week prior to the
Stress reinstatement tests
Grubb's Test analyses identified one rat in the 7.5 mg/kg AV411 stress-reinstatement group as an outlier (z = 2.93) and its data were excluded from subsequent analyses. The mean numbers (± S.E.M.) of active lever presses during the last day of self-administration for the vehicle, 2.5 mg/kg AV411 and 7.5 mg/kg AV411 groups were 47.00 (± 7.65), 48.00 (± 5.39) and 54.17 (± 7.85), respectively, and were non-significantly different amongst one another, indicating that the rats had been trained to
Discussion
The footshock conditions used in this study effectively reinstated responding previously reinforced with methamphetamine in vehicle-treated rats. To our knowledge, there has only been one other published report in which footshock has been used to reinstate responding previously reinforced with methamphetamine, and that was by Shepard et al. (2004). The conditions used in that study were different in many ways compared to the present study, although the strain of rat (Long–Evans hooded),
Conclusions
In the current studies, AV411 was shown to effectively attenuate stress-induced and prime-induced reinstatement of extinguished responding previously reinforced with methamphetamine. These results are consistent with a growing literature which indicates that PDE inhibitors and glial cell modulators, including those which increase GDNF levels, can modulate the effects of the drugs of abuse. In tandem with recent studies with opioids, the current results reinforce interest in under-recognized
Disclosure statement
Research was conducted under support by the National Institute on Drug Abuse contract N01DA-4-8848 to P. M. B. Throughout all testing, laboratory personnel were blinded to test compounds and to their nature. Subsequent to the completion of testing, P. M. B. has served as a consultant to Avigen Inc. K. W. J. is an employee of Avigen, Inc.
Acknowledgements
The authors wish to thank Dr. Frank Vocci of Friends Research Institute and Drs. David McCann and Jane Acri of the National Institute on Drug Abuse for their substantive scientific input regarding the execution of these studies.
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