Mice lacking the galanin gene show decreased sensitivity to nicotine conditioned place preference

Abstract

Previous work has indicated that the neuropeptide galanin decreases sensitivity to the rewarding effects of morphine and cocaine, but increases alcohol drinking. The aim of the current study was to examine the role of galanin signaling in nicotine reward by testing the effects of nicotine in mice lacking galanin peptide (Gal −/−) as compared to wild-type (Gal +/+) controls. Using an unbiased, three-chamber conditioned place preference (CPP) paradigm the dose-response function for nicotine CPP was tested in Gal −/− and Gal +/+ mice. Since activation of extracellular signal-related kinase (ERK2) is involved in the rewarding effects of several classes of drugs of abuse, we then measured the level of ERK2 phosphorylation in the nucleus accumbens shell (NACsh) and core (NACco) of Gal −/− and Gal +/+ mice following re-exposure to the CPP chamber previously paired with nicotine as a marker of mesolimbic system activation. Finally, we examined whether acute nicotine administration affects ERK2 activity in Gal −/− and Gal +/+ mice. Gal −/− mice required a higher dose of nicotine to induce a significant CPP compared to Gal +/+ mice. Upon re-exposure to the CPP apparatus, only Gal +/+ mice showed activation of ERK2 in the NACsh after training with the optimal dose for nicotine CPP, suggesting that the CPP observed following training with a higher dose of nicotine in Gal −/− mice resulted in differential recruitment of ERK signaling in the NACsh. In addition, no activation of ERK2 was observed following acute nicotine administration in either genotype. These data, along with prior results, suggest that galanin alters sensitivity to drugs of abuse differentially, with morphine, cocaine and amphetamine place preference suppressed, and nicotine and alcohol preference increased, by galanin signaling.

The Neuropeptide Galanin and Variants in the GalR1 Gene are Associated with Nicotine Dependence

“…Galanin is reported to have an inhibitory effect on dopamine release in rat striatal slices (Tsuda et al, 1998), a finding that supports the ability of galnon to attenuate rewarding effects of drugs of abuse. Interestingly, a recent study found that Gal À/À mice are less sensitive to the rewarding effects of nicotine, as higher nicotine doses were required to produce a significant CPP in these mice compared with + / + counterparts (Neugebaur et al, 2011). This finding is the opposite of what would be expected, given our current results.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…Reduced mechanical allodynia after nerve injury (Kerr et al, 2000a;Holmes et al, 2003) (Mazarati et al, 2000) Marked reduction in levels of prolactin in the anterior pituitary and in plasma (Wynick et al, 1998) Decreased severity of cerulein-induced acute pancreatitis (Bhandari et al, 2010b) Reduced insulin secretion in response to non-neuronal stimulation and impaired glucose elimination (Ahren et al, 2004) Decreased food consumption on high-fat diet (Adams et al, 2008;Karatayev et al, 2010) Decreased ethanol intake and preference in female mice. Decreased orexin and melanin-concentrating hormone in the perifornical lateral hypothalamus (Karatayev et al, 2010) Increase in opiate withdrawal behavior (Zachariou et al, 2003) Decreased sensitivity to nicotine and no increase in ERK2 activation in mice that showed nicotine conditioned place preference (increase in WT) (Neugebauer et al, 2011) Increase in secreting sweat glands following thermal stimulation (Vilches et al, 2012) GAL 1 (Jacoby et al, 2002)/C57BL/6J and 129T2/SvEmsJ Increased sensitivity to both heat and cold intact. Increased duration of pain-like behavior after nerve injury (Blakeman et al, 2003) No difference in mechanical or thermal thresholds in intact animals but increased hyperalgesia after thermal injury and faster recovery after spinal nerve ligation (Malkmus et al, 2005) No difference in regeneration in vivo (Blakeman et al, 2003) or in vivo (Blakeman et al, 2003;Mahoney et al, 2003a) Increase in opiate withdrawal behavior Spontaneous seizures and reduced plasma levels of IGF-1.…”

“…For example, galanin-KO mice have reduced sensitivity to nicotine reward, and galanin-mediated signaling via GAL 1 blocks nicotine reward (Jackson et al, 2011;Neugebauer et al, 2011).…”

“…All three galanin receptors are reported to be present in brain regions implicated in drug addiction in mice (Hawes and Picciotto, 2004;Lu and Bartfai, 2009), including the dopamine neuron systems within the substantia nigra/caudate putamen and ventral tegmental area/nucleus accumbens, and in the LC, which contains noradrenergic neurons that are galanin and NPY positive, with similar or partial indications in rats Galanin Family Peptides and Receptors (Rovin et al, 2012) and humans (Le Maître et al, 2013). Galanin-KO mice have a decreased sensitivity to nicotine reward, and galanin-mediated signaling via GAL 1 blocks nicotine reward (Jackson et al, 2011;Neugebauer et al, 2011). In a clinical context, craving for tobacco (nicotine) is a major challenge for individuals with nicotine dependence, and craving is one of the most important factors contributing to smoking relapse.…”

Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation

“…Galanin, acting through its receptor subtypes, has been shown in rodent models to modulate reward and withdrawal responses from drugs of abuse (Hawes et al, 2008;Zachariou et al, 1999). Of relevance to nicotine dependence, mice lacking the galanin peptide display decreased sensitivity to nicotine reward (Neugebauer et al, 2011). Further, galanin, mediated via GALR1, blocks nicotine reward and reverses physical nicotine withdrawal signs (Jackson et al, 2011).…”