The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse

Abstract

Stress and renewed contact with drug (a “slip”) have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior. Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 (FR1) reinforcement schedules during daily, 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions and doses of 0 (vehicle), 2.5 and 7.5 mg/kg AV411 were then administered intraperitoneally b.i.d. on the last two days of extinction and then once on the testday to separate groups of 12 rats. During testing, the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-h reinstatement test session. AV411 significantly reduced response levels of footshock-induced (2.5 and 7.5 mg/kg) and prime-induced (7.5 mg/kg) reinstatement of extinguished methamphetamine-maintained responding. AV411 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine “slips” during abstinence. These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders.

Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats

“…To date, the research by Beardsley and colleagues has provided some of the best preclinical evidence for the potential utility of ibudilast in treatment of methamphetamine abuse and relapse (Beardsley et al, 2010;Snider et al, 2013). For example, Snider et al (2013) found that 7.5 and 10 mg/kg ibudilast attenuated methamphetamine intake.…”

“…Studies have shown the potential of this drug in reducing neuroinflammation in a number of neurological conditions such as relapsing-remitting multiple sclerosis (Barkhof et al, 2010), Tat-induced neurotoxicity (Kiebala and Maggirwar, 2011), potentiation of opioid analgesia (Hutchinson et al, 2009), and attenuation of methamphetamine-taking and relapse in animal models (Beardsley et al, 2010;Snider et al, 2013). At present, it is unknown how ibudilast impacts the synapse-a key structure involved in neurotransmission and neuroplasticity.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Ibudilast, commonly used in the treatment of asthma, inhibits PDE activity and possesses anti-inflammatory and neuroprotective effects (Rolan et al, 2009). Systemic administration of ibudilast inhibits ethanol (Bell et al, 2015) and methamphetamine intake (Snider et al, 2013), sensitization of the locomotor response to methamphetamine (Snider et al, 2012), as well as stress-and drug-primed reinstatement of methamphetamine seeking (Beardsley et al, 2010). Ibudilast also reduces morphine withdrawal and CPP, likely as a result of its ability to reduce morphine-induced dopamine release in the NAc (Rolan et al, 2009;Schwarz and Bilbo, 2013).…”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…In the MA-reinstatement model, rats were trained to lever press for MA after which MA infusions were discontinued and lever pressing extinguished. IBUD significantly reduced MA prime-and stress-induced reinstatement of active lever pressing (Beardsley, Shelton, Hendrick, & Johnson, 2010) suggesting that IBUD may be effective in reducing relapse during clinical treatment for MA dependence. While both high and low IBUD doses reduced stress-induced reinstatement, only the higher IBUD dose reduced prime-induced reinstatement.…”