Available online at Changed accumbal responsiveness to alcohol in rats pre-treated with nicotine or the cannabinoid receptor agonist WIN 55,212-2 Jos´e Antonio L´opez-Moreno , Mar´ıa Scherma , Fernando Rodr´ıguez de Fonseca , Gustavo Gonz´alez-Cuevas , Walter Fratta , Miguel Navarro a Laboratory of Psychobiology, Faculty of Psychology, Campus de Somosaguas, Complutense University of Madrid, 28223, Madrid, Spain b B.B. Brodie Department of Neuroscience, University of Cagliari, 09042 Monserrato, Cagliari, Italy c Fundaci´on IMABIS, Avda Carlos Haya 82, 29010, M´alaga, Spain Received 14 April 2007; received in revised form 27 October 2007; accepted 29 November 2007 Abstract
Alcohol, nicotine, and cannabinoid acutely increase the activity of the mesolimbic dopamine (DA) pathway. Although polysubstance consumption is a common pattern of abuse in humans, little is known about dopamine release following pre-exposure to these drugs. The purpose of this studywas to test whether alcohol-induced dopamine release into the nucleus accumbens (NAc) shell is modified by different pre-treatments: water (i.g.),alcohol (1 g/kg, i.g.), nicotine (0.4 mg/kg, s.c.), and WIN 55,212-2 (1 mg/kg, s.c.). Male Wistar rats were treated (i.g.) for 14 days with either wateror alcohol. In the following 5 days rats were injected (s.c.) with vehicle, nicotine, or WIN 55,212-2. Finally, a cannula was surgically implantedinto the NAc shell and alcohol-induced extracellular dopamine release was monitored in freely moving rats. Alcohol (1 g/kg; i.g.) only increasedthe release of dopamine when animals were previously treated with water. This DA increase was markedly inhibited by (subchronic) treatment (5days) with nicotine or WIN 55-212-2 as well as by previous (chronic) exposure to alcohol (14 days). These data demonstrate that pre-treatmentwith nicotine and the cannabinoid agonist WIN 55,212-2 is able to change the sensitivity of the NAc shell in response to a moderate dose of alcohol.
Therefore, cannabinoid and nicotine exposure may have important implications on the rewarding effects of alcohol, because these drugs lead tolong-lasting changes in accumbal dopamine transmission.
2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Alcohol; Dopamine; Nicotine; Cannabinoid; Addiction; Polysubstance abuse The mesolimbic dopamine (DA) system has an important role In light of these observations, we performed a series of in the motivational aspects of rewarding stimuli (for reviews, experiments using a model of alcohol relapse: “Drug During see has an important role in the phenomenon Deprivation”. In brief, this model suggests that exposure to a of addiction to drugs such as alcohol, nicotine, and cannabi- drug challenge during the deprivation period of a chronically noids, among others , the role of dopamine, taken drug (distinct to the previous one) will cause a higher expressed as an increase in extracellular DA, has been observed probability of relapse after reinstatement of the regularly used in animal models as well as in human subjects com- drug. In our studies, the drug used regularly was alcohol. With mon element in the phenomenon of addiction is polysubstance this model we demonstrated that exposure to either nicotine or abuse of several different drugs. Both contingent administra- the cannabinoid receptor agonist WIN 55,212-2 (WIN) during tion (i.e., administration of drugs simultaneously or spaced by a alcohol deprivation, caused a long lasting increase in relapse to short period of time noncontingent polysubstance alcohol in order to explore the neurobiolog- abuse (i.e., the use of one drug during abstinence from another ical correlates for these observations, we designed the present study (see We have tried to establish an analogy withthe behavioral data previously shown. We are aware that thesedata referred to self-administration, but it is well known that forced alcohol intake, as well as alcohol self-administration, Corresponding author. Tel.: +34 91 394 31 89; fax: +34 91 394 30 69.
increases extracellular DA in the nucleus accumbens (NAc) E-mail address: (J.A. L´opez-Moreno).
1 Both authors have participated equally to this work.
particularly in the shell subregion. Similarly 0304-3940/$ – see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
doi: J.A. L´opez-Moreno et al. / Neuroscience Letters 433 (2008) 1–5 a dose of 1 ml/kg of body weight, were administered subcuta-neously for 5 consecutive days.
All rats were habituated to the chronic gavage procedure. For 5 days they were weighed everyday and intubated intragastri-cally to receive tap water (5 ml/kg) and then returned to theirhome cages. After that, half of the rats were assigned, in a coun-terbalanced way, to either alcohol or water treatment. Alcoholtreated rats received a daily dose of alcohol (10% w/v in tapwater, 1.0 g/kg; i.g.) for 14 consecutive days. Afterwards, theywere divided in three counterbalanced groups and assigned toone of the following treatments: vehicle, nicotine, or WIN. Injec- Fig. 1. Schematic representation of the “Drug During Deprivation” model used.
tions were given subcutaneously between the shoulder blades for The critical point is the avoidance of exposing animals to both drugs (either 5 consecutive days. Rats receiving water followed the same pro- alcohol–nicotine or alcohol–WIN 55,212-2) concomitantly for evaluating long- cedure. On day 6 in vivo samplings using microdialysis were carried out in all rats (see details).
Rats were anesthetized with Equitesin (5 ml/kg i.p.) and occurrences have been observed with nicotine and WIN placed in a stereotaxic frame (David Kopf Instruments, Tujunga, CA, USA). A concentric microdialysis probe with 2 mm dia- We consider the key point of this model is alcohol relapse lyzing surface length (AN 69AF; Hospal-Dasco, Bologna Italy; during exposure to a drug during the alcohol deprivation period.
cut-off at 40,000 Da, in vitro recovery about 30%) was implanted Therefore, we considered it of great interest to study the reg- vertically into the shell of the NAc and then fixed to the skull ulation of alcohol-induced extracellular DA after exposure to using dental acrylic cement. The coordinates relative to the nicotine or WIN during alcohol deprivation.
bregma were: AP + 1.7, L ± 0.7, V – 7.8 (according to the Pax- Male Wistar rats (Harlan, Italy) initially weighing between 200 and 250 g were used for these experiments. All animals Starting at 24 h after the implantation of the dialysis probe, were housed six per cage with food and water ad libitum except artificial cerebrospinal fluid (aCSF) (147 mM NaCl, 4 mM KCl, for the 6 h prior to intragastric alcohol (i.g.) treatment, during 1.5 mM CaCl2, pH 6–6.5) was pumped through the dialysis which they were food deprived. In this way, the stomachs of membrane at a constant rate of 2.5 ␮l/min with a CMA/100 all animals were normalized in a similar condition previous to microinjection pump (Carnegie Medicine, Sweden). Dialysate alcohol exposure. The animals were kept under a standardized samples (50 ␮l) were taken every 20 min and directly injected dark/light cycle (light 8:00 a.m. to 8:00 p.m.); 21 ± 1 ◦C room into a high performance liquid chromatography (HPLC) sys- temperature, and 60% relative humidity. All procedures were tem in order to quantify DA levels. The system consisted of conducted with strict adherence to the European Community an isocratic pump (ESA model 580), a 7125 Rheodyne injector connected to a Hewlett Packard series 1100 column thermo- The doses and route of administration were chosen based on stat with a reverse phase column (LC18 DB Supelco, 5 ␮m, the results obtained from our previous work The dose 4.6 mm × 150 mm), and an ESA Coulochem II detector. The first of alcohol (1.0 g/kg) corresponds approximately to the highest electrode of the detector analytical cell was set at +400 mV and alcohol intake of a Wistar rat during the 30 min alcohol self- the second at −180 mV; the column temperature was set at 30 ◦C.
administration session (approximately, 80–90% of the alcohol The mobile phase was delivered at 1.2 ml/min, consisting of: intake occurs during the first 10 min). The route of adminis- 50 mM sodium acetate, 0.073 mM Na2EDTA, 0.35 mM OSA, tration of alcohol (i.g.) was chosen because this is the most 12% methanol and pH 4.21 with acetic acid. All experiments common route used for alcohol ingestion. Furthermore, intra- were performed between 8:00 a.m. and 4:00 p.m.
gastric administration by a trained experimenter may produce The average value of DA levels in the last three pre-drug less stress in rats than other routes of administration (e.g. i.p.
(baseline) samples (varying no more than 10%) was taken as 100%, and all subsequent post treatment values were expressed The doses and route of administration of nicotine and WIN as mean ± S.E.M. percent variation of basal values. Only signifi- (0.4 mg/kg and 1 m/kg respectively, s.c.), were chosen according cant effects (P-values <0.05) from the two-way ANOVA analysis to our previous behavioral data, where their effects were charac- (time: repeated measures factor/treatment: between groups fac- terized over a range of doses Each animal was exposed tor) were subjected to Tukey’s honestly significant difference to single daily injections for 5 days of either nicotine or WIN test. These analyses were performed using the SPSS (Chicago, during the alcohol deprivation period, in an analogous way to IL, USA) statistical software package (version 11.0) for Win- Alcohol (10% w/v in tap water, 5 ml/kg) was administrated Pre-treatment with nicotine or WIN in animals exposed i.g. (1.0 g/kg) for 14 consecutive days. WIN 55,212-2 (Tocris chronically to water showed a significant blockade Cookson, Bristol, UK), which was dissolved in sterile physio- of DA levels induced by alcohol in the dialysate recov- logical saline with 0.1% Tween 80, and (−) nicotine bitartrate ered from the shell of the NAc with respect to the group (Sigma, Milan, Italy), which was dissolved in saline solution at pre-treated merely with vehicle (two way ANOVA: between J.A. L´opez-Moreno et al. / Neuroscience Letters 433 (2008) 1–5 Fig. 3. Changes in dialysate DA levels in the shell of the NAc after acute alcohol Fig. 2. Changes in dialysate DA levels from the shell of the NAc after acute administration (1 g/kg; i.g.) in rats chronically exposed to alcohol (1 g/kg; i.g.) alcohol administration (1 g/kg; i.g.) in rats chronically exposed to water (i.g.) and later subchronically treated (s.c.) with either vehicle, nicotine or the agonist and later subchronically treated (s.c.) with either vehicle, nicotine or the agonist cannabinoid WIN 55,212-2. Values are expressed as percentage of baseline. No cannabinoid WIN 55,212-2. Values are expressed as percentage of baseline, significant differences were found between vehicle, nicotine and WIN 55,212-2 *P < 0.05; **P < 0.01 (Tukey’s post hoc test), vehicle vs. nicotine and vehicle vs.
treatments F2,16 = 10.55 P = 0.001; within time F8,128 = 2.38 of DA is due to a phenomenon of cross-tolerance after exposure P < 0.05; interaction time × treatments F16,128 = 2.77 P = 0.001).
to nicotine or cannabinoid, and not due to a summation of effects The alcohol-induced increase in extracellular levels of DA in from either alcohol–nicotine or alcohol–WIN.
the NAc observed here (is consistent with other studies Finally, the basal extracellular levels (fmol/␮l of dialysate, n addition, other works have shown that WIN and nicotine mean ± S.E.M.) of DA in the NAc from different group of rats increase the efflux of DA in the NAc alcohol, did not differ significantly (one way ANOVA, P = 0.25 n.s.).
nicotine, and WIN can act directly or indirectly over a common These levels were the following (see group details): and limited resource: an increase in the extracellular levels of group water-vehicle: 55.6 ± 7.5 fmol/50 ␮l; group water-WIN: 55.6 ± 8.6 fmol/50 ␮l; water–nicotine: 54.3 ± 9.8 fmol/50 ␮l; The DA release elicited by alcohol was slightly lower when animals were treated chronically with alcohol and pre-exposed alcohol–WIN: 52.5 ± 7.9 fmol/50 ␮l; group alcohol–nicotine: to vehicle The peak DA concentrations in these animals were around 18% above baseline, which was not a significant Only the results derived from rats with correctly positioned difference (two way ANOVA: between treatments F2,16 = 2.45 dialysis probes were included in the data analysis. The loca- n.s.; within time F8,128 = 1.84 n.s.; interaction time × treatments tion of the probe was verified histologically at the end of each F16,128 = 0.70 n.s.). This suggests that DA release into the shell of experiment in coronal brain sections (50 ␮m) stained with cresyl the NAc is slightly modified after moderate alcohol exposure.
violet. ws a schematic illustration of the placement of Therefore, DA responsiveness would show a process of toler- the probes (see electronic supplementary material).
ance. Nevertheless, it is important to point out that the groups The major findings in the present study are the following: that were exposed to alcohol and pre-treated with nicotine and First, the administration of a moderate dose of alcohol (1 g/kg) WIN did not show DA release evoked by alcohol. This could be increased DA levels in the NAc shell when animals were exposed due to an increased tolerance to alcohol caused by the combi- to water and pre-treated with vehicle. Second, water exposed rats nation of nicotine or cannabinoid. However, this hypothesis can pre-treated with either nicotine or the cannabinoid receptor ago- be discarded because when the animals were never exposed to nist WIN showed a significant inhibition of the alcohol-induced alcohol, but were pre-treated with nicotine and WIN (see DA release. Third, no differences in DA levels were found we observed the same altered extracellular DA responsiveness.
between rats chronically exposed to alcohol and pre-treated Therefore, the decrease in alcohol-induced extracellular levels with either nicotine or WIN. And fourth, chronic alcohol expo- J.A. L´opez-Moreno et al. / Neuroscience Letters 433 (2008) 1–5 sure produced a reduction in the alcohol-induced DA release (a The neurochemical alterations mentioned above, as well as the lack of alcohol-induced DA release following WIN/nicotine The observed ability of alcohol to significantly increase pre-treatment shown here, could lead to an adjustment in addic- the extracellular levels of DA in the NAc is modest when tive behaviors in some individuals. It is interesting to note that compared with cocaine and methamphetamine. This finding is the blockade of alcohol-induced dopamine release in the shell nucleus acumbens by the administration of nicotine or WIN well as the cannabinoid receptor agonist WIN are could explain, in part, the significant increase in alcohol relapse found to increase DA levels in the NAc, but the latter effect may evaluated in operant self-administration when animals were not occur by a direct mechanism However, CB1 recep- exposed either to nicotine or WIN during alcohol deprivation tors seem to be crucial for alcohol-induced dopamine release Thus, we hypothesize that animals were less sensitive since it has been demonstrated that mice lacking these receptors to the effects of alcohol, which led to greater alcohol consump- do not show alcohol-induced dopamine release tion, as we showed previously. Low sensitivity to alcohol has alcohol, nicotine, and WIN are thought to act over a common been characterized as one of the best predictors for alcoholism mechanism: the increase in the efflux of DA in the NAc. Thus, the and a determinant of risk for becoming alcoholic release of DA would be compromised after chronic exposure to In this line, it has been widely demonstrated that dopamine alcohol, or subchronic exposure to nicotine or to a cannabinoid release and dopamine function are decreased in animal and receptor agonist. This process would be similar to the “stable human studies after chronic alcohol exposure. By using in vivo low changed state” during dopamine-mediated neurotransmis- microdialysis, it has been revealed that forced intoxication of sion described by Bonci et al. Moreover, in vitro studies alcohol as well as voluntary alcohol self-administration leads have shown that chronic alcohol exposure reduces nicotine- to a decrease in the release of dopamine in the nucleus accum- induced dopamine release in PC12 cells All together, bens Furthermore, electrophysiological studies show that these observations suggest that subchronic activation of nico- previous exposure to alcohol (e.g. prenatal and/or chronic tinic acetylcholine receptors, CB1 receptors, and other receptors exposure) results in lower activity of the ventral tegmen- affected by alcohol (essentially GABAergic and glutamatergic tal area, which highly innervates the nucleus accumbens receptors) may regulate the release of dopamine in the shell In humans, neuroimaging findings show that alcohol of the NAc. However, it should be taken in consideration that dependence is associated with a dysfunctional dopamine sys- alcohol has other actions in the central nervous system (e.g. on tem Taken together, these results support the view the opioid peptide and serotonin systems that may help of a tolerance to DA release following repeated alcohol explain, at least in part, the modest but significant increase of In conclusion, altered alcohol-induced DA release in the shell As commented, a previous exposure to nicotine or cannabi- NAc could explain the greater alcohol relapse after exposure noid receptor agonist seems to be more critical than the addition to nicotine and the cannabinoid agonist WIN, as previously of the two drugs: alcohol–cannabinoid or alcohol–nicotine.
reported. The decrease in the release of alcohol-induced DA after Consequently, two possible explanations are offered for the nicotine or WIN treatment could change the sensitivity of the reduction of alcohol-induced DA release observed when the mesolimbic DA system. This could be one of the factors under- animals were chronically exposed to alcohol and pre-treated lying the phenomenon of vulnerability to alcohol, assuming this with nicotine or WIN. On the one hand, this effect may be vulnerability is the predisposition to consume large amounts of caused by specific cross-tolerance between nicotine and alcohol.
Alcohol exposure would affect nicotinic acetylcholine recep-tors reciprocally, nicotine exposure would influence Acknowledgements
alcohol-induced modifications in glutamatergic and GABAergicneurotransmission For example, chronic nicotine expo- This work was supported by The European Fith Frame- sure causes the deactivation and subsequent upregulation of work Programme QLRT-2000-01691, Ministerio de Ciencia y nicotinic acetylcholine receptors On the other hand, this Tecnolog´ıa Grant BFI-2001-C02-01, Fondo de Investigaci´on diminished alcohol-induced DA release could be due to a spe- Sanitaria (Red Trastornos Adictivos), M.S.C (Plan Nacional cific cross-tolerance between cannabinoids and alcohol. Indeed, CB1 receptors and their functionality can be downregulated afterchronic alcohol exposure Moreover, this effect may result Appendix A. Supplementary data
from a more general process caused by the pre-exposure of anydrug of abuse that causes the release of dopamine t Supplementary data associated with this article can be found, is well known that repeated exposure to common drugs of abuse produces long lasting changes in the circuitry of reinforcement(for review, see Such changes affect dopaminergic, glu- References
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