Table 2.
Pharmacological and genetic findings linking nAChR subunits to nicotine addiction phenotype
| Subunit | Manipulation | Behavioral Outcome | Reference |
|---|---|---|---|
| β2 | KO | Nicotine self-administration blocked (rescued by re-expression in VTA) Nicotine CPP blocked (not rescued by low-level re-expression in VTA) Conditioned reinforcement blocked Nicotine locomotor activation blocked (rescued by low-level re-expression in VTA) Nicotine evoked DA release blocked Blocks nicotine-stimulated DAergic neuron firing Loss of anxiety-related behavior (EPM) Loss of withdrawal-induced increases in anxiety (EPM) Withdrawal-induced increases in somatic signs intact |
Picciotto et al. 1998; Maskos et al. 2005; Besson et al. 2006; Pons et al. 2008 Walters et al. 2006; Mineur et al., 2009 Brunzell et al. 2006 King et al. 2004, Mineur et al., 2009 Zhou et al. 2001 Picciotto et al. 1998 Jackson et al. 2008 Jackson et al. 2008 Salas et al. 2004; Jackson et al. 2008 |
| DHβE | Nicotine self-administration blocked (infusion in VTA) Nicotine CPP blocked Evoked DA release blocked Anxiolytic (EPM; marble burying) Antidepressant (tail suspension; forced swim) Precipitates somatic signs of withdrawal Precipitates withdrawal-induced increases in anxiety (EPM) Precipitates withdrawal-induced increases in ICSS |
Corrigall et al. 1994 Walters et al. 2006 Zhou et al. 2001 Anderson and Brunzell 2012 Andreasen et al. 2009 Epping-Jordan et al. 1998; Damaj et al. 2003 Malin et al. 1998 Epping-Jordan et al. 1998; Damaj et al. 2003 |
|
| Varenicline | Anxiolytic (marble burying, NIH) Antidepressant (forced swim) Reduces withdrawal-induced increases in ICSS thresholds |
Turner et al. 2010; Hussman et al. 2014 Rollema et al. 2009; Caldarone et al. 2011 Igari et al. 2003 |
|
| ABT-089 | Anxiolytic during nicotine withdrawal and anxiogenic in naïve mice (NIH) | Yohn et al. 2014 | |
| Cytisine | Antidepressant (tail suspension; forced swim) | Mineur et al. 2009 | |
| A-85380 | Trained rats self-administer this selective agonist Antidepressant (forced swim) |
Liu et al., 2003 Buckley et al. 2004; Caldarone et al. 2011 |
|
| β3 | KO | Decreased anxiety levels (EPM) | Booker et al. 2007 |
| β4 | KO | Decreased anxiety levels (EPM; light dark) Reduced withdrawal-induced somatic signs and hyperalgesia |
Salas et al. 2003; Semenova et al. 2012 Salas et al. 2004; Stoker et al. 2012; Jackson et al. 2013 |
| α-CTX AuIB | Precipitates nicotine withdrawal-induced somatic signs | Jackson et al. 2013 | |
| α2 | KO | Increased self-administration | Lotfipour et al. 2013 |
| α4 | KO | Nicotine self-administration blocked (rescued by re-expression in VTA) and blunted nicotine-stimulated DA release CPP blocked and blunted nicotine-stimulated DA release Blunted basal and nicotine-stimulated DA release Nicotine-stimulated anxiolysis blocked Increased anxiety levels (EPM) |
Pons et al. 2008; Exley et al. 2011 McGranahan et al. 2011 Marubio et al. 2003 McGranahan et al. 2011 Ross et al. 2000 |
| L9S | Anxiogenic (EPM; mirrored chamber) | Labarca et al. 2001 | |
| L9A | Hypersensitive to nicotine-stimulated DAergic neuron firing and nicotine CPP | Tapper et al. 2004 | |
| Sazetidine | Anxiolytic (NIH) Antidepressant (tail suspension; forced swim) |
Hussman et al. 2014 Turner et al. 2010; Caldarone et al. 2011 |
|
| α5 | KO | Increased nicotine self-administration Reduced nicotine withdrawal-induced somatic signs Nicotine withdrawal-induced increases in anxiety intact (EPM) |
Fowler et al. 2011 Jackson et al. 2008; Salas et al. 2009; Jackson et al. 2013 Jackson et al. 2008 |
| α6 | KO | Nicotine CPP blocked Nicotine self-administration blocked (rescued by re-expression in VTA) and blunted nicotine-stimulated DA release |
Sanjakdar et al. 2014 Pons et al. 2008; Gotti et al. 2010; Exley et al. 2011 |
| L9S | Hypersensitive DAergic neuron firing and DA release α4 required for hyperlocomotion |
Drenan et al. 2008 Drenan et al. 2010 |
|
| α-CTX MII α-CTX PIA |
Nicotine CPP blocked Nicotine self-administration blocked (infusion NAc and VTA) Blocks nicotine-stimulated DAergic neuron firing |
Jackson et al. 2009; Sanjakdar et al. 2014 Brunzell et al. 2010; Gotti et al. 2010 Liu et al. 2012 |
|
| α7 | KO | Leftward shift in nicotine CPP (enhanced at low doses) Nicotine self-administration unaffected Nicotine-stimulated DA release increased, nicotine self-administration blunted Chronic oral nicotine intake decreased Anxiety-like behavior unaffected (EPM; light dark; open field) Loss of nicotine withdrawal-induced increases in somatic signs Spontaneous nicotine withdrawal-induced increases in anxiety intact MEC precipitated nicotine withdrawal-induced anxiety reduced Leftward shift in MEC dose response curve, as measured by withdrawal induced increases in ICSS thresholds |
Harenza et al. 2014 Pons et al. 2008 Besson et al. 2012 Levin et al. 2009 Salas et al. 2007; Jackson et al. 2008 Jackson et al. 2008; Stoker et al. 2012 Jackson et al. 2008 Jackson et al. 2008 Stoker et al. 2012 |
| MLA | Nicotine self-administration unaffected Nicotine self-administration blocked Reversed nicotine-induced anxiogenesis Antidepressant (tail suspension; forced swim) Precipitates nicotine withdrawal-induced increases in somatic signs No effect on nicotine withdrawal-induced increases in anxiety (EPM) No effect on nicotine withdrawal-induced increases in ICSS thresholds |
Grottick et al. 2000 Markou and Paterson 2001 Tucci et al. 2003 Andreasen et al. 2009 Markou and Paterson 2001; Damaj et al. 2003; Salas et al. 2007 Damaj et al. 2003 Markou and Paterson 2001 |
|
| α-CTX ArIB | Nicotine self-administration increased (NAc and ACC infusion) | Brunzell et al. 2012 | |
| PHA-543613 | Nicotine self-administration blocked | Harenza et al. 2014 | |
| PNU-282987 | Nicotine self-administration blocked (NAc infusion) Increased anxiety levels |
Brunzell et al. 2012 Pandya et al. 2013 |
Abbreviations: nicotinic acetylcholine receptor non-selective antagonist mecamylamine (MEC), semi-selective antagonist methyllycaconitine (MLA), selective antagonists dihydro-beta-erythroidine (DHβE), α conotoxin MII (α-CTX MII), PIA (α-CTX PIA), ArIB (α-CTX ArIB) and AuIB (α-CTX AuIB), selective partial agonists (cytisine, varenicline, sazetidine, ABT-089), selective agonists (A-85830; PHA-54613; PNU282987); leucine to serine (L9S) or leucine to alanine (L9A) single point mutation in pore forming domain resulting in gain-of-function phenotype; null mutation of subunit resulting in total “knock out” of the receptor (KO); brain areas ventral tegmental area (VTA), nucleus accumbens (NAc) and anterior cingulate cortex (ACC); and behavioral assays conditioned place preference (CPP), elevated plus maze (EPM), novelty induced hypophagia (NIH) and intracranial self stimulation (ICSS)