Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption

Abstract

Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.

Figures

Figure 1

Illustration of the tDCS device used to deliver the current stimulation. (a) The mouse is placed in a custom-made restraint box. The anode (contact area 3.5 mm2) is positioned over the left frontal cortex and the cathode (rubber-plate electrode, 9.5 cm2) onto the ventral thorax. A 2 × 20 min/day constant current of 0.2 mA is applied transcranially using a direct current stimulator (DC-Stimulator Plus) for five consecutive days, with a linear fade in/fade out of 10s. (b) The center of the electrode is positioned over the left frontal cortex 1 mm anterior to the coronal fissure and 1 mm left of the sagittal fissure (adapted from Paxinos and Franklin, 2001). (c) Anode: a tubular plastic jacket (internal diameter: 2.1 mm) is surgically fixed onto the skull and filled with saline solution before the stimulation. The stimulation electrode is screwed into the tubular plastic jacket and dip in the saline solution. Only the saline solution is in contact with the skull.

Figure 2

Experiment 1. (a) Experimental design. Four-month-old Swiss female mice never exposed to nicotine were subjected to repeated anodal tDCS for five consecutive days (2 × 20 min/day constant current, 0.2 mA). Behavioral effects of tDCS were screened from 3 days to 5 weeks following the last electrical stimulation. The same animals were used in all behavioral tests (sham N=8, tDCS N=8) except in the CPP test at 3 days for which another batch of mice was used (sham N=10, tDCS N=10). EPM: elevated plus maze, FST: forced swim test, CPP: conditioned place preference, NiC: nicotine. Effect of repeated anodal tDCS on (b) locomotor activity, (c) anxiety-related behavior, (d) depression-related behaviors, and (e) addiction-related behavior 3 days and 3–5 weeks following the last electrical stimulation. (f) Effect of repeated anodal tDCS on working memory 4 weeks after the last stimulation and (g) effect of repeated anodal tDCS on long-term spatial memory (training, left; test, right) 2 weeks after the last stimulation. *p<0.05 and **p<0.01 vs sham, °°p<0.01 3 days vs 3 weeks, #p<0.05 and ##p<0.01 vs 0%, §§§p<0.001 vs 50%, &p<0.05 and &&p<0.01 vs 25%.

Figure 3

Experiment 2. (a) Experimental design. Adolescent mice were treated twice a day for 14 consecutive days with nicotine (1 mg/kg i.p.) postnatal day (PND) 30–43. Control mice were injected with NaCl 0.9% following the same schedule. Nicotine and NaCl-treated animals were submitted to repeated anodal tDCS or sham stimulations for five days (PND 60–64). Animals were then tested for locomotor activity, anxiety- and depression-related behaviors, and for their sensitivity to the rewarding effects of nicotine. CPP, conditioned place preference; EPM, elevated plus maze; FST, forced swim test; NiC, nicotine. NaCl-sham (N=10), NiC-sham (N=9), NiC-tDCS (N=10). (b) Effect of nicotine exposure during adolescence and subsequent repeated anodal tDCS on locomotor activity, (c) anxiety-related behavior, (d) depression-related behaviors, and (e) addiction-related behavior 3 days and 3-4 weeks following the last electrical stimulation. *p<0.05 and **p<0.01 vs NaCl-sham or as indicated, #p<0.05 and ###p<0.001 vs 0%.