Biobehavioural Pharmacology
Heads: Drs. Denise Tomkins and A.D. Le
The research goals of the Biobehavioural Pharmacology Section are: to
understand the underlying mechanisms of behavioural and neurobiological
factors or processes that initiate and maintain alcohol dependence; and
to use this understanding to explore the potential development of therapeutic
agents for treatment of alcohol dependence. The majority of this research
has focused on two important behavioural processes related to alcohol
use and dependence: mechanisms underlying alcohol reinforcement and mechanisms
underlying relapse to alcohol drinking behaviour, with an emphasis on
the role of stress in relapse. During the past year, the section has continued
to explore the role of specific central neurochemical systems in regulating
these behavioural processes, in addition to examining the possible genetic
factors involved in problem drinking and concurrent problems with other
substances, such as nicotine.
Priming and Relapse
to Alcohol Use
Relapse has been the major challenge in treating alcohol dependence.
However, there has been little investigation of the mechanisms underlying
alcohol relapse in animal experimental models, due to a lack of an animal
model to study this phenomenon.
Over the last five years, the section's work has concentrated on developing
such an animal model and using it to study the neurobiological mechanisms
underlying relapse to alcohol use initiated by exposure to stress or by
re-exposure (priming) to alcohol.
The notion of "one drink leads to a drunk" illustrates the
action of alcohol re-exposure and relapse. We are exploring the neurobiological
mechanisms that allow re-exposure to small amounts of alcohol to trigger
relapse to alcohol. Using our animal model to study relapse to alcohol-seeking
behaviour, we found that priming with low doses of alcohol reinstates
alcohol-seeking. This was indicated by an increase in responding on a
lever previously associated with alcohol delivery. Naltrexone, but not
fluoxetine, blocks such reinstatement. Both of these compounds reduced
alcohol self-administration across species. The effect of naltrexone is
consistent with reports in humans, which showed that naltrexone has more
pronounced effects in reducing relapse in patients who drank some alcohol
during treatment. Current studies are examining the effects of environmental
cues previously associated with alcohol self-administration, and the role
of selective opioid receptor agonists and antagonists in priming-induced
reinstatement of alcohol-seeking behaviour.
Stress and Relapse to
Alcohol Use
Studies with humans suggest that stressful life events play a prominent
role in relapse to alcohol use. However, most, if not all, experimental
studies have focussed on the effect of stress on the quantity of alcohol
consumption, rather than the role stress plays in relapse. Despite the
extensive amount of research in this area, no clear picture has emerged
of how stress might affect alcohol consumption.
In our animal model, we have found that exposure to stress can produce
relapse to alcohol-seeking. This relapse effect is mediated by corticotropin
releasing factor, a hormone that co-ordinates stress response. This hormone
is released by stress and suppresses activity of the mesolimbic serotonin
pathway. This suppression has been shown to reduce inhibitory control.
We believe this is one of the major mechanisms in stress-induced relapse
to drug use.
5-HT Receptor Subtypes
and Alcohol Reinforcement Processes
Multiple neurotransmitter systems help to modulate the impact alcohol
has on the behaviours linked to problem alcohol use and alcohol's dependence
liability. A major focus of the section is on selectively manipulating
central neurotransmitter function in animal models of alcohol drinking
behaviour. It is hoped that this research will further our understanding
of the neurobiological mechanisms underlying excessive alcohol consumption.
Studies in humans and animals suggest an association between the central
neurotransmitter, 5-HT, and problem alcohol use and dependence. 5-HT interacts
with many different receptors within the brain. These receptors have very
different effects on human and animal behaviour and physiology. Over the
past several years, we have been assessing how modulating activity at
these various 5-HT receptor subtypes affects alcohol self-administration
behaviour.
Recent evidence suggests that the 5-HT1B
receptor, in particular, may play an important role in modulating the
rewarding effects of alcohol. Animal studies have demonstrated that manipulating
5-HT1B receptors can modify the reinforcing,
intoxicating and discriminative stimulus effects of alcohol. We have recently
identified two potential brain areas, the amygdala and the ventral tegmental
area, that may be important in mediating 5-HT1B
receptor effects on alcohol intake. By exploring the behavioural mechanisms
and the neural substrates involved, we will further our understanding
of the neural circuitry important in regulating drinking behaviour.
The relevancy of these findings for human alcohol dependence is supported
by a recent report suggesting a locus that predisposes people to antisocial
alcoholism is linked to the 5-HT1B
receptor gene. Such intriguing human data strongly support the need for
further research in this area.
We have previously reported that the 5-HT uptake blocker and releaser,
dexfenfluramine, also attenuates alcohol intake, and that reduction in
alcohol intake may be mediated via another 5-HT receptor subtype, the
5-HT2C receptor. We have continued
this research to further determine the role the 5-HT2C receptor subtype plays in modulating
alcohol intake. Research completed to date supports a role for 5-HT2C
receptors in modifying alcohol intake and further suggests that these
receptors, under normal situations, can limit the amount of alcohol consumed.
Further research will examine the behavioural mechanisms that mediate
this alteration in alcohol self-administration.
GABAA
Receptor Subunits, Drinking Behaviour and Voluntary Intake
Compelling evidence at both the preclinical and clinical levels also
suggests that central GABAergic systems play an important role in regulating
alcohol's effects, particularly those effects mediated via the GABAA
receptor.
Of particular interest are regional differences in the expression of
the GABAA receptor subunits. These differences
have been demonstrated in the brains of high-alcohol preferring rats,
and humans with drinking problems. It has been postulated that these differences
represent one of the neurobiological factors underlying problem alcohol
use. However, the influence of different populations of GABAA
receptors, within the brain, on voluntary alcohol intake has not been
rigorously investigated.
We have used selective pharmacological manipulations of central GABAergic
systems within discrete neural pathways to determine the impact of such
manipulations 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 observed increase in alcohol intake following GABAA
agonist injection is mediated, in part, by a facilitatory effect on central
dopamine neurotransmission -- the increase in alcohol intake is reversed
by the peripheral administration of selective dopamine antagonists. We
have further shown that this process involves increased activation of
dopamine receptors within the nucleus accumbens, because discrete blockade
of this receptor population also led to a selective reversal.
Our ongoing research includes examining the potential involvement of
serotonergic pathways in the circuitry linking dorsal raphe GABA mediated
effects with increased dopamine function within the nucleus accumbens.
GABAA receptors within the amygdala
have also been implicated in problem alcohol use and alcohol dependence,
although little behavioural data has been done to examine this phenomena
systematically. In future studies, we will examine the selective manipulations
of GABA function in this brain region, to see the impact of such manipulation
on alcohol self-administration behaviour and reinforcement processes.
The novel data generated in this project has led to a multidisciplinary
collaborative research program between Drs. Tyndale, Nobrega and Tomkins,
which has received funding from the Ontario Mental Health Foundation.
Recent data suggest that regional differences in GABAA
receptor expression and subunit conformation affect alcohol's rewarding
effects and the initial propensity to consume alcohol. In this program,
we have found significant differences in the GABAA
receptor between animals with a propensity to self-administer alcohol
and those without. Consistent with our observations, rat lines bred for
high- and low-alcohol preferences also exhibited differences in GABAA
receptor densities in specific brain regions.
The relevancy of these preclinical findings for human alcoholism is supported
by the reports that altered brain, cerebral spinal fluid and plasma GABA
levels are associated with alcohol dependence and withdrawal. In addition,
altered GABAA receptor binding, and region- and subunit-specific
changes in GABAA receptors, have been
reported in the brains of people who are alcohol-dependent. Finally, association
analyses have identified a tentative link between various GABAA
receptor subunit genes and a risk for alcoholism, which may be related
to differences in the expression of alcohol's behavioural effects. These
intriguing human data strongly support the need for further research in
this area.
Our current project combines behavioural and biological approaches to
investigate our preliminary observations: are higher levels of GABAA
receptor subunits within discrete brain loci a predictor and/or a consequence
of high-alcohol drinking behaviour? One aspect of this investigation,
largely neglected in previous research, relates to potentially crucial
differences between "self-administered" versus "experimenter-administered"
alcohol. There is considerable evidence that different neurochemical systems
may be involved in voluntary drug-seeking behaviour and in forced intake,
the former being more analogous to drug-taking by humans. However, much
of the research on neurochemical effects of alcohol has used force administration.
As a further aspect of our research, we will use rat lines selectively
bred for high- versus low-alcohol preference to explore this issue of
method of administration on alcohol's neurochemical effects. These studies
will provide information on the following aspects of alcohol drinking.
- Are there genetic differences in the GABAA
receptor system in brain regions that regulate alcohol consumption?
- Does alcohol cause additional changes to this receptor system in the
brain, and do these changes differ in the genetically bred high- and
low-alcohol drinking animals?
- Do the changes in the brain differ if the subjects are forced to drink
alcohol, as is done in most studies, compared to when they choose to
drink themselves?
This information is important for understanding the genetics of alcoholism
and for identifying neural substrates that could represent good targets
for developing pharmacotherapies to treat alcoholism. It has been recognized
for some time that serotonergic and GABAergic systems play a central role
in regulating alcohol reinforcement and other behaviours related to the
development of problem alcohol use and dependence.
We hope our research will provide new knowledge about the contribution
made by specific elements in the brain that are important for regulating
these behaviours.
|
1-800-463-6273
