Biopsychology
Head: Dr. Paul J. Fletcher
The Biopsychology Section studies the biological foundations of normal
and abnormal behaviours relevant to psychiatry. The major focus of our
work is the role that various brain neurotransmitter systems play in controlling
behaviour. We are particularly interested in the serotonin and dopamine
systems, and the interactions between these systems. Our general strategy
involves using pharmacological and/or lesioning procedures to manipulate
specific aspects of neurotransmitter function, and to observe the resulting
changes in behaviour. The range of work conducted in the section is broad,
encompassing studies directed toward understanding neurochemical mechanisms
involved in addictive behaviours, cognitive behaviours relevant to schizophrenia,
and the mode of action of antipsychotic drugs.
Research
Activities
5-HT2C
Receptors, Cocaine and Drug-Taking Behaviour
A long-standing project in the Biopsychology Section is concerned with
understanding the behavioural consequences of altered serotonin function
on reward-related behaviour, with special emphasis on drug-seeking behaviour.
During the past year we have focused on the 5-HT2C
receptor subtype and its potential modulation of behavioural effects induced
by cocaine. A selective agonist for this receptor was found to significantly
reduce the locomotor stimulant effect of cocaine and to reduce cocaine
self-administration. This agonist also blocked the ability of cocaine
to reinstate drug-seeking behaviour after responding for the drug had
been eliminated. We have also found that a 5-HT2C
antagonist increases the behavioural and rewarding effects of cocaine.
These results are important on two levels. First, they suggest that the
5-HT2C receptors may exert a tonic modulatory
influence over the mesolimbic dopamine system that directly mediates the
effects of cocaine. Second, these findings may have some implications
for pharmacological treatments of substance use problems, including relapse
to drug-taking behaviour. Currently, we are extending this work to examine
the effects of 5-HT2C receptor manipulations
on the effects of other drugs, including nicotine and opioids.
5-HT2C
Receptors and Ecstasy
MDMA (ecstasy) alters the activity of both dopamine and serotonin. Given
our interests in these two brain neurotransmitter systems, we have begun
to investigate the roles of these systems in mediating some of the behavioural
effects of MDMA.
In one completed study, we found that previous exposure to MDMA increases
the development of cocaine self-administration, and could indicate a higher
propensity to problems with cocaine or stimulant use. We do not yet know
the brain mechanism responsible for this effect -- it could involve either
reduced serotonin functioning or sensitization of dopamine systems. Our
future experiments will try to distinguish between these two mechanisms.
In keeping with our results on 5-HT2C
receptor function, we have found that the stimulant effects of MDMA are
greatly enhanced following treatment with a 5-HT2C
antagonist. This finding further illustrates the potential role that 5-HT2C
receptors could play in mediating effects of drugs of abuse.
Serotonin Damage and Ecstasy
Studies in animals have consistently shown that MDMA can damage brain
serotonin neurons, but there is considerable controversy over whether
this happens in humans. In collaboration with Dr. Martin Zack (Clinical
Neuroscience) and Dr. Stephen Kish, we have been investigating the effects
of light-to-moderate MDMA use on tests of impulse control. As
low serotonin function has been consistently linked to impulsive behaviour,
we are using tests of impulse control as a possible behavioural index
of damage to serotonin neurons in the human brain.
Dopamine Systems in
the Prefrontal Cortex
The prefrontal cortex (PFC) is involved in controlling attention, working
memory and response inhibition. Deficits in these processes have been
observed in people with schizophrenia. Schizophrenia is also associated
with disturbances of the neurotransmitters serotonin and dopamine. Within
the PFC, 5-HT modulates dopamine function. An ongoing project is examining
the roles of both of these systems in controlling attention, working memory
and response inhibition. We have also begun to investigate the impact
that early-life damage to dopamine systems in the PFC has on the expression
of these behaviours in adulthood.
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