Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway

Abstract

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional ␣4␤2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and ␣4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-␤-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3-1000 M ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional ␣4* nAChRs were not found on the neuronal somata; however, nicotine acts via ␣4␤2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these ␣4␤2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of ␣4␤2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease.

Chronic Nicotine Treatment Impacts the Regulation of Opioid and Non-opioid Peptides in the Rat Dorsal Striatum

“…This suggests that the increase of these peptides may reflect elevated precursor synthesis, consistent with the elevated preproenkephalin mRNA levels in the striatum after chronic nicotine application (15). Another class of opioid peptides, dynorphins derived from PDYN including dynorphin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) and dynorphin(1-8), was not modulated by chronic nicotine. This is consistent with previous literature linking PDYN peptides to aversive states associated with drug withdrawal (47), which were not induced in our experiment.…”

“…In particular, the DS is involved in habit formation during the preoccupation/craving (later) phase of nicotine dependence characterized by compulsive drug-taking (6). Behavioral changes associated with nicotine dependence have been linked to small molecule neurotransmitter systems, including the glutamate and dopamine system in the DS (7). The DS is also known to contain diverse neuropeptides, many of which are probably critical mediators of physiological processes that are associated with nicotine, such as the regulation of reinforcement and energy metabolism.…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…Long-term nicotine administration, delivered in multiple forms (injection, minipump, drinking water, or self-administration), increases the numbers of ␣4␤2* binding sites throughout the brain in experimental animal models and humans (Marks et al, 1983;Schwartz and Kellar, 1983;Benwell et al, 1988;Perry et al, 1999;Staley et al, 2006;Xiao et al, 2009;Moretti et al, 2010). There was some initial controversy concerning ␣4␤2* receptor up-regulation in the striatum, because increases were observed in some studies but not others.…”

“…The molecular basis for the differential regulation of various striatal nAChR subtypes is an area actively under investigation, the ␣4␤2* nAChR subtype being most extensively investigated to date (Govind et al, 2009; Marks et al, 1983;Schwartz and Kellar, 1983;Benwell et al, 1988;Perry et al, 1999;McCallum et al, 2006;Staley et al, 2006;Xiao et al, 2009;Moretti et al, 2010 ␣4␣5␤2 No change Rats Moretti et al, 2010 ␣7 1or No change Rats, mice, monkeys Pauly et al, 1991;Quik et al, 2000a;Lai et al, 2005;Moretti et al, 2010 ␣6␤2* AND ␣4␤2* NACHRS: DRUG TARGETS FOR PARKINSON'S DISEASEal., 2009). There is a consensus that up-regulation of ␣4␤2* nAChRs is primarily controlled at the post-transcriptional level, with little change in ␣4 or ␤2 nAChR mRNA levels (Marks et al, 1992).…”

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations

“…These results were corroborated later by Yang et al (2009), who used acutely dissociated DA neuron preparations to demonstrate expression of functional, ␣7 nAChR currents in a substantial fraction of DA neurons. In addition, electrophysiology and pharmacology methods have been used to localize ␣7 nAChR function to several cell types in striatum (Azam et al, 2003;Xiao et al, 2009) (Fig. 3A).…”