Behavioral Cross-Tolerance between Repeated Intracerebellar Nicotine and Acute Δ9-Tetrahydrocannabinol-Induced Cerebellar Ataxia: Role of Cerebellar Nitric Oxide

  1. Aaron D. Smith and
  2. M. Saeed Dar
  1. Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina
  1. Address correspondence to:
    Dr. M. Saeed Dar, Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. E-mail address: darm{at}ecu.edu

Abstract

We have previously demonstrated that acute intracerebellar nicotine or N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), a selective α4β2 nicotinic acetylcholine receptor (nAChR) agonist, dose dependently attenuates Δ9-tetrahydrocannabinol (Δ9THC)-induced ataxia. Presently, we have shown that intracerebellar nicotine (1.25, 2.5, and 5 ng; once daily for 5 days) and RJR-2403 (250, 500, and 750 ng; once daily for 5 days) significantly attenuate cerebellar Δ9-THC-induced ataxia dose dependently, suggesting the development of cross-tolerance between nicotine or RJR-2403 with Δ9-THC in male CD-1 mice. Intracerebellar RJR-2403 (750 ng) microinfused for 1, 2, 3, 5, and 7 days (once daily) significantly attenuated Δ9-THC-induced ataxia in the 3-, 5-, and 7-day treatment groups; optimal cross-tolerance was evident at day 5 and persisted till 36 h after the last RJR-2403 microinfusion. Intracerebellar microinfusion of hexamethonium (nAChR antagonist; 1 μg) or dihydro-β-erythroidine hydrobromide (α4β2 nAChR antagonist; 500 ng) for 5 days 10 min before daily intracerebellar nicotine or RJR-2403 microinfusion virtually abolished cross-tolerance between nicotine or RJR-2403 and Δ9-THC, indicating nAChR participation. In addition, microinfusion of antagonists 10 min after daily intracerebellar nicotine or RJR-2403 failed to alter the cross-tolerance, suggesting possible involvement of downstream cerebellar second-messenger mechanisms. Finally, the cerebellar concentration of nitric oxide products [total sum of nitrite + nitrate (NOx)] was increased after 5 days of intracerebellar nicotine or RJR-2403 treatment, which was decreased by acute intracerebellar Δ9-THC treatment. The “nicotine or RJR-2403 + Δ9-THC” treatments significantly increased cerebellar NOx levels compared with treatment with Δ9-THC alone, supporting a functional correlation between cerebellar nitric oxide production and cerebellar Δ9-THC-induced ataxia and suggesting participation of nitric oxide in the observed cross-tolerance between nicotine/RJR-2403 and Δ9-THC.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.120634.

  • ABBREVIATIONS: Δ9THC, Δ9-tetrahydrocannabinol; nAChR, nicotinic acetylcholine receptor; AP, anteroposterior; ML, mediolateral; DV, dorsoventral; DHβE, dihydro-β-erythroidine hydrobromide; RJR-2403, N-methyl-4-(3-pyridinyl)-3-buten-1-amine; DMSO, dimethyl sulfoxide; aCSF, artificial cerebrospinal fluid; DAN, 2,3-diaminonaphthalene; G-6-P, glucose 6-phosphate; G-6-PDH, glucose-6-phosphate dehydrogenase; NOx, total sum of nitrite + nitrate; NO, nitric oxide; ANOVA, analysis of variance; AUC, area under the curve; ICB, intracerebellar.

    • Received January 29, 2007.
    • Accepted April 5, 2007.
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  1. Published online before print April 6, 2007, doi: 10.1124/jpet.107.120634 JPET July 2007 vol. 322 no. 1 243-253
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