Functional magnetic resonance imaging (fMRI) is an ideal technique for longitudinal studies to investigate long-term effects of chronic cocaine use because non-invasive imaging permits direct comparison of the acute response to drug in the same subject when drug naive, after chronic cocaine exposure, and in withdrawal. While ethical concerns preclude these studies in humans, they can be performed in animal models. Therefore, the purpose of this proposal is to use a non-human primate model to map the response to acute administration of cocaine with the high spatial and temporal resolution permitted by contrast agent- enhanced fMRI to elucidate the longitudinal adaptations of drug exposure and withdrawal. The rhesus monkey (Macaca mulatta) is an ideal candidate for these imaging studies because these animals can be trained to self-administer cocaine and neural adaptations have been identified after long-term cocaine exposure. More importantly, however, we have imaged a robust region-specific pattern of brain activation in the awake, behaving monkey produced by cocaine. Therefore, the goal of this proposal is to develop an awake, behaving non-human primate model of cocaine self-administration that is applicable for use in an MRI scanner. Accordingly, drug self-administration must be accomplished by awake macaques in a confined space, and with a minimum of motion. We propose to apply our extensive experience at training this species for awake, behaving imaging to the development of cocaine self-administration using eye-fixation as an operant conditioning technique. We will train macaques to make visual saccade and eye fixation on visual cues to signal self-administration and compare results of training with traditional lever pressing strategy modified for use in the MRI environment. We will employ these drug exposed monkeys to investigate longitudinal effects of long-term cocaine exposure and withdrawal on regional cerebral blood flow and cerebral vascular physiology critical to the formation of fMRI signal. We anticipate that these studies will elucidate how cocaine exposure and withdrawal influence acute response to drug anlteration in baseline perfusion. These studies will also inform us concerning adaptations of cerebral vasculature and aid in interpretation of fMRI data acquired in human subjects. ? ? ?
| Nelissen, Koen; Jarraya, Bechir; Arsenault, John T et al. (2012) Neural correlates of the formation and retention of cocaine-induced stimulus-reward associations. Biol Psychiatry 72:422-8 |
| Mandeville, Joseph B; Choi, Ji-Kyung; Jarraya, Bechir et al. (2011) fMRI of cocaine self-administration in macaques reveals functional inhibition of basal ganglia. Neuropsychopharmacology 36:1187-98 |
