Repeated exposure of the posterior ventral tegmental area to nicotine increases the sensitivity of local dopamine neurons to the stimulating effects of ethanol

Abstract

Clinical evidence indicates a frequent co-morbidity of nicotine and alcohol abuse and dependence. The posterior ventral tegmental area (pVTA) appears to support the reinforcing and dopamine-stimulating effects of both drugs. The current study tested the hypothesis that repeated exposure of the pVTA to one drug would increase the sensitivity of local dopamine neurons to the stimulating effects of the other drug. Female Wistar rats received repeated daily microinjections of either 100 μM nicotine or vehicle directly into the pVTA for 7 days. On the 8th day, rats received microinjections of either vehicle or ethanol (100 or 200 mg%) into the pVTA while extracellular dopamine samples were collected from the ipsilateral nucleus accumbens shell (NACsh) with microdialysis. Another experiment tested the effects of challenge microinjections of 200 μM nicotine in the pVTA on extracellular dopamine levels in the NACsh following 7 daily pretreatments with 200 mg% ethanol in the pVTA. Nicotine pretreatments increased the dopamine-stimulating effects of ethanol in the pVTA (100 mg% ethanol: 115% vs 160% of baseline in the vehicle and nicotine groups, respectively, p < 0.05; 200 mg% ethanol: 145% vs 190% of baseline in the vehicle and nicotine groups, respectively, p < 0.05). In contrast, ethanol pretreatments did not alter the stimulating effects of nicotine in the pVTA. The results suggest that repeated exposure of the pVTA to nicotine increased the response of local dopamine neurons to the stimulating effects of ethanol, whereas repeated exposure of the pVTA to ethanol did not alter the responses of pVTA dopamine neurons to nicotine.

Figure 1

Representative placements of microdialysis probes in the nucleus accumbens shell (NACsh) and microinjection sites in the posterior ventral tegmental area (pVTA). Overlapping probes and injection sites are not shown for clarity purposes. 1A: The lines represent the 1.5-mm length of microdialysis probes in the NACsh. 1B: The open and filled circles represent microinjection sites within the pVTA.

Figure 2

Effects of challenge injections of ethanol (0, 100 or 200 mg%) into the posterior ventral tegmental area (pVTA) on extracellular dopamine levels in the nucleus accumbens shell following repeated exposure of the pVTA to either aCSF or nicotine (100 μM). ‘aCSF/aCSF’: group pretreated with aCSF and challenged with aCSF; ‘Nic/aCSF’: group pretreated with 100 μM nicotine and challenged with aCSF; ‘aCSF/100 E’: group pretreated with aCSF and challenged with 100 mg% ethanol; ‘Nic/100 E’: group pretreated with 100 μM nicotine and challenged with 100 mg% ethanol; ‘aCSF/200 E’: group pretreated with aCSF and challenged with 200 mg% ethanol; ‘Nic/200 E’: group pretreated with 100 μM nicotine and challenged with 200 mg% ethanol. * p < 0.05, significantly greater than levels in the corresponding aCSF-treated group. # p < 0.05, significantly greater than baseline levels.

Figure 3

Effects of challenge injections of nicotine (200 μM) into the posterior ventral tegmental area VTA (pVTA) on extracellular dopamine levels (averaged peak values of extracellular dopamine levels during the 0–40 min period after the initiation of the challenge injection) in the nucleus accumbens shell following repeated exposure of the pVTA to either aCSF or 200 mg% ethanol. ‘aCSF-Nic’: nicotine induced dopamine release in aCSF-pretreated rats; ‘EtOH-Nic’: nicotine induced dopamine release in ethanol-pretreated rats. For simplicity, baseline levels from only one group were presented because baseline levels were almost identical in the two groups. The insert shows time-course effects of microinjections of nicotine on dopamine release in the nucleus accumbens shell after pretreatments. Since there was no significant differences between groups receiving either aCSF or 200 mg% ethanol pretreatments (F_{1, 16} = 2.16, p = 0.16), data were collapsed across groups. * p < 0.05, significantly greater than baseline levels.