Biopsychology: Research Annual Report 2003

Section Head: Dr. Paul J. Fletcher

The Biopsychology Section studies the biological foundations of normal and abnormal behaviours relevant to psychiatry. Our work focuses on the role that brain neurotransmitter systems -- particularly the serotonin and dopamine systems and the interactions between these systems -- play in controlling behaviour. We mainly use pharmacological and/or lesioning procedures to manipulate specific aspects of neurotransmitter function and to observe the resulting changes in behaviour. Our work includes studies of the neurochemical mechanisms involved in addictive behaviour, cognitive behaviour relevant to schizophrenia and impulsive behaviour.

Serotonin Receptors and the Effects of Drugs of Abuse

Dopamine has been the neurotransmitter most closely linked to the behavioural and neurochemical effects of drugs of abuse. However, manipulating serotonin (5-HT) function also leads to changes in the behavioural effects of drugs of abuse.

In recent years, we have shown differing roles of two serotonin receptor subtypes, the 5-HT2A and 5-HT2C receptors, in modulating effects of cocaine. We have found that activating the 5-HT2C receptor reduces the locomotor stimulant and reinforcing effects of cocaine. Blocking this receptor leads to the opposite profile of effects. In contrast, blocking the 5-HT2A receptor reduces the stimulant effects of cocaine. In interpreting these results, we are trying to find whether the effects of 5-HT2C receptor agonists and antagonists alter the effects of other types of reinforcers, or whether they are specific to drug reinforcers.

We now have shown that, while the 5-HT2C agonist also reduces the reinforcing effects of food, the 5-HT2C antagonist does not enhance the reinforcing effects of food. The former effect is consistent with the notion that elevations in serotonin result in a generalized reduction in motivated behaviour. However, the latter finding implies that reducing serotonin transmission via the 5-HT2C receptor may have an effect that is restricted to cocaine.

Amphetamine Sensitization and Schizophrenia

Dr. Fletcher is part of a large, multidisciplinary project, led by Dr. Shitij Kapur (Schizophrenia Research Section), that received funding from the Ontario Mental Health Foundation to investigate amphetamine sensitization as a model for schizophrenia. Part of the rationale for this study is the observation that repeated psychostimulant use can induce psychosis in humans. In the Biopsychology Section, we will first examine whether amphetamine sensitization results in cognitive deficits that are also found in schizophrenia.

We have focused our attention on measuring changes in three behaviours; these behaviours are impaired in some people who have schizophrenia. The first is prepulse inhibition of the acoustic startle reflex, which reflects abnormal sensorimotor gating. The second is latent inhibition, which measures the ability to tune out, or ignore, irrelevant stimuli. The third can loosely be described as "cognitive flexibility," which is measured in humans by the Wisconsin Card Sorting Test.

Our results to date strongly indicate that amphetamine sensitization markedly disrupts these behaviours; this disruption is analogous to the disruptions that are observed in schizophrenia. Our results suggest that amphetamine sensitization appears to be a valid model for cognitive disturbances in schizophrenia.
In our future work, we will examine whether deficits caused by amphetamine sensitization can be reversed by antipsychotic drugs, and we will explore the neurobiological changes that may underlie these deficits.

Serotonin and Impulsivity

Impulsive behaviour is associated with reduced serotonin function, both in humans and in animals. However, we know little about which areas of the brain are involved in mediating impulsive behaviour, or which serotonin receptors are involved. We continued to explore both questions in the past year.

We compared the effects of lesioning either the prefrontal cortex or the nucleus accumbens to deplete serotonin innervation of these areas in tasks where subjects receive food reinforcement if they show a degree of inhibitory control. Our results to date suggest that depleting serotonin in the nucleus accumbens, but not the prefrontal cortex, leads to reduced inhibitory control.

In a second project, in collaboration with Dr. Guy Higgins (Schering-Plough Research Institute, New Jersey), using subjects receiving reinforcement for inhibitory control, we have found that 5-HT2A receptor antagonists reduce impulsive behaviour, but 5-HT2C receptor antagonists enhance this behaviour. Overall, our findings suggest that the relationship between reduced 5-HT activity and impulsivity is complex and may depend on which brain areas and which receptor subtypes are affected.

Our observation that 5-HT2A and 5-HT2C receptors have opposing influences on impulsive behaviour is similar to our finding that these receptors exert opposing influences over the expression of cocaine-mediated effects. This work is beginning to reveal the diversity and complexity of 5-HT receptor function at the behavioural level.

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