Dopamine Signaling through D₁-Like versus D₂-Like Receptors in the Nucleus Accumbens Core versus Shell Differentially Modulates Nicotine Reward Sensitivity

Abstract

Considerable evidence implicates the mesolimbic dopamine (DA) system in the processing of nicotine's reinforcing properties, specifically the ventral tegmental area (VTA) and the terminal fields of VTA DAergic projections to the "core" (NAcore) and "shell" (NAshell) subdivisions of the nucleus accumbens (NAc). However, the specific roles of DA D 1 -like and D 2 -like receptor subtypes in nicotine reward processing within these NAc subregions have not been elucidated. We report that microinfusions of DA D 1 -like or D 2 -like receptorspecific antagonists into NAcore or NAshell double dissociate the rewarding and aversive properties of systemic or intra-VTA nicotine, and differentially regulate sensitivity to the rewarding properties as well as the motivational valence of either intra-VTA or systemic nicotine administration. Using a place conditioning procedure, NAshell infusions of a D 2 -like receptor antagonist switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-reward threshold intra-VTA nicotine doses. In contrast, NAcore infusions of a D 1 -like receptor antagonist switched intra-VTA nicotine aversion to reward, and potentiated reward sensitivity to sub-reward threshold nicotine doses. Thus, D 1 -like versus D 2 -like receptors in NAcore versus NAshell subdivisions play functionally dissociable roles in modulating systemic or intra-VTA nicotine motivational processing.Key words: nicotine; addiction; dopamine; ventral tegmental area; receptors; nucleus accumbens IntroductionNicotine, the psychoactive component of tobacco smoke, produces a variety of motivational effects and has strong addictive properties. Several neural regions and neurotransmitter systems have been implicated as critical mediators of nicotine's dependence-producing effects. Notably, evidence from humanand animal-based research implicates the mesolimbic dopamine (DA) system, comprising the ventral tegmental area (VTA) and its projections to the nucleus accumbens (NAc) core (NAcore) and shell (NAshell) subregions, as important regulators of nicotine's motivational properties (Picciotto and Corrigall, 2002;Laviolette and van der Kooy, 2004). The importance of DA neurotransmission in nicotine's motivational effects is further underscored by evidence showing that DA release is strongly increased by nicotine, by directly exciting VTA DAergic neurons and/or increasing release of DA in the terminal fields of the mesolimbic DAergic projections (Nisell et al., 1994;Yin and French, 2000;Mansvelder and McGehee, 2002). Furthermore, nicotine can act directly within the VTA to produce motivational effects (Laviolette and van der Kooy, 2003;David et al., 2006;Ikemoto et al., 2006) through either DA-dependent or non-DAergic neural systems (Picciotto et al., 1998; van der Kooy, 2003, 2004). Like many drugs of abuse, nicotine possesses both reinforcing and aversive stimulus properties, and nicotine dosedependently produces rewarding or aversive effects directly within the VTA w...

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

“…It is unlikely that the present results are because of a learning deficit in D 2 (À/À) mice as these mice can learn morphine (Dockstader et al, 2001) and ethanol place preferences (Ting-A- ). This result confirms previous work showing that D 1 and D 2 antagonists block conditioned aversions to nicotine withdrawal using pharmacologically precipitated withdrawal (Laviolette et al, 2008) and further extends these findings to spontaneous withdrawal, which more closely models the human condition.…”

“…We also examined D 2 receptor involvement in chronic nicotine withdrawal aversions. The DA D 2 receptor has been implicated in nicotine dependence (Fehr et al, 2008) and withdrawal (Laviolette et al, 2008). Our results show that acute aversive and chronic rewarding nicotine lead to opponent a-and bprocesses and that dopaminergic signaling, specifically at the D 2 receptor, mediates the opponent motivational process of chronic aversive but not acute rewarding nicotine.…”

“…Nicotine also produces motivational effects through non-dopaminergic neural systems, such as the cholinergic tegmental pedunculopontine (TPP) nucleus (Lanca et al, 2000;Laviolette et al, 2002;Picciotto and Corrigall, 2002). The mesolimbic DA system has been implicated in the processing of the acute motivational properties of nicotine (Laviolette and van der Kooy, 2003;Laviolette et al, 2008;Spina et al, 2006;Tanabe et al, 2008); however, the involvement of dopaminergic signaling in the aversive response to chronic nicotine withdrawal is largely unknown.…”

“…The negative affective state of withdrawal and its alleviation by nicotine is one of the primary factors driving nicotine craving in nicotine-dependent subjects. A majority of the studies on nicotine motivation in dependent animals involve antagonist precipitated withdrawal (George et al, 2007;Kenny and Markou, 2001;Laviolette et al, 2008;Watkins et al, 2000). However, a spontaneous withdrawal procedure more closely models human withdrawal.…”

“…Acute nicotine produces both rewarding and aversive stimulus properties (Laviolette and van der Kooy, 2004;Sellings et al, 2008;Wilkinson and Bevins, 2008). Dopaminergic signaling is involved in acute nicotine aversion (Laviolette and van der Kooy, 2003;Tan et al, 2009) and chronic nicotine motivation (Bruijnzeel and Markou, 2005;Kenny and Markou, 2001;Laviolette et al, 2008;Smolka et al, 2004); however, little is known regarding the role of dopaminergic signaling in the opponent motivational processes of acute and chronic nicotine.…”