Cocaine is a powerful inhibitor of catecholamine transporters and chronic use of cocaine alters catecholamine dependent functions. Numerous studies have documented dampened dopaminergic signaling and reward response in relation to habitual drug seeking. On the other hand, relatively little is known about how noradrenergic processes influence drug use. A growing body of evidence suggests impaired cognitive control and altered prefrontal activities as well as noradrenergic deficits in chronic stimulant misuse. For instance, we observed impaired prefrontal cortical activation during inhibitory control in cocaine dependent individuals. In a pharmacological study, methylphenidate improved inhibitory control by influencing prefrontal cortical activation. Furthermore, these regional brain effects manifest with functional connectivity to the locus coeruleus (LC), suggesting a noradrenergic mechanism. Located in the midbrain, the LC provides the major source of noradrenergic inputs to the cerebral cortex and responds to salient stimuli to support arousal, attention and many other behavioral contingencies. However, the LC is a very small structure and exhibits low MR signals in conventional imaging. This limitation in spatial resolution and signal intensity may have hampered the research of LC in humans. Here we propose to address this issue by combining neuromelanin-sensitive MRI to identify the LC and ventral tegmental area/substantia nigra (VTA/SN) and fMRI of cognitive control. By accurately locating the LC and VTA/SN for individual participants, we seek to examine whether and how the noradrenergic and dopaminergic mechanisms of cognitive control are compromised in cocaine addiction. Forty-eight abstinent cocaine dependent individuals (CD) and 48 demographics matched healthy control individuals (HC) will participate in fMRI during performance of a stop signal task as well as a neuromelanin sensitive scan in the same native space. We hypothesize diminished LC signal intensity and LC response to salient stimuli as well as altered LC prefrontal functional connectivity and prefrontal activations during cognitive control in CD as compared to HC. We hope that the study will substantiate the role of noradrenergic circuits in an etiology of habitual drug use and facilitate the development of new therapeutic agents for cocaine addiction. If successful, the study may also have important implications for research of many other clinical conditions that implicate noradrenergic dysfunction.
Chronic cocaine users frequently report that they lose control of their drug using behavior. Many studies have suggested that loss of control is related to the effects of prolonged use of cocaine on cerebral functions mediated by catecholamines. Here we propose to examine the neural mechanisms of these deficits by imaging small nuclei in the midbrain that provide catecholaminergic inputs to the rest of the brain.
| Manza, Peter; Schwartz, Guy; Masson, Mala et al. (2018) Levodopa improves response inhibition and enhances striatal activation in early-stage Parkinson's disease. Neurobiol Aging 66:12-22 |
| Hu, Sien; Ide, Jaime S; Chao, Herta H et al. (2018) Structural and functional cerebral bases of diminished inhibitory control during healthy aging. Hum Brain Mapp 39:5085-5096 |
| Zhang, Sheng; Zhornitsky, Simon; Angarita, Gustavo A et al. (2018) Hypothalamic response to cocaine cues and cocaine addiction severity. Addict Biol : |
| Wang, Wuyi; Worhunsky, Patrick D; Zhang, Sheng et al. (2018) Response inhibition and fronto-striatal-thalamic circuit dysfunction in cocaine addiction. Drug Alcohol Depend 192:137-145 |
