Biopsychology: CAMH Research Annual Report 2002

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.