Prominent Role of α3/α6β2^*nAChRs in Regulating Evoked Dopamine Release in Primate Putamen: Effect of Long-Term Nicotine Treatment

Abstract

Brain dopaminergic systems are critical in motor control as evidenced by findings that their disruption results in movement disorders such as Parkinson's disease. Nicotinic acetylcholine receptor (nAChR) activation plays an important role in regulating striatal dopaminergic function. Rodent studies show that short-term nicotine exposure influences stimulated striatal dopamine release with responsiveness dependent on neuronal activity. However, studies have not yet been done in nonhuman primates, nor has work been done to evaluate the effect of long-term nicotine exposure, which is relevant for therapies for chronic neurological disorders. Here, we used voltammetry to assess the role of nAChRs on evoked dopamine release from monkey putamen slices. In both ventral and dorsal putamen, ␣3/␣6␤2* nAChRs regulated Ն80% of non-burst-(single pulse) nAChR-modulated dopamine release, and ␣4␤2* nAChRs regulated the remainder. Similar results were observed with burstfiring in ventral but not dorsal putamen, indicating that nAChRmodulated effects on release depend on the subregion and firing frequency. Next, we investigated the consequence of long-term nicotine exposure via the drinking water on nAChR-modulated responsiveness. Nicotine treatment altered both non-burst-and burst-stimulated dopamine release in ventral but not dorsal putamen. Altogether, these data support a predominant role for ␣3/ ␣6␤2* nAChRs in the regulation of evoked dopamine release in nonhuman primate putamen. They also show that long-term nicotine treatment selectively modifies nAChR-modulated release in distinct striatal subregions. These findings have implications for the development of treatments for addiction and neurological disorders with nAChR dysfunction.The nigrostriatal dopaminergic system plays a critical role in motor function under physiological conditions and in neurodegenerative disorders such as Parkinson's disease. Striatal dopaminergic afferents are in intimate contact with numerous neuronal elements from other neurotransmitter systems, including those of the cholinergic system (Zhou et al., 2002;. Indeed, there exists an extensive overlap of dopaminergic and cholinergic markers in the striatum, providing the anatomical basis for the close functional interrelationship between these two neurotransmitter systems (Zhou et al., 2002).Acetylcholine, secreted from cholinergic interneurons, modulates striatal dopamine release primarily via activation of nicotinic acetylcholine receptors (nAChRs), which are pentameric ligand-gated ion channels. The principal nAChRs in the striatum are the ␣4␤2* and ␣6␤2* subtypes (the asterisk denotes the possible presence of other subunits in the receptor complex) Quik et al., 2007;. Receptor expression studies in rodents indicate that ␣4␤2* nAChRs are in the majority (ϳ85%) compared with the ␣6␤2* nAChR subtype (ϳ15%). However, functional studies (synaptosomal nAChR-evoked [ 3 H]dopamine release) show that ␣4␤2* nAChRs control only ϳ70% and ␣6␤2* nAChRs 30% of striatal dopamine release. This discrepa...

Sympathetic α3β2-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine

“…It has been reported that ␣ 3 ␤ 2 -nAChRs mediate tonic inhibition of the spinal transmission of nociceptive mechanical stimuli during peripheral injury (49), modulation of dopamine release in the striatum of the rat (18,20,36), and visual processing and ocular pathologies such as neovascularization in the retina (26,32). In peripheral nervous system, most ␣ 3 -subunits knockout mice have defects in the autonomic nervous system and are usually lethal.…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…Long-term nicotine treatment selectively modifies dopamine release in distinct striatal sub-regions: i.e. ventral but not the dorsal putamen [119]. The same treatment upregulates αconotoxinMII-resistant 125 I-epibatidine binding (putative α4β2* receptors) whithout changing 125 I-αconotoxinMII binding (α3/α6β2* receptors) in both the dorsal and the ventral putamen.…”

Long-Term Nicotine Exposure Depresses Dopamine Release in Nonhuman Primate Nucleus Accumbens

“…The stimulating electrode was consistently placed on the dorsal half of the nucleus accumbens shell so that it just touched the surface of the slice and the carbon fiber electrode was positioned ϳ100 m away. Evoked release was elicited by either a single electrical pulse applied every 2.5 min or a train of two to four pulses (2-4 ms in duration) at 30 or 100 Hz applied every 5 min as described previously (Perez et al, 2009). It was not feasible to assess a wider range of frequencies because of the limited amount of primate tissue available.…”

“…Their potential functional relevance is evident from a body of work showing that ␣6␤2* nAChRs modulate the majority (75-100%) of nAChR-mediated release in nucleus accumbens and striatum of rodents and monkeys Exley et al, , 2011Perez et al, 2008Perez et al, , 2009). In addition, recent behavioral studies show that ␣6␤2* nAChRs play a critical role in nicotine-conditioned place preference, self-administration, and withdrawal (Pons et al, 2008;Jackson et al, 2009;Brunzell et al, 2010).…”