Different nicotinic acetylcholine receptor subtypes mediating striatal and prefrontal cortical [3H]dopamine release
Introduction
Functional nicotinic acetylcholine receptors (nAChRs), existing as heteromeric complexes comprised of α (α2–α6) and β (β2–β4) subunits, or homomeric complexes comprised of five α (α7–α8) subunits, have been identified throughout the central nervous system (for review, see Romanelli and Gualtieri, 2003). Additionally, two other nAChR subunits, α9 and α10, have been identified in the hair cells of the inner ear (Elgoyhen et al., 1994, Elgoyhen et al., 2001), and the dorsal root ganglia (Lips et al., 2002). A major role of nAChRs is in the modulation of neurotransmitter release (Role and Berg, 1996). Neurotransmitter release can be significantly affected by activation of nAChRs. For example, nAChR activation can cause a robust stimulation in dopamine (DA) release from several areas of the brain (Puttfarcken et al., 2000, Grady et al., 2002). The ability of nAChRs to modulate DA release is of particular interest because of the roles that DA can play in various brain functions, including cognition, locomotion, and reward. Since various nAChR subunit combinations can form functional receptors with varied physiological and pharmacological profiles, the potential exists for extensive diversity in the function of these receptors to regulate neurotransmitter release. Indeed, previous studies from our laboratory have shown that nicotine-evoked [3H]dopamine ([3H]DA) release from slices of rat striatum and prefrontal cortex is mediated by distinct nAChRs (Puttfarcken et al., 2000). In these studies, the role of α3- vs. α4-containing nAChRs in [3H]DA release from striatum and cortex was investigated. The goal of the present study was to further investigate the involvement of specific nAChRs in [3H]DA release from these two regions. The ability of the α7-selective antagonists, methyllycaconitine (MLA) (Alkondon et al., 1992), α-bungarotoxin (α-BTX) (Chen and Patrick, 1997), α-conotoxin ImI (α-CtxImI) (McIntosh et al., 1994), and the α3β2β3* (* indicates possibility of other unidentified subunits present) and/or α6β2β3* antagonist, α-conotoxin MII (α-CtxMII) (Cartier et al., 1996, Champtiaux et al., 2002), to affect [3H]DA release from both regions was examined. N,N,N-Triethyl-2-[4-(2-phenylethenyl) phenoxy] ethanaminium iodine (MG 624), a compound reported to be selective toward the α7-containing receptors in chick (Gotti et al., 1998, Gotti et al., 2000), was also examined. Finally, in combination with these studies, the release evoked by two agonists with distinct receptor subtype selectivity, (−)-nicotine and (±)-UB-165, was characterized. To our knowledge, this is the first study to characterize the pharmacological actions of MG 624 on nicotine-evoked [3H]DA release from either region, where very little is known regarding its selectivity toward non-α7-containing nAChRs in rodent brain. In addition, it is also the first study to examine the effects of the nicotinic agonist, (±)-UB-165, in the prefrontal cortex.
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Materials
[3H]Dopamine ([3H]DA) (3,4-[ring-2,5,6-3H]dihydroxyphenylethylamine, 60 Ci/mmol) was purchased from Perkin Elmer Life Science (Boston, MA). (−)-Nicotine bitartrate, mecamylamine (Mec), MLA, desipramine, pargyline and ascorbic acid were purchased from Sigma (St. Louis, MO). Nomifensine was purchased from Sigma-RBI (Natick, MA). α-CtxMII was obtained from Tocris (Bristol, UK). (±)-UB-165 fumarate, and MG 624 were obtained from Tocris (Ellisville, MO). α-CtxImI was purchased from either American
The effect of α-CtxMII on nicotine-evoked [3H]DA release from striatum and prefrontal cortex
Multiple experiments performed within each study indicate that the maximal amount of release evoked by nicotine is different between striatum and prefrontal cortex (striatum=2.7±0.1%, prefrontal cortex=2.0±0.1%, ), suggesting regional differences in distribution, expression and/or type of nAChR subtype(s) involved, as well as the extent of dopaminergic innervation.
Subsequent studies compared the ability of 120 nM α-CtxMII, a concentration previously found to inhibit anatoxin-a- (
Discussion
Previous reports from our laboratory (Puttfarcken et al., 2000), as well as others, have described studies on the characterization of nAChR-mediated [3H]DA release from striatum (Sacaan et al., 1995, Sharples et al., 2000, Whiteaker et al., 1995) and, to some extent, from cortex (Whiteaker et al., 1995). The present study has extended these studies by investigating the involvement of other nAChRs in striatum and prefrontal cortex.
Initial studies examined the ability of α-CtxMII to affect
Acknowledgements
The authors wish to thank Dr. Clark Briggs, Dr. Wilfried Hornberger, Dr. Michael Meyer, and Dr. Susan Wonnacott for their helpful comments on the manuscript.
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