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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
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.
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)
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.
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
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
< 0.05; **P
< 0.01 (Tukey’s post hoc test), vehicle vs. nicotine and vehicle vs.
2,16 = 10.55 P
= 0.001; within time F
8,128 = 2.38
of DA is due to a phenomenon of cross-tolerance after exposure
< 0.05; interaction time × treatments F
16,128 = 2.77 P
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 F
2,16 = 2.45
dialysis probes were included in the data analysis. The loca-
; within time F
8,128 = 1.84 n.s.
; interaction time × treatments
tion of the probe was verified histologically at the end of each
16,128 = 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
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
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
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International Journal of Environmental Engineering Research, Volume 1, Issue 1, 2012, 1-4 © Copyright 2012, All rights reserved Research Publishing Group Effect of application of amoxicillin and ampicillin on the commercial parameters of silkworm Bombyx Mori. L M. D. Anandakumar1*, Ann Sandhya Michael2 and S. R. Ananthanarayana2 1 Department of Biochemistry, Adarsh Institute of
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