Behavioral and Neural Substrates of Habit Formation in Rats Intravenously Self-Administering Nicotine

Abstract

Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behavior that becomes increasingly resistant to quitting. The development of smoking habits may reflect a loss of behavioral control that can be modeled in rats. This study investigated the behavioral and neural substrates of habit formation in rats exposed to either brief (10 days) or extended (47 days) intravenous (IV) nicotine self-administration training. Following training, the first cohort of rats were exposed to a nicotine devaluation treatment, which involved repeated pairings of IV nicotine with lithium injection. They were then tested for sensitivity of responding to nicotine devaluation under extinction and reinstatement conditions. The second cohort of rats received equivalent self-administration training followed by processing of brain tissue for c-Fos immunohistochemistry. After brief training, devaluation suppressed nicotineseeking during tests of extinction and reinstatement, confirming that responding is initially sensitive to current nicotine value, and therefore, goal directed. In contrast, after extended training, devaluation had no effect on extinction or reinstatement of responding, indicating that responding had become habitual. Complementary neuroanalysis revealed that extended nicotine self-administration was associated with increased c-Fos expression in brain regions implicated in habitual control of reward seeking, including activation of the dorsolateral striatum and substantia nigra pars compacta. These findings provide evidence of direct devaluation of an IV drug reward, that nicotine self-administration is initially goal-directed but becomes habitual with extended training, and that this behavioral transition involves activation of brain areas associated with the nigrostriatal system.

Nicotine self‐administration remodels perineuronal nets in ventral tegmental area and orbitofrontal cortex in adult male rats

“…However, as expected, nicotine self-administration increased c-Fos expression in NAc (shell and core) 45 min after the last session. In agreement with this, previous studies have shown that nicotine self-administration increases c-Fos immunoreactivity 30 min after the last session in each of these reward-relevant brain regions (Clemens et al, 2014). There was also a rebound decrease in c-Fos activity obtained in NAc shell at 72 hr in the current study.…”

“…Nicotine excites GABA neurons and enhances GABAergic transmission transiently (Alkondon et al, 2000). Nicotine not only affects the activity of DA neurons through its actions on the inhibitory GABA neurons (Erhardt et al, 2002), but it also enhances glutamatergic transmission, with the net effect being a shift toward excitation of the DA reward system (Clemens et al, 2014). However, little is known about the morphological and structural changes induced in the VTA after nicotine self-administration.…”

Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On

“…This demonstration was later confirmed and extended by Zapata et al (2010), who showed additionally that cocaine-seeking behavior became insensitive to devaluation, i.e., habitual, after extended training (Zapata et al 2010). This effect of extended training to promote habitual drug seeking has further been shown in rats self-administering nicotine (Clemens et al 2014).…”

“…Early demonstrations of the rapid resistance to devaluation of oral cocaine or alcohol (Dickinson et al 2002, Miles et al 2003 have been independently confirmed in the responding of rats for alcohol (Corbit et al 2012) and for the intravenous (i.v.) self-administration of nicotine (Clemens et al 2014). Using a novel method in which cocaine-seeking responses on one lever gave access to a second, "taking" lever delivering i.v.…”

Neuropeptide systems and new treatments for nicotine addiction

“…However, a recent study investigated Fos expression in the brain after 10 versus 47 days of nicotine self-administration (Clemens et al 2014). Interestingly, both self-administration protocols induced Fos expression in brain areas that have been associated with reward function such as the NAcc core and shell, VTA, CeA, and basolateral amygdala (BLA).…”