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ADMINISTRATION BEHAVIOR: STUDIES IN
ALCOHOL-PREFERRING AA AND ALCOHOL-
AVOIDING ANA RATS
Helsinki, Finland
with them, such as the opioid systems, have been implicated in the development of
drug addiction. The role of these neuronal systems in alcohol addiction has been
examined using the alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA
(Alko Non-Alcohol) rat lines, developed in this laboratory. Data from microdialysis
studies reveal that extracellular dopamine is elevated in the nucleus accumbens after
an acute injection of ethanol similarly both in ethanol naive AA and ANA rats, and
that the rats do not become sensitized to this effect after repeated administration of
ethanol. Since only small increases in accumbal dopamine levels are found during
ethanol drinking, dopamine does not seem to be crucially involved in the mediation
ethanol reinforcement in AA rats.
ANA rats. Furthermore, the AAs show higher locomotor activity after morphine
administration and are more liable than the ANAs to the sensitizing effects of
repeated opioid injections on locomotor activity and dopamine overflow in the
nucleus accumbens. These observations are in line with the findings showing that
especially the content of proenkephalin mRNA is higher in the brain of AA than ANA
rats and that there are differences in the density of the mu opioid receptors in
numerous brain parts, particularly in the shell of nucleus accumbens and in the
prefrontal cortex, the AA rats showing higher densities than the AA rats. Such
differences are not seen in delta receptor density.
mu receptor antagonist CTOP and delta receptor antagonist naltrindole on ethanol
self-administration in an operant chamber and on ethanol-induced dopamine overflow
in the nucleus accumbens, has been studied in AA rats. In these experiments
administration of CTOP and naltrindole into the nucleus accumbens or basolateral
amygdala decreases ethanol responding whereas injections into the VTA have little
effect on ethanol intake. Ethanol-induced increase in the extracellular levels of
dopamine is also attenuated by CTOP and naltrindole. Since nonselective opioid
antagonist naltrexone attenuates ethanol intake dose-dependently also in animals that
have received injections of 6-hydroxydopamine into the nucleus accumbens, the
suppressive effect of opioid antagonists on ethanol self-administration is probably,
however, not based on the inhibition of ethanol-induced dopamine release by opioid
antagonists in the nucleus accumbens.
Brain dopamine may, however, play a role in other behavioral functions related to
ethanol intake. There are strain specific differences in the opioidergic systems among
the AA and ANA rats suggesting a role for the opioidergic mechanisms in the
mediation of ethanol intake. This view is supported by findings showing that opioid
antagonists decrease ethanol drinking and responding by AA rats.
OPIOID ANTAGONISTS IN TREATMENT OF
ALCOHOLISM: A REVIEW OF HUMAN STUDIES
from alcohol dependence suggest efficacy. While in earlier studies abstinence was the
usual treatment goal, naltrexone has now been tested as a treatment to improve control
of drinking, rather than achieve abstinence. The basis for this controversial approach
is that naltrexone’s chief effect appears to be to reduce the frequency of heavy
drinking sessions rather than prolonging complete abstinence.
In the clinic, it is important to monitor objectively the progress of patients taking
these medications, because only a proportion will respond. There are few pointers, as
yet, to help decide which patients are likely to be responders. However, current
research suggests that one particular type of clinic patient who should be offered an
opioid antagonistis the person who declines to aim for abstinence.
The culture of the treatment setting may have influence whether opioid antagonists
are effective. The multicentre study Veterans Administration study, where abstinence
oriented twelve-step facilitation was the predominant treatment, failed to show a
benefit from naltrexone. This result may represent the greater difficulty in showing
efficacy of a drug when studies move from single centre, research-oriented, settings to
a wider range of services. On the other hand, it may be further evidence, seen in other
studies, that coping skills therapy, which teaches handling rather than avoiding
drinking situations, is the most appropriate conjunctive psychotherapy approach when
an opioid antagonist is prescribed.
CANNABINOID RECEPTORSIN THE
CONTROL OF ALCOHOL INTAKE
the opioid and cannabinoid CB1receptors may reduce alcohol intake and
reinforcement in different animal models of alcoholism. The present investigation
extended to the agonists the study on the role of the opioid and cannabinoid receptors
in controlling alcohol consumption.
The present study was conducted using the Sardinian alcohol-preferring (sP) rats, a rat
line selectively bred for high alcohol preference and intake. Rats were individually
housed and offered a choice between 10% (v/v) alcohol and water under the
homecage, two-bottle regimen with continuous access for 24 hour/day. In all
experiments, recording of alcohol intake was limited to the first hour of the dark
phase of the light/dark cycle.
The cannabinoid receptor agonists, WIN 55,212-2 (0, 0.5, 1 and 2 mg/kg; i.p.) and CP
55,940 (3, 10 and 30 mg/kg; i.p.), were acutely injected 20 min before lights off. Both
drugs induced a significant, dose-dependent stimulation of alcohol intake; at the
highest doses, the increase in alcohol intake averaged approximately 70-80% when
compared to vehicle-treated rats. Pre-treatment with doses of the cannabinoid CB1
receptor antagonist, SR 141716 (0.3 mg/kg; i.p.), or the opioid receptor antagonist,
naloxone (0.1 mg/kg; i.p.), which did not alter alcohol intake when given alone,
resulted in the complete suppression of the stimulation of alcohol intake produced by
2 mg/kg WIN 55,212-2 or 30 mg/kg CP 55,940 (Figure 1).
Morphine (0.3 and 1 mg/kg, s.c.) was administered acutely 20 min before lights off.
The dose of 1 mg/kg produced a significant increase, by approximately 70% when
compared to vehicle-dosed rats, in alcohol intake. This increase was completely
suppressed by pre-treatment with either 0.3 mg/kg SR 141716 (i.p.) or 0.1 mg/kg
naloxone (i.p.) (Figure 2).
The finding that alcohol drinking can be stimulated interchangeably by either
morphine or cannabinoids and is suppressed by either naloxone or SR 141716 may
suggest the hypothesis that CB1and opioid receptors involved in this effect coexist in
the same neuron, and that their concomitant activation is needed for the stimulating
effect to occur. Accordingly, the fact that blockade of one or the other receptor
prevents the stimulation of alcohol intake indicates that the morphine effect is
permitted by the concomitant activation of CB1receptors by endogenous
cannabinoids and, vice versa, opioid receptor activation by endogenous opioids is
needed for the cannabinoid response. Taken together, the results of the present study
add a further piece of evidence to the hypothesized cross-talk between opioid and
cannabinoid brain systems.
REDUCING EFFECT OF BACLOFEN ON ALCOHOL
INTAKE AND REINFORCEMENT - ANIMAL STUDIES
B. Brodie” Department of Neuroscience, University of Cagliari, Cagliari, Italy.
the reducing effect of the GABABreceptor agonist, baclofen, on alcohol intake and
reinforcement in selectively bred Sardinian alcohol-preferring (sP) rats.
An initial study from this laboratory demonstrated that the daily administration of 2.5
and 5 mg/kg (i.p.) baclofen dose-dependently reduced voluntary daily alcohol intake
in sP rats tested under the homecage, two-bottle free choice regimen between 10%
alcohol and water. Baclofen-induced reduction in alcohol intake was accompanied by
a significant increase in water intake, which left total fluid virtually unchanged. This
study used alcohol-experienced sP rats, which may model the “active drinking” phase
of human alcoholism.
More recently, this laboratory has found that the repeated administration of relatively
low doses of baclofen (1 and 3 mg/kg/day; i.p.) or of the GABABreceptor agonist,
CGP 44532 (0.1, 0.3 and 1 mg/kg/day; i.p.), suppressed the acquisition of alcohol
drinking behavior in sP rats which had never been exposed to the alcohol-water
choice before the start of the study (i.e., a model of the development of excessive
alcohol consumption in individuals at genetic risk of alcoholism). These results
suggest the involvement of the GABABreceptor in the mechanisms underlying the
disclosure and experience of the reinforcing properties of alcohol.
A subsequent experiment assessed the effect of baclofen on the alcohol deprivation
effect, i.e. the temporary increase in voluntary alcohol intake occurring after a period
of alcohol abstinence, which has been proposed to reflect the compulsive,
uncontrolled alcohol seeking and taking behavior characterizing alcohol relapses in
alcoholics. The acute administration of baclofen (1, 1.7 and 3 mg/kg; i.p.) resulted in