Several hypothalamic neuropeptides, including galanin, modulate the neurochemical and behavioral responses to drugs of abuse. Previous research has indicated that mice with constitutive knockout of the galanin peptide display increased sensitivity to the rewarding effects of morphine and cocaine, suggesting that endogenous galanin signaling opposes or inhibits the neurochemical actions of morphine and cocaine (Hawes et al., 2008
; Narasimhaiah et al., 2009
). In contrast, results from the current study indicate that mice lacking the galanin peptide display decreased sensitivity to nicotine in the CPP paradigm
, suggesting that galanin does not modulate drug-induced neurochemical changes similalry across all classes of abused drugs.
Although each drug of abuse has different initial effects on neurotransmission through interactions with specific receptors and subsequent sigaling pathways, these initally different mechanisms of action converge to increase mesolimbic and nigrostriatal dopamine transmission; however, it is important to keep in mind that each of these drug classes has unique effects in parts of the mesocorticolimbic circuitry that can modulate reward-related behavior (Pierce and Kumaresan 2006
). For example, systemic administration of nicotinic acetylcholine receptor antagonists and α-noradrenergic receptor decrease nicotine reward, but have little or no effect on cocaine reward (Sershen et al., 2010
). In addition, it has been shown that antagonism of hippocampal nicotinic receptors and ablation of prefrontal cortical noradrenergic afferents inhibits morphine CPP (Rezayof et al., 2006
; Ventura et al., 2005
). Since galanin can modulate both acetylcholine and noradrenergic release in the hippocampus, it is possible that galanin differentially modulates the effects of drugs of abuse dependent on function of these neurotransmitters (Kehr et al. 2001
; Elvander and Ogren 2005
An imbalance between cholinergic and dopaminergic signaling in the nucleus accumbens has been implicated in a variety of neurological disorders, likely because alterations in these neurotransmitter systems can impair the functioning of cortico-basal ganglia-thalamocortical loops (for review see Aosaki et al., 2010
; Livingstone & Wonnacott, 2009
). Cholinergic innervation of the ventral tegmental area and substantia nigra can influence the firing of dopaminergic neurons via nicotinic receptors on dopaminergic cell bodies, presynaptic glutamatergic terminals and GABAergic interneurons, resulting in modulation of dopamine release in target nuclei, such as the striatum (Mansvelder et al., 2002
; Mena-Segovia et al., 2008
). In addition, presynaptic nicotinic receptors on dopaminergic terminals and neurotransmission from striatal cholinergic interneurons in the striatum can affect dopamine release (Exley and Cragg 2008
). It has also been suggested that the cholinergic system may be involved in galanin-mediated modulation of dopamine signaling (Picciotto, 2008
). Galanin administration into the paraventricular nucleus of the hypothalamus can decrease extracellular levels of acetylcholine and increase extracellular dopamine levels in NAC (Rada et al., 1998
). Given the ability of acetylcholine release to alter dopamine dynamics and the important role of dopamine in both feeding and drug-related behaviors, it seems possible that galanin-induced alterations in cholinergic signaling could modulate drug-abuse related behaviors. Further research is needed to assess whether the basal levels of acetylcholine and dopamine are changed in Gal −/− mice, an effect that may result in differential responses to cocaine, morphine and nicotine reward. In addition, it will be important to determine the role of galanin in the reinforcing effects of morphine, alcohol, and nicotine using the self-administration paradigm as previous research has indicated galanin may modulate cocaine reward, but not reinforcement (Brabant et al., 2010
; Narasimhaiah et al., 2009
Exposure to a previously nicotine-paired chamber results in activation of CREB in several brain regions, including the VTA, NACsh, cingulate cortex and pedunculopontine tegmental nucleus and CREB activation is required in the NACsh for expression of nicotine CPP (Brunzell et al., 2009
; Walters et al., 2003
). One prominent regulator of CREB activity in neurons is ERK. Activation of the ERK signaling pathway in the NAC, which plays an important role in associative learning, is necessary for the expression of cocaine and morphine reward (Valjent et al., 2006
). While acute nicotine (0.4 mg/kg) has been reported to induce ERK activation in the NAC, similar to cocaine and morphine, it is unknown if ERK activation in the NAC is necessary for the expression of nicotine CPP (Valjent et al., 2004
In contrast to previous studies using the CD-1 strain of mouse, acute nicotine administration did not alter ERK activation in the NAC. This may be due to strain differences since the Gal +/+ and Gal −/− mice were developed on the 129/OlaHsd background. Despite the lack of an acute increase in ERK phosphorylation following nicotine administration, both Gal +/+ and Gal −/− mice showed a significant nicotine CPP, raising the possibility that ERK activation occurs at a different time-point post nicotine administration in these mice compared to CD-1 mice (Valjent et al., 2004
). In the current study, levels of ERK activation in the NACsh and NACco were determined in a random subset of mice from each conditioning group following behavioral assessment of nicotine CPP. Gal +/+ mice that exhibited significant nicotine (0.18 mg/kg) CPP showed increased ERK activation in the NACsh. However, no ERK activation was observed in the NAC of Gal −/− mice that exhibited significant nicotine (0.36 mg/kg) CPP, suggesting that ERK activation in NACsh may not be required for nicotine CPP in these mice or that the time-course of ERK activation was altered in these animals. While speculative, it is possible that the CREB activity in the NACsh, which is critical for nicotine CPP, is not regulated by ERK, but instead by another signaling cascade such as PKA or CaMKIV (Selcher et al., 2002
). It is also possible that the ERK/CREB signaling pathway in other brain regions (not assessed in the current study) are critical for acquisition of nicotine CPP, such as the hippocampus.
In conclusion, the current results demonstrate that constitutive loss of the galanin peptide does not modulate the conditioned reinforcing effects of all classes of abused drugs uniformly, as assessed using the CPP paradigm. It is possible that compensatory mechanisms in these mice underlie the current results and further studies are needed to fully elucidate the role of galaninergic receptor signaling in drug-induced behaviors. Given the role of galanin, as well as other orexigenic neuropeptides, in motivated behavior for both food and drug-reward, galanin signaling remains a potential target for development of therapeutics to combat drug abuse.
- Mice lacking the galanin peptide showed decreased sensitivity to nicotine in the conditioned place preference paradigm compared to wild-type mice.
- Only Gal+/+ mice showed an increase in ERK2 activity following re-exposure to the CPP apparatus.
- No activation of ERK2 was observed following acute nicotine administration in either genotype.