[Abstract Title]. - Society for Neuroscience

Topic: C.16.k. Nicotine
Support: Academy of Finland
Sigrid Jusélius Foundation
Title: Effects of acute and chronic nicotine treatment on ventral tegmental area GABA -
interaction with morphine
Authors: *T. VIHAVAINEN, T. R. A. RELANDER, R. K. TUOMINEN, L. AHTEE, P.
PIEPPONEN;
Fac. of Pharm., Univ. Helsinki, Helsinki, Finland
Abstract: We have shown earlier that chronic oral nicotine treatment enhances morphineinduced
behaviors and dopamine turnover/metabolism and release in mouse brain. Using in vivo
brain microdialysis of conscious mice, we have now studied the role of substantia nigra/ventral
tegmental area (SN/VTA) GABAergic system in the effects of nicotine and in nicotine-morphine
-interaction. We investigated whether the GABA output provoked by an inhibitor of GABA
uptake, nipecotic acid, in SN/VTA is affected by acute nicotine, or by seven-week oral nicotine
treatment. In addition, we studied whether a single administration of morphine differently affects
GABA output in control mice and mice chronically treated with nicotine. The guide cannula for
the microdialysis probe was aimed above SN/VTA (coordinates: A/P -3.1; L/M +0.8; D/V -3.8
mm relative to bregma) of NMRI male mice under isoflurane anesthesia one week before the
microdialysis experiments. The concentrations of GABA were measured with HPLC and a
fluorescence detector with pre-column derivatization from the dialysates collected in 15 min
intervals. After stable baselines were achieved, nipecotic acid (100 µM in the dialysis fluid) was
perfused through the probes for 90 min. Drugs were administered 15 min after starting the
nipecotic acid perfusion. Acute nicotine (0.3 mg/kg or 0.5 mg/kg i.p.) dose-dependently
decreased extracellular GABA in SN/VTA. Also, at 24 h after cessation of chronic nicotine
treatment the extracellular GABA concentration was decreased in the SN/VTA as compared with
controls. The effects of nicotine on GABA might be due to desensitization of alpha4beta2nicotinic
acetylcholine receptors by nicotine, which leads to weakening of acetylcholine control
on GABA release. In control mice, a single dose of morphine (15 mg/kg s.c.) decreased
extracellular GABA as expected, but in mice withdrawn from chronic nicotine treatment
morphine surprisingly increased GABA levels. Thus, chronic nicotine modifies the GABAergic
transmission in the VTA/SN which may reflect the changes observed in mesolimbic
dopaminergic neurotransmission. Chronic nicotine also unmasks a stimulatory component of
opioidergic control on GABA release. In conclusion, our results suggest that changes in VTA/SN
GABAergic transmission by chronic nicotine treatment are involved in the cross-sensitization to
the effects of morphine, as reflected by augmented locomotor activity and striatal dopaminergic
transmission.
Disclosures: T. Vihavainen, None; T.R.A. Relander, None; R.K. Tuominen, None; L. Ahtee,
None; P. Piepponen, None.