Conditioned Response Evoked by Nicotine Conditioned Stimulus Preferentially Induces c-Fos Expression in Medial Regions of Caudate-Putamen

Abstract

Nicotine has both unconditioned and conditioned stimulus properties. Conditioned stimulus properties of nicotine may contribute to the tenacity of nicotine addiction. The purpose of this experiment was to use neurohistochemical analysis of rapidly developing c-Fos protein to elucidate neurobiological loci involved in the processing of nicotine as an interoceptive conditioned stimulus (CS). Rats were injected (SC) in an intermixed fashion with saline or nicotine (16 sessions of each) and placed in conditioning chambers where they were given one of the three conditions depending on group assignment: (a) nicotine paired 100% of the time with intermittent access to sucrose (nicotine-CS condition), (b) nicotine and saline each paired 50% of the time with sucrose (chamber-CS condition), or (c) no sucrose US control (CS-alone condition). Rats in the nicotine-CS condition acquired the discrimination as evidenced by goal-tracking (ie, increased dipper entries before initial sucrose delivery) only on nicotine sessions. The chamber-CS condition showed goal-tracking on all sessions; no goal-tracking was seen in the CS-alone condition. On the test day, rats in each condition were challenged with saline or nicotine and later assessed for c-Fos immunoreactivity. In concordance with previous reports, nicotine induced c-Fos expression in the majority of areas tested; however, learning-dependent expression was specific to dorsomedial and ventromedial regions of caudate-putamen (dmCPu, vmCPu). Only rats in the nicotine-CS condition, when challenged with nicotine, had higher c-Fos expression in the dmCPu and vmCPu. These results suggest that medial areas of CPu involved in excitatory conditioning with an appetitive nicotine CS.

Interoception and Learning: Import to Understanding and Treating Diseases and Psychopathologies

“…Also, research investigating the neuroanatomical substrates has just begun. Early indications suggest an important role for the dorsal striatum, 40 an area thought to be important for habit learning. 41 Although c-Fos activation in the insula was not quantified or reported in that initial publication, 40 later examination of brain sections that contained a portion of the posterior insula reveal very little c-Fos activation and was, hence, not quantified.…”

“…Early indications suggest an important role for the dorsal striatum, 40 an area thought to be important for habit learning. 41 Although c-Fos activation in the insula was not quantified or reported in that initial publication, 40 later examination of brain sections that contained a portion of the posterior insula reveal very little c-Fos activation and was, hence, not quantified. Given the relative import placed on the insula by some theories for the processing of interoception-related information (refs 7 and 8; see the introduction above), future research will need to more programmatically investigate this area.…”

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus

“…For example, when nicotine in a controlled manner is repeatedly paired with access to sucrose, it acquires the ability to evoke an anticipatory food-seeking response in rats (goal-tracking). Although there has been significant progress in understanding the behavioral aspects of learning with nicotine as an interoceptive stimulus (for review see Bevins and Murray, 2011), there remains a significant gap in understanding neural mechanisms underlying this type of learning (Charntikov et al, 2012). …”

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

“…First, rats are relatively poor at titrating nicotine intake with changing infusion dose, but are highly sensitive to non-pharmacological factors, including physical response requirements (nose poke vs lever press; Clemens et al, 2010) and the presence of nicotine-related cues (Caggiula et al, 2009). Second, nicotine produces strong interoceptive cues that can enter into associations with other stimuli (Charntikov et al, 2012), such as lithium-induced nausea (Pittenger and Bevins, 2013). Accordingly, the first aim of the current study was to use lithium devaluation to examine habit formation in rats receiving extended nicotine self-administration.…”