1996 — 2000 |
Shi, Wei-Xing |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Mesoprefrontal Da System and Antipsychotic Drug Action
DESCRIPTION (Adapted from applicant's abstract): The mesoprefrontal cortical (MC) dopamine (DA) system may play a key role in the development of schizophrenia. This application proposes to characterize this system using the newly developed in vitro technique. The long-term goal of this project is to understand how the MC DA system functions in the brain and how it may be altered by antipsychotic drug (APD) treatment. Information obtained from these studies may provide new insights into the pathogenesis of schizophrenia and the mechanism of action of APDs. Compared with other DA neurons, MC DA neurons are more active and particularly sensitive to stress. They also show distinct responses to APDs. To determine whether some of these unique properties are mediated intrinsically, identified MC DA cells will be recorded in a brain slice preparation. To determine whether they possess unique membrane properties that make them more active and more sensitive to synaptic inputs, their membrane properties will be compared with those other DA neurons. To determine whether a lack of DA autoreceptors plays a role in the observed differences between MC and other DA neurons, their function will be studied in nigral DA neurons. It will be investigated whether DA autoreceptors in nigral DA neurons inhibit excitatory input-induced responses, and whether MC DA neurons, due to a lack of autoreceptors, are more responsive to excitatory inputs. It will be determined whether APDs by blocking DA autoreceptors, selectively enhance the excitability of other DA neurons but not MC DA neurons. In the prefrontal cortex (PCC), DA has been suggested to be hypoactive in schizophrenia. However, since how DA acts in the PFC is still controversial, it is difficult to predict what the consequences of this hypoactivity would be and how it may be related to the hypofrontality observed in schizophrenia. To better understand the function of DA in the PFC, the second part of this application proposes to study the effect of DA on identified PFC neurons and correlate the response of a cell to DA with the cell's physiological, morphological and anatomical properties. To obtain information on how PFC DA influences mesolimbic and nigrostriatal systems, the effects of DA on PFC neurons projecting to the accumbens and the caudate will be compared. To test whether DA excites GABA interneurons, as suggested previously, they will be identified and recorded. Using selective DA agonists and antagonists, the receptors responsible for different DA effects will be determined. The application also proposes to compare the effects of clozapine and haloperidol on DA-induced responses of different PFC neurons. Such comparison may help us understand why clozapine is more effective in treating negative symptoms and lacks extrapyramidal side effects.
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1 |
2000 — 2004 |
Shi, Wei-Xing |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Da-NE Interaction in Drug Abuse
The reinforcing property of d-amphetamine and related psychostimulants has been attributed to their ability to block dopamine (DA) uptake and to increase DA release. Through the same mechanisms and by affecting feedback pathways of DA neurons, these drugs also inhibit DA cell firing. However, when DA-mediated feedback inhibition is blocked, d-amphetamine is found to powerfully excite DA cells, in part, through adrenergic alpha1 receptors. Thus, d-amphetamine produces two opposite effects on DA cells mediated by DA- and non-DA mechanisms, respectively. The non-DA-mediated excitation is mimicked by all psychostimulants tested and not by antidepressants, suggesting that it may have an important role in behaviors induced by psychostimulants. To further understand the significance of the non-DA effects, especially the alpha1-mediated increase in DA cell bursting, two series of studies are proposed. The first series will investigate further the mechanisms through which the alpha1 effect is produced by d-amphetamine. Selective antagonists will be used to identify the alpha1 receptor subtype responsible for the effect. DA neurons will be recorded in slices to confirm that the effect is not due to activation of alpha1 receptors on DA cells. Both in vivo and in vitro techniques will be used to test whether the effect involves areas, such as the prefrontal cortex and the raphe nucleus, known to express alpha1 receptors and to project to DA cells. The second series of studies will assess how the alpha1-mediated excitation may contribute to the acute and chronic effects of d- amphetamine on DA cells. The alpha1 effect will be blocked to see whether the blockade enhances the ability of d-amphetamine to inhibit DA cells. The response of DA cells to d-amphetamine will be examined in non-anesthetized rats to determine whether chronic treatment with d-amphetamine converts the response from an inhibition to an excitation, as reported previously. Studies will be carried out to further determine whether the conversion occurs with a time course parallel the development of behavioral sensitization and whether the excitation is alpha1-mediated. The proposed work will provide crucial information for a complete understanding of how psychostimulants may act through central DA neurons to produce their behavioral effects and may also provide information leading to the development of novel and effective treatments for drug abuse.
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1 |
2012 — 2013 |
Shi, Wei-Xing |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Prefrontal Control of Dopamine Neurons
DESCRIPTION (provided by applicant): Abnormal activity of dopamine (DA) neurons in the ventral tegmental area (VTA) has been suggested to play a key role in disorders including schizophrenia, drug addiction, and attention deficit hyperactivity disorder (ADHD). Evidence further suggests that the activity of VTA DA cells is under the influence of the prefrontal cortex (PFC), an area critically involved in the brain's executive functions including decision making and impulse control. However, due to the presence of multiple pathways between the PFC and VTA and due to the lack of selectivity of previous techniques, our understanding of how the PFC regulates DA cells remains limited. The goal of this project is to use recently developed optogenetic techniques to selectively activate or inhibit individual PFC-VTA pathways and then to study their effects on DA cells. The key hypothesis to be tested is that the PFC regulates DA neurons through both its direct and indirect projections to the VTA. However, due to the difference in synapses involved, different PFC-VTA pathways may conduct signals in different ways. To test these possibilities, two series of studies will be conducted. The aim of the first series is to express the excitatory channelrodopsin-2 (ChR2) in PFC neurons based on their projection site and then to test whether optical activation of different PFC-VTA pathways produces different effects on DA cells. To express ChR2 in PFC neurons projecting to the VTA, two adeno-associated viral (AAV) vectors will be used: a cre-dependent AAV carrying the ChR2 gene and an AAV encoding WGA-Cre fusion protein. Viruses containing the former will be injected into the PFC and those containing the latter into the VTA. Both in vivo and in vitro recordings will then be used to determine whether optical stimulation of the pathway alters the activity of DA cells. It is predicted that low-frequency stimulation excites DA cells projecting back to the PFC and produces no effect or an inhibition of DA cells projecting the nucleus accumbens (NAc). When stimulated at high frequencies, however, PFC terminals may excite NAc-projecting DA cells via volume transmission. To determine if the PFC also regulates DA cells indirectly, similar methods will be used to express ChR2 and to activate PFC neurons projecting to areas such as the NAc, pedunculopontine tegmental nucleus (PPT), and lateral hypothalamus (LH). The aim of the second series of studies is to understand the role of PFC-VTA pathways in the generation of firing patterns of DA neurons. Previous studies have shown that most spontaneously active VTA DA neurons display a slow oscillation (SO) in firing rate or rhythmic bursting. The activity is at least partially derived from the PFC since it is highly correlated with PFC local field potentials and is inhibited when PFC inputs are blocked. Further analysis suggests, however, that the SO is transferred to DA cells indirectly via inhibitory neurons. To identify the inhibitory pathway, the inhibitory halorhodopsin eNpHR will be expressed in PFC cells projecting to the VTA or NAc. If GABA neurons in the two areas relay the SO to DA cells, inactivation of the two pathways would reduce or eliminate the SO. PFC projections to the PPT and LH will be similarly studied to determine whether they influence only the baseline firing rate and are not required for the SO in most DA cells. The results of the above studies will provide a basis for further investigation of PFC control of DA neurons in schizophrenia, drug addiction, and ADHD.
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0.97 |