Intermittent nicotine exposure upregulates <scp>nAChR</scp>s in VTA dopamine neurons and sensitises locomotor responding to the drug

Baker, Lorinda K.; Mao, Danyan; Chi, Henry; Govind, Anitha P.; Vallejo, Yolanda; Iacoviello, Michael P.; Herrera, Stacy; Cortright, James J.; Green, William N.; McGehee, Daniel S.; Vezina, Paul

doi:10.1111/ejn.12114

Cited by 33 publications

(26 citation statements)

References 48 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This GluR2-lacking receptor pool typically displays inward rectification (Isaac et al, 2007;Liu and Zukin, 2007), and one study confirms the appearance of this type of AMPAR after a single exposure to nicotine (Gao et al, 2010). Another study on nicotine (Baker et al, 2013) exposure to VTA DA neurons, however, demonstrated increases in AMPA/NMDA ratios but no appearance of an AMPAR pool displaying inward rectification. We find no appearance of inward rectification in AMPA-evoked currents (Fig.…”

Section: Discussionmentioning

confidence: 92%

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

et al. 2013

View full text Add to dashboard Cite

Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine's action in humans. However, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing a6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-offunction a6 nAChRs (a6L99S mice). In voltage-clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via a6b2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through a6b2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, a6b2* activation did not enhance N-methyl-D-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from a6L99S mice lacking a4 nAChR subunits, suggesting that a4a6b2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of a4a6b2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. a4a6b2* nAChRs may be a promising target for future smoking cessation pharmacotherapy.

show abstract

Section: Discussionmentioning

confidence: 92%

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For instance, intermittent exposure to drug achieved via experimenter-administered i.p. injections of cocaine (Downs and Eddy, 1932, Post, 1980, Post and Rose, 1976, Reith et al, 1987and Stewart and Badiani, 1993 or nicotine (Baker et al, 2013 andDi Chiara, 2000) more readily induces sensitization to the psychomotor activating effect of these drugs, while continuous infusion produces tolerance to this effect. Fig.…”

Section: Preclinical Studies Show That Drug Pharmacokinetics Determinmentioning

confidence: 99%

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

Allain

Minogianis

Roberts

et al. 2015

Neuroscience & Biobehavioral Reviews

169

120

View full text Add to dashboard Cite

How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, 'spiking' brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder.

show abstract

“…Recently, it has been demonstrated that intermittent exposure to nicotine (one dose on alternate days) does evoke a transient (hours) functional upregulation of AChRs in VTA dopaminergic neurons (Baker et al, 2013). This work also documented that intermittent nicotine exposure produced no functional upregulation on VTA GABAergic neurons.…”

Section: Upregulation Of Achrs Depends On Achr Subtypementioning

confidence: 99%

Inside-out neuropharmacology of nicotinic drugs

Henderson

Lester

2015

Neuropharmacology

View full text Add to dashboard Cite

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology.

show abstract

Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug

Cited by 33 publications

References 48 publications

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

Inside-out neuropharmacology of nicotinic drugs

Contact Info

Product

Resources

About