Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice

Abstract

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/Kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/Kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/Kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/Kg) rescued visual memory retention to control values. We also measured ERK phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 hr before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated Extracellular signal-regulated kinase (ERK) phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects (p<0.05). The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/Kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls (p<0.05). We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or nucleus accumbens (NAc) of vehicle- and METH-treated mice receiving acute 90 mg/Kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions.

Regulatory Effect of Bee Venom on Methamphetamine-Induced Cellular Activities in Prefrontal Cortex and Nucleus Accumbens in Mice

“…In support of a pivotal role of ERK phosphorylation in the PFC, some promising antiaddictive drugs have been shown to improve METH-induced behavioral changes through normalizing ERK phosphorylation in the PFC. 8,23) In contrast, our previous 6) and current studies show that single or chronic administration of METH significantly decreases CaMKII phosphorylation in the PFC and that this change was significantly reversed by either dopamine D1 receptor antagonist or N-methyl-D-aspartate receptor antagonist.…”

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

“…For example, Reichel et al (2010) reported that self-administration of methamphetamine in an extended access model (6 h/day), following by a week of abstinence, produced memory deficits in object-recognition. Reichel et al further found that treatment with modafinil, a pro-cognitive drug that has anti-neuroinflammatory effects (González et al, 2014;Raineri et al, 2012), reversed this deficit. Extinction reflects new learning regarding nonreinforcement that competes, in part, with previous learning (Bouton et al, 2012).…”

Methamphetamine blunts Ca2+currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex

“…All drugs were diluted with 0.9% saline. We have selected the METH dose based on previous studies showing that repeated non-contingent 7 days METH treatment (1 mg/kg) was able to induce cognitive impairments associated with deficits of the ERK1/2 pathway in the mPFC (González et al, 2014; also see Kamei et al, 2006). In the present study, METH was administered subcutaneously (s.c.) once a day for 7 days (1 mg/Kg, calculated as free base).…”