Study of the Mnemonic Functions of Dopamine Using a Novel Molecular Imaging

Lay Summary

Can Molecular PET Imaging Show the Neurochemistry of Human Memory?

The investigators will use PET with a molecular tracer to see if this approach can reveal the neurochemistry of dopamine transmission that is involved in human memory.

The effects of impaired dopamine transmission on cognition in a number of neurological and psychiatric conditions is unclear, because scientists lack reliable methods for studying the neurochemical changes that are associated with cognition.  Conventional imaging has not been able to detect the relatively small and transient neurochemical changes in dopamine transmission that scientists suspect are involved in cognition.  To address this problem, the researchers have modified PET imaging by combining it with a molecular imaging technique.  This technique involves radioactively labeling a molecule that binds to the same receptor on brain cells to which dopamine usually binds.  According to the researchers’ prior studies, however, when dopamine is activated, it displaces this molecule.

The researchers, therefore, will use PET with this labeled molecular tracer in healthy volunteers to determine whether this technique can measure the extent to which dopamine displaces the labeled molecule on brain cell receptors during volunteers’ performance of nonprocedural memory tasks.  If so, the researchers would be able to identify aspects of human memory that are dopamine-dependent.  Success in using this technique in healthy volunteers would pave the way for using it in patients with conditions such as Parkinson’s disease and schizophrenia, to see how dopamine is altered in patients as they perform memory tasks.

Significance: The findings may provide a better understanding of the role of the neurotransmitter dopamine in human cognition and memory and may lead to the development of new therapies for diseases in which dopamine transmission is impaired, such as Parkinson’s disease, Huntington’s disease, Tourette syndrome, schizophrenia, bipolar disorder, and depression.

Abstract

Study of the Mnemonic Functions of Dopamine Using a Novel Molecular Imaging

Because of the lack of a reliable technique to study neurochemistry of human cognition, the brain regulation of cognitive functions has not been well understood. We have recently demonstrated that the neurotransmitter released during a cognitive task performance can be detected using the molecular imaging technique if the technique is appropriately modified to allow detection of transient and relatively small changes in receptor kinetics (expected during cognitive activations). In our experiments, we modified the technique and exploited the competition between endogenously released striatal dopamine and its ligand for receptor occupancy to show that dopamine released during performance of a motor planning and a procedural memory task displaces the ligand from receptor sites. The displacement suggested that endogenous dopamine is released during performance of the studied tasks.

In the proposed study we plan to use the modified method to test our hypotheses that molecular imaging can be used to explore the neurochemistry of human memory and to resolve controversies in cognitive concepts. Proposed experiments will probe dopaminergic involvement in the processing of nonprocedural memory tasks that are impaired following the striatal lesions. These tasks include associative, non-associative, and semantic memory tasks. Since nonprocedural memory tasks do not consistently activate the basal ganglia in neuroimaging experiments, despite being impaired in the patients with striatal lesions, the role of striatum in the processing of human nonprocedural memory is unclear. It is not known whether the inconsistency between the neuroimaging and lesion studies is due to subthreshold hemodynamic response or disruption of neural tracts in the brain-damaged patients.

Proposed experiments may help explain the inconsistency by probing involvement of striatal dopamine in the processing of nonprocedural memory. The results will provide better insight into dopaminergic control of human memory and will help in formulation of novel therapeutic strategies for the treatment of neurological and psychiatric conditions that are associated with impaired dopamine neurotransmission. These conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, schizophrenia, bipolar disorder, and depression. More significantly, the proposed study will provide preliminary data to help us develop the molecular imaging technique so that it can be used to study the neurochemistry and pathophysiology of cognitive disorders that are dependent on dopamine neurotransmission.