Multiple
neurotransmitter systems have been implicated in modulating the behavioural
effects of alcohol, effects that have been linked to its abuse and dependence
liability. The focus of the Alcohol Research Section is to examine the
impact of selective manipulations of central neurotransmitter function
in animal models of alcohol-drinking and relapse behaviour to further
our understanding of the neurobiological mechanisms underlying excessive
alcohol consumption. In addition, the Section conducts research examining
the possible genetic factors involved in alcohol abuse, as well as co-abuse
of alcohol with other substances, such as nicotine.
Stress and Relapse to Alcohol Use
One
line of research is aimed at identifying factors involved in relapse to
alcohol. At present, our focus is the role of stress in relapse to alcohol.
All our work is carried out in experimental rodents. Over the last two
years we have shown that exposure to stress can potently reinstate alcohol-seeking
in animals in which their alcohol self-administration has been extinguished.
Corticotropin Releasing Factor (CRF), a peptide involved in stress co-ordination,
appears to play an important role in relapse to alcohol. Administration
of CRF can reinstate alcohol-seeking after a long period of abstinence
from alcohol and administration of a CRF antagonist can reverse stress-induced
relapse to alcohol.
Current
work aims at studying the interaction between CRF and the serotonin (5-HT)
system in stress-induced relapse to alcohol. We have found that fluoxetine,
a serotonin reuptake inhibitor, but not naltrexone, an opiate receptor
antagonist, can block stress-induced relapse to alcohol. Serotonin has
been shown to play an important role in behavioural inhibition. We are
working on a hypothesis that stress or CRF can cause behavioural disinhibition
and lead to resumption of drug-seeking behaviour. Such behavioural disinhibition
is mediated by the interaction of CRF with the serotonergic system.
Alcohol and Nicotine
A
second line of research deals with the interaction between alcohol and
nicotine. The prevalence of smoking in alcoholics or heavy drinkers is
about 95 per cent compared to about 25 per cent in the normal population.
We have shown that treatment with nicotine can enhance alcohol consumption.
In addition, we have also recently shown that rats that have been selectively
bred for high alcohol consumption self-administer more nicotine than do
those that were bred for low alcohol consumption. These studies suggests
possible common genes that determine alcohol and nicotine abuse. Current
work focuses on the nicotinic receptor subtypes that are involved in regulating
alcohol consumption by using rodent lines that have been selectively bred
for high and low alcohol consumption, as well as mice in which certain
subtypes of nicotinic receptors have been deleted.
This
work has been funded by the National Institute on Alcohol Abuse and Alcoholism,
Ontario Mental Health Foundation, and Pfizer Canada Inc.
Receptor Subtypes and Alcohol Reinforcement Processes
Studies
in humans and animals have suggested that there is an association between
the central neurotransmitter, 5-HT, and alcohol abuse and dependence.
5-HT interacts with many different receptors within the brain, which have
very different effects on human and animal behaviour and physiology. However,
recent converging evidence has suggested that one of these receptor subtypes,
the 5-HT1B receptor, may play an important role in modulating the rewarding
effects of alcohol. We have commenced a line of research to systematically
explore the role of this receptor subtype both in modulating alcohol self-administration
behaviour and in modifying the neurochemical consequences of alcohol intake
within discrete brain areas. Work completed to date supports the hypothesis
that 5-HT1B receptors may play an important and selective role in modifying
alcohol reinforcement processes. Future research will help identify the
brain areas and neurochemical substrates via which these effects are mediated.
Compelling
evidence at both the preclinical and clinical level has also suggested
that central GABAergic systems play an important role in regulating alcohol's
effects, particularly those mediated via the GABAA receptor. Of particular
interest, regional differences in the expression of the GABAA receptor
subunits have been demonstrated in the brains of high- alcohol preferring
rats and human alcoholics and it has been postulated that these differences
represent one of the neurobiological factors underlying alcohol abuse.
However, the influence of different populations of GABAA receptors within
the brain on voluntary alcohol intake has not been rigorously investigated.
We
have employed selective pharmacological manipulations of central GABAergic
systems within discrete neural pathways to determine their impact on alcohol
self-administration behaviour. We have shown that discrete injections
of GABAA, but not GABAB agonists, into the 5-HT cell body region, the
dorsal raphe, selectively increased alcohol self-administration, whereas
similar pharmacological manipulations in the adjacent brain area, the
median raphe, had non-selective effects. We have also demonstrated that
the increase in alcohol intake observed following activation of dorsal
raphe GABAA receptors is mediated, in part, via a facilitatory effect
on central dopamine neurotransmission.
The
novel data generated in this project has led to a multidisciplinary collaborative
research program between Drs. Tyndale, Norbrega and Tomkins, with funding
from the Ontario Mental Health Foundation. The project combines behavioural
and biological approaches to investi-gate if higher levels of GABAA receptor
subunits within discrete brain loci, which we observed in our preliminary
studies, are a predictor and/or a consequence of high alcohol drinking
behaviour.
A
central role of serotonergic and GABAergic systems in regulating alcohol
reinforcement and other behaviours related to the development of alcohol
abuse and dependence has been recognized for some time; this research
will provide new knowledge about the contribution made by specific elements
within the brain important for regulating these behaviours.
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