Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine

Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT3 antagonist ondansetron or non-selective 5-HT2A/2C antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0–6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10 mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide–mirtazapine combination was ineffective. The role of reactivation of addiction “circuit” by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT3 or 5-HT2 antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.

► Psychostimulant abuse exerts profound socioeconomic, legal and medical problems.
► More than two-dozen medications tested in humans with limited success.
► Efficacy of drug combinations determined for reversing methamphetamine sensitization in rats.
► Ondansetron or ketanserin but not mirtazapine is effective when combined with pergolide.
► Therapeutic erasure of dysfunctional memory may be achieved with drug combination treatments.