Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens

Abstract

The mesolimbic pathway comprising the ventral tegmental area (VTA) and projection terminals in the nucleus accumbens (NAc) has been identified as a critical neural system involved in processing both the rewarding and aversive behavioral effects of nicotine. Transmission through dopamine (DA) receptors functionally modulates these effects directly within the NAc. Nevertheless, the neuronal mechanisms within the NAc responsible for these bivalent behavioral effects are presently not known. Using an unbiased conditioned place preference procedure combined with in vivo neuronal recordings, we examined the effects of nicotine reward and aversion conditioning on intra-NAc neuronal sub-population activity patterns. We report that intra-VTA doses of nicotine that differentially produce rewarding or aversive behavioral effects produce opposite effects on sub-populations of fast-spiking interneurons (FSIs) or medium spiny neurons (MSNs) within the shell region of the NAc (NAshell). Thus, while the rewarding effects of intra-VTA nicotine were associated with inhibition of FSI and activation of MSNs, the aversive effects of nicotine produced the opposite pattern of NAshell neuronal population activity. Blockade of DA transmission with a broad-spectrum DA receptor antagonist, a-flupenthixol, strongly inhibited the spontaneous activity of NAshell FSIs, and reversed the conditioning properties of intra-VTA nicotine, switching nicotineconditioned responses from aversive to rewarding. Remarkably, DA receptor blockade switched intra-NAshell neuronal population activity from an aversion to a reward pattern, concomitant with the observed switch in behavioral conditioning effects.

Variability in nicotine conditioned place preference and stress‐induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine

“…In contrast, our mice were not reexposed to nicotine‐paired contexts following stress and prior to Arc immunohistochemistry. The NAc shell is activated in response to nicotine and nicotine‐associated cues, while the NAc core has been implicated in nicotine aversion and drug‐stress interactions for alcohol and cocaine . We found low NAc Arc expression overall, likely because mice were not reexposed to nicotine or nicotine‐paired contexts prior to perfusion.…”

Co-administration of ethanol and nicotine: the enduring alterations in the rewarding properties of nicotine and glutamate activity within the mesocorticolimbic system of female alcohol-preferring (P) rats

“…Local application of NIC into the AcbSh increases extracellular concentrations of DA and GLU (Toth et al 1992; Marshall et al 1997). Microinjections of DA antagonists into the AcbSh block the rewarding properties of systemically administered NIC (Sun et al 2014). Chronic systemic administration of EtOH and NIC can alter GLU levels within the Acb (Lallemand et al 2011).…”

Acute administration of nicotine into the higher order auditory Te2 cortex specifically decreases the fear-related charge of remote emotional memories

“…Nicotine hydrogen tartrate salt (Glentham Life Sciences, Corsham, UK) was dissolved in physiological saline (0.9% NaCl) and the pH was adjusted to 7.4. Different doses of nicotine (0.54, 27 and 54 nmol/μl; 0.6 μl per site, as calculated on the tartrate salt weight) were applied, based on previous studies ( Laviolette et al., 2008 , Sun and Laviolette, 2014 ) and on our preliminary experiments. In particular, we applied a dose of 54 nmol/μl, as this is similar to that of Laviolette et al.…”

“…Stress is also a major precipitating factor for smoking relapse ( Shiffman et al., 1997 ) and for the increase in cigarette use ( Skara et al., 2001 ). This depiction is, however, complicated by the fact that nicotine, like many drugs of abuse, possesses both rewarding and aversive properties ( Grieder et al., 2012 , Laviolette and van der Kooy, 2003 , Laviolette and van der Kooy, 2004 ; Sun and Laviolette, 2014 ). Nicotine can also induce effects in anxiety disorders such as post-traumatic stress disorder (PTSD), as evidenced by the high comorbidity between these diseases and nicotine dependence through habitual tobacco use ( Breslau et al., 2004 , Dalack et al., 1998 , Hughes et al., 1986 , Lasser et al., 2000 , Tipps et al., 2014 , Ziedonis et al., 2008 , Ziedonis and George, 1997 ).…”