The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice

Abstract

Over 800,000 Americans abuse the psychomotor stimulant, methamphetamine, yet its abuse is without an approved medication. Methamphetamine induces hypermotor activity, and sensitization to this effect is suggested to represent aspects of the addiction process. Methamphetamine's regulation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels may be partially responsible for its behavioral effects, and compounds that inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP, can alter methamphetamine-induced behaviors. Methamphetamine also activates glial cells and causes a subsequent increase in pro-inflammatory cytokine levels. Modulation of glial cell activation is associated with changes in behavioral responses, and substances that oppose inflammatory activity can attenuate drug-induced behaviors. Ibudilast (aka AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), inhibits both PDE and glial pro-inflammatory activity. Ibudilast's amino analog, AV1013, modulates similar glial targets but negligibly inhibits PDE. The present study determined whether ibudilast and AV1013 would attenuate methamphetamine-induced locomotor activity and its sensitization in C57BL/6J mice. Mice were treated b.i.d. with ibudilast (1.8-13 mg/kg), AV1013 (10-56 mg/kg) or their vehicles intraperitoneally for 7 days, beginning 48 h before 5 days of daily 1-h locomotor activity tests. Each test was initiated by either a methamphetamine (3 mg/kg) or a saline injection. Ibudilast significantly (P<0.05) reduced the acute, chronic, and sensitization effects of methamphetamine's locomotor activity without significantly affecting activity by itself. AV1013 had similar anti-methamphetamine effects, suggesting that glial cell activity, by itself, can modulate methamphetamine's effects and perhaps serve as a medication target for its abuse.

Fig. 1

Upper frame: Results on distance travelled (cm) by mice treated b.i.d. for seven days with ibudilast (IBUD) or its vehicle (VEH1), beginning two days before five days of treatment with 3 mg/kg methamphetamine. Ibudilast was administered at 1.8, 7.5, or 13 mg/kg. Data points represent group means (±S.E.M.) obtained during 1-h experimental sessions. Filled data points represent sessions preceded by 3 mg/kg i.p. methamphetamine injections. Unfilled data points represent sessions preceded by i.p. saline injections. N=8 for each treatment group. *P<0.05 with respect to mice treated with ibudilast's vehicle. Lower frame: Results on distance travelled (cm) by mice treated b.i.d. for seven days with ibudilast (IBUD) or its vehicle (VEH1), beginning two days before four days of saline administration and acute treatment with 3 mg/kg methamphetamine on the fifth day. Ibudilast was administered at 1.8, 7.5, or 13 mg/kg. Data points represent group means (±S.E.M.) obtained during 1-h experimental sessions. Other details are as in the upper frame.

Fig. 2

Upper frame: Results on distance travelled (cm) by mice treated b.i.d. for seven days with AV1013 or its vehicle (VEH2 for 10 and 30 mg/kg and VEH1 for 56 mg/kg), beginning two days before five days of treatment with 3 mg/kg methamphetamine. AV1013 was administered at 10, 30, or 56 mg/kg. *P<0.05 with respect to mice treated with AV1013's vehicle. Other details are as in Figure 1. Lower frame: Results on distance travelled (cm) by mice treated b.i.d. for seven days with AV1013 or its vehicle (VEH2 for 10 and 30 mg/kg and VEH1 for 56 mg/kg), beginning two days before four days of saline administration and acute treatment with 3 mg/kg methamphetamine on the fifth day. Other details are as in the upper frame.