Repeated exposure of the posterior ventral tegmental area to nicotine increases the sensitivity of local dopamine neurons to the stimulating effects of ethanol
Introduction
Alcohol drinking and tobacco smoking have been frequently reported to be co-used and/or co-abused in humans. The rates of alcohol abuse or dependence were two to three times more in regular smokers or nicotine dependent individuals than in the general population, and increased with the number of cigarettes smoked (Grant, Hasin, Chou, Stinson, & Dawson, 2004; John, Hill, Rumpf, Hapke, & Meyer, 2003). Approximately 90% of individuals diagnosed with alcohol dependence reported cigarette smoking and/or nicotine dependence, a rate significantly higher than that in the general population (Batel, Pessione, Maitre, & Rueff, 1995; Burling & Ziff, 1988; Grant et al., 2004). The amount of cigarette smoking in alcoholics is positively correlated with the amount of alcohol consumed and severity of alcohol dependence (Batel et al., 1995; Burling & Ziff, 1988; Dawson, 2000). Furthermore, concurrent dependence on alcohol and nicotine reduced the likelihood of cessation from tobacco smoking or alcohol drinking (DiFranza & Guerrera, 1990; Miller, Hedrick, & Taylor, 1983).
Research in rodents also indicates an inter-relationship between alcohol and nicotine. Cross tolerance developed between ethanol and nicotine (Burch, de Fiebre, Marks, & Collins, 1988; Collins, Burch, de Fiebre, & Marks, 1988). The sensitivity to and preference for ethanol in animals appear to be correlated with responsiveness to nicotine. Rodents selectively bred for high sensitivity to ethanol stimulation were also more responsive to the effects of nicotine on locomotor activity (Bergstrom et al., 2003; de Fiebre, Dawson, , & de Fiebre, 2002). Alcohol-preferring P rats self-administered greater amounts of nicotine and exhibited more robust nicotine-seeking behavior than alcohol non-preferring NP rats (Le et al., 2006). High alcohol drinking C57BL/6 mice also showed greater preference for and consumed more nicotine solutions than the low alcohol drinking DBA/2 mice (Meliska, Bartke, McGlacken, & Jensen, 1995). Chronic voluntary drinking of ethanol by Wistar rats enhanced nicotine-induced locomotor stimulation (Blomqvist, Ericson, Johnson, Engel, & Soderpalm, 1996). On the other hand, repeated exposure to nicotine increased voluntary ethanol drinking and preference (Blomqvist et al., 1996), whereas administration of a nicotinic receptor antagonist or partial agonist reduced ethanol drinking (Blomqvist et al., 1996; Kamens, Andersen, & Picciotto, 2010). Mice lacking the α7 subunit of the nicotinic receptor consumed less ethanol than wild type mice (Kamens et al., 2010). Repeated exposure to nicotine also increased ethanol-induced locomotor activation, as well as dopamine release and turnover in the limbic forebrain (Blomqvist et al., 1996; Johnson, Blomqvist, Engel, & Soderpalm, 1995). Furthermore, a recent study indicated that an acute injection of nicotine 4 h prior to testing significantly increased ethanol seeking behavior and relapse-like drinking in P rats (Hauser et al., 2011).
The mesolimbic dopamine system appears to be a common substrate mediating the action of alcohol or nicotine. Systemic administration of either drug preferentially increased dopamine release in the nucleus accumbens (NAC; Di Chiara & Imperato, 1988), one region closely involved in mediating the reinforcing and rewarding effects of drugs of abuse (Chao & Nestler, 2004; Koob & Volkow, 2010). Activation of dopamine neurons in the ventral tegmental area (VTA) appeared to mediate the dopamine-stimulating effects of either ethanol (Brodie, Shefner, & Dunwiddie, 1990; Ding, Rodd, Engleman, & McBride, 2009; Ding et al., 2011) or nicotine (Nisell, Nomikos, & Svensson, 1994a, 1994b; Sziraki, Sershen, Hashim, & Lajtha, 2002). Nicotine is rewarding within the VTA as indicated by conditioned place preference induced by intra-VTA administration of nicotine (Laviolette & van der Kooy, 2003). Ethanol or nicotine can be self-infused into the VTA, specifically the posterior VTA (pVTA), indicating the pVTA as an anatomical substrate supporting the reinforcing effects of both nicotine and ethanol (Ikemoto, Qin, & Liu, 2006; Rodd-Henricks, McKinzie, Crile, Murphy, & McBride, 2000). Furthermore, acute exposure to ethanol or nicotine produced similar synaptic plasticity in the VTA, involving increased glutamate synaptic function onto dopamine neurons (Saal, Dong, Bonci, & Malenka, 2003). Therefore, the mesolimbic dopamine system originating from the pVTA and projecting to the NAC could be a neural substrate underlying the interaction between alcohol and nicotine.
Given these findings, it is possible that prior exposure of one drug could influence the effects of the other drug on the mesolimbic dopamine system. One recent study using a combined microinjection-microdialysis technique demonstrated that repeated exposure of the pVTA to ethanol sensitized the responses of local dopamine neurons to the stimulating effects of a subsequent ethanol challenge (Ding et al., 2009). Therefore, the current study utilized the same technique and investigated the interaction between ethanol and nicotine on the mesolimbic dopamine system. The hypothesis to be tested was that prior exposure of the pVTA to one drug would increase the sensitivity of local dopamine neurons to the simulating effects of the other drug.
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Animals
Adult female Wistar rats (weight 270–320 g, Harlan, Indianapolis IN, USA) were housed in temperature- and humidity-controlled rooms maintained on a reversed 12-hr light cycle (light on at 9:00 p.m.). Food and water were available ad libitum. Female rats were used because these rats maintain their head size better than male rats for more accurate stereotaxic placements and have been used in previous studies requiring precise cannula placements (Ding et al., 2009; Rodd-Henricks et al., 2000). The
Results
Fig. 1 shows the representative placements of probes and injection sites. The probes were mainly in the NACsh (at least 75% of the active membrane). Some probes also covered a portion of the olfactory tubercle. The injection sites were mainly inside the pVTA at coronal sections from 5.3 mm to 6.0 mm posterior to bregma (Rodd-Henricks et al., 2000). Approximately 80% of rats had correct placements and were included in the analysis.
Fig. 2 shows the time-course effects of challenge microinjections
Discussion
The major findings of the current study are that repeated exposure of the pVTA to nicotine enhanced local ethanol-stimulated dopamine release in the NACsh, suggesting that prior nicotine exposure produced neuroadaptive changes within the pVTA, leading to increased sensitivity of local dopamine neurons to the stimulating effects of ethanol. On the other hand, repeated exposure of the pVTA to ethanol did not alter the stimulating effects of nicotine on pVTA dopamine neurons projecting to the
Acknowledgments
We thank Sarah R. Hall, Erin M. Larrabee, and Joseph McClaren for their skillful technical assistance.
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