Neurons communicate with one another by secreting chemical signals called neurotransmitters. The neurotransmitters secreted from one neuron bind specific receptors on the membranes of other cells and elicit a cascade of responses in these cells. Dopamine is a neurotransmitter that regulates a diverse array of biological processes including cognition and emotion, motivation and reward, locomotion, and the release of certain hormones. Imbalances in the dopamine system have been implicated in disorders as diverse as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease, and hypertension. The mammalian genome encodes five different receptors for dopamine that can be grouped into two classes based on their cellular signaling and sequence homology. The various types of receptors are thought to mediate different biological functions and are implicated in different disorders. The two classes of dopamine receptors can also be distinguished pharmacologically, but this discrimination is not absolute. Furthermore, it is much more difficult to distinguish pharmacologically between receptors within the same class. A given drug often acts on multiple receptors, producing unwanted side effects. Thus, having highly specific drugs for the various dopamine receptors is critical for the successful treatment of a disorder that involves a particular dopamine receptor type with minimal side effects. Since many neurons express multiple types of dopamine receptors, it is currently impossible to attribute the effects of a particular drug to a specific receptor. Clinically, this gap of knowledge translates into an inability to predict and address the side effects of a given drug. Here we present a novel molecular method to selectively record activation of a particular dopamine receptor subtype in the murine brain. Since our system is extremely selective, it can be used to unequivocally determine which receptor subtype has been activated in a particular neuron in response to a given drug. This is accomplished regardless of the presence of other kinds of dopamine receptors in this neuron. The animal models that we will generate will enable the development and testing of specific drugs with fewer side effects. Moreover, our technology can be used to identify changes that occur in particular circuits in mouse models for human diseases such as schizophrenia and Parkinson's disease, providing clues regarding the mechanisms underlying the progression of these diseases. Finally, the current inability to monitor the activation of a particular receptor subtype also applies to other families of receptors. Since our system is modular, it can be readily adapted to study other receptors. A method to selectively monitor activation of specific receptors in an animal model will thus have a major impact on a very broad segment of the biomedical research community.
We are proposing to generate a novel molecular method to selectively record the activation of a particular dopamine receptor subtype in an animal model. The dopamine system has been implicated in multiple disorders such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease and hypertension. The availability of such animal models will enable the development and testing of much more specific dopamine receptor agonists and antagonists with fewer side effects.
