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-hour 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 2 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-hour 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.

Fig. 1

Upper panel, “A”: Mean number of active lever presses during the footshock-induced reinstatement test session as a function of AV411 dose. Brackets through the bars indicate ±S.E.M. “VEH” = results of the vehicle-treatment group. Dashed horizontal lines indicate the range of the means of active lever presses across dosage groups occurring during the last session of extinction. Asterisks (*) indicate significantly different (P<0.05) from vehicle. Lower panel, “B”: Mean number of inactive lever presses during the footshock-induced reinstatement test session as a function of AV411 dose. Other details as in the upper panel.

Fig. 2

Upper panel, “A”: Mean number of active lever presses during the methamphetamine-prime reinstatement test session as a function of AV411 dose. Brackets through the bars indicate ±S.E.M. “VEH” = results of the vehicle-treatment group. Dashed horizontal lines indicate the range of the means of active lever presses across test groups occurring during the last session of extinction. Asterisk (*) indicates significantly different from vehicle (P<0.05). Lower panel, “B”: Mean number of inactive lever presses during the methamphetamine-prime reinstatement test session as a function of AV411 dose. Other details as in the upper panel.