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Biopsychology
Dr. Paul
J. Fletcher, Head
 The Biopsychology Section focuses on the role
that 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 is to use
pharmacological and/or lesioning procedures to manipulate specific aspects
of neurotransmitter function, and to observe the resulting changes in
behaviour. Our current studies explore neurochemical mechanisms involved
in addictive behaviours, cognitive behaviours relevant to schizophrenia
and the mode of action of antipsychotic drugs.
Serotonin and Drug Use
A long-standing project in the Biopsychology
Section explores the consequences of altered serotonin function on reward-related
behaviour, with special emphasis on drug-seeking behaviour. Over the
past two years we have been especially interested in the role of a specific
serotonin receptor subtype, the 5-HT2C receptor, in modulating the behavioural
effects of drugs of abuse.
5-HT2C Receptors and Cocaine
We previously found that stimulation of 5-HT2C
receptors, with the 5-HT2C receptor agonist Ro60-0175, attenuated a
variety of behavioural effects elicited by cocaine, including cocaine
self-administration.
We have now determined that blocking the activity
of 5-HT2C receptors enhances the effects of cocaine. Specifically, the
5-HT2C receptor antagonist sb242,084 increases the locomotor stimulant
effect of cocaine, increases intravenous self-administration of cocaine
and potentiates cocaine's ability to induce relapse to cocaine-seeking
in subjects whose self-administration behaviour has been extinguished.
Our complementary findings with 5-HT2C agonists and antagonists demonstrate
that 5-HT2C receptors exert a bi-directional influence over the expression
of the effects of cocaine.
The 5-HT2C receptor is expressed in a part of
the brain, the ventral tegmental area (VTA), that gives rise to the
mesolimbic dopamine pathway, which is critically involved in mediating
the effects of many drugs of abuse. Our most recent findings indicate
that injecting the 5-HT2C receptor agonist Ro60-0175 into the VTA reduces
cocaine-induced locomotor activity, and cocaine self-administration.
Serotonin, acting via 5-HT2C receptors, modulates the effects of cocaine
specifically in the VTA, perhaps by indirectly altering the function
of the mesolimbic dopamine pathway.
5-HT2C Receptors and Other Drugs
A parallel series of studies examined the effects
of 5-HT2C receptor blockade on the locomotor stimulant effect of several
other drugs of abuse, including amphetamine, phencyclidine, morphine,
nicotine, and methylenedioxymethamphetamine (mdma). The receptor blockade
SB242,084 significantly increased the activation induced by all of these
drugs. The effect was most pronounced in the case of mdma. mdma releases
both serotonin and dopamine. The fact that 5-HT2C receptor blockade
greatly enhances the stimulant effect of mdma could indicate that, under
normal circumstances, serotonin acting via the 5-HT2C receptor subtype
might inhibit the activating effects of mdma. Removal of this inhibition
then leads to greater activation.
5-HT2C Receptors and Addiction
The 5-HT2C receptor has several different polymorphisms
and isoforms. We have observed that 5-HT2C receptor blockade leads to
exaggerated responses to drugs of abuse. This indicates that individual
differences in 5-HT2C receptor function could be one neurobiological
mechanism underlying vulnerability to addiction. We recently found,
in collaboration with Dr. Peter Clifton (University of Sussex, England),
that mice lacking 5-HT2C receptors show an increased behavioural response
to mdma. Thus, we have evidence that a genetic alteration in 5-HT2C
receptor function has an identical effect to pharmacological blockade
of 5-HT2C receptors.
Models of Schizophrenia: Amphetamine Sensitization
In a different line of research, we have been
collaborating with Dr. Shitij Kapur and Dr. Catherine Tenn (Schizophrenia
Research Division, CAMH) to explore the usefulness of amphetamine sensitization
as a model for schizophrenia. Repeated amphetamine use can induce psychosis
in humans, while in animals the behavioural responses to amphetamine
are augmented, or sensitized, with repeated use. Some people with schizophrenia
show augmented DA release, as inferred by a greater shift in the binding
of [3H]raclopride following a challenge with amphetamine. As well, some
people with schizophrenia exhibit a disrupted prepulse inhibition of
the acoustic startle response, which is thought to reflect altered information
processing.
We have shown that these behavioural and neurochemical
abnormalities are also present in rats exposed to a sensitizing regimen
of amphetamine. Thus, amphetamine sensitization could be a useful model
for understanding pathophysiological mechanisms in schizophrenia, as
well as mechanisms of action of antipsychotic drugs.
Models of Schizophrenia: Damage in the Prefrontal
Cortex
Dysfunctional dopamine activity is linked to
schizophrenia, and schizophrenia is a neurodevelopmental illness. We
know that the mesolimbic dopamine system is modulated by the prefrontal
cortex, including dopamine elements within the prefrontal cortex. We
have begun to explore the effects of early damage to dopamine in the
prefrontal cortex on adult behaviour. To date, we have found that even
modest damage to dopamine projections to the prefrontal cortex has repercussions
for the expression of adult behaviours. In particular, early-life damage
to prefrontal cortex dopamine appears to greatly facilitate the development
and expression of amphetamine sensitization.
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