Region-specific effects of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo

S. Rahman, Z. Zhang, R. L. Papke, P. A. Crooks, L. P. Dwoskin, M. T. Bardo

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background and purpose: Systemic administration of N,N′-dodecane-1, 12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). Experimental approach: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. Key results: Nicotine (0.4 mg kg -1, s.c.) increased extracellular dopamine in NAcc, which was attenuated by intra-VTA perfusion of mecamylamine (100 μM). Intra-VTA perfusion of bPiDDB (1 and 10 μM) reduced nicotine-induced increases in extracellular dopamine in NAcc. In contrast, intra-NAcc perfusion of bPiDDB (1 or 10 μM) failed to alter the nicotine-induced increase in dopamine in NAcc. Intra-VTA perfusion of bPiDDB alone did not alter basal dopamine levels, compared to control, nor the increased dopamine in NAcc following amphetamine (0.5 mg kg -1, s.c.). Using Xenopus oocytes, bPiDDB (0.01-100 μM) inhibited the response to ACh on specific combinations of rat neuronal nAChR subunits, with highest potency at α3β4β3 and lowest potency at α6/3β2β3. Conclusions and implications: bPiDDB-Sensitive nAChRs involved in regulating nicotine-induced dopamine release are located in the VTA, rather than in the NAcc. As bPiDDB has properties different from the prototypical nAChR antagonist mecamylamine, further development may lead to novel nAChR antagonists for the treatment of tobacco dependence.

Original languageEnglish
Pages (from-to)792-804
Number of pages13
JournalBritish Journal of Pharmacology
Volume153
Issue number4
DOIs
StatePublished - Feb 2008

Keywords

  • Acetylcholine receptor
  • Dopamine
  • Electrophysiology
  • HPLC
  • Nicotine
  • Nucleus accumbens
  • Ventral tegmental area
  • Xenopus oocytes
  • in vivo microdialysis

ASJC Scopus subject areas

  • Pharmacology

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