The cocaine epidemic has produced a demand for pharmacologic treatments that may blunt either the dysphoria during pharmacologic withdrawal from cocaine, or the intense cue-triggered craving that often precedes relapse. Cocaine withdrawal has been attributed to mesolimbic dopamine depletion, while cue-induced craving has been linked to increased dopamine release in the same brain regions. Confirming the involvement of specific brain regions in either withdrawal or craving would be an important step in the understanding and in the treatment of these states. The proposed studies will measure and localize the change in brain activity during cocaine withdrawal and cue-induced craving states in humans, testing hypotheses about limbic involvement in both states. Changes in brain activity will be inferred from changes in regional cerebral blood flow (rCBF), known to closely reflect brain synaptic activity. Additional studies will assess the specificity of the effects, using the rCBF paradigm. One long-term objective of these studies is a single-session procedure that could be used simultaneously to screen for """"""""anti-withdrawal"""""""" and """"""""anti-craving"""""""" properties in potential medications for cocaine dependence. Specifically, the initial studies will image patterns of rCBF in abstinent cocaine patients during a single session featuring a resting baseline condition (Study 1a) and exposure to Cocaine-related and to Non-drug cues (Study 1b). A group of age and sex-matched controls without a cocaine history will be imaged under the same conditions. Imaging of rCBF will be accomplished with PET (Positron Emission Topography) scans, using radioactively labeled (0-15) water as the flow tracer. Regarding withdrawal (Study 1a), the hypothesis is that resting rCBF in recently abstinent cocaine users may be relatively lower than in controls, particularly in mesolimbic dopamine regions considered important for maintaining euthymia. Hypoactivity in these regions may underlie the dysphoria experienced by some cocaine users following cocaine cessation. Regarding craving (Study 1b), the hypothesis is that rCBF in the limbic regions of cocaine patients may increase in response to cocaine cues, reflecting the drug-like arousal and euphoria which often accompany cue-induced cocaine craving. Pilot data support this hypothesis: rCBF in several limbic regions increased significantly during cocaine cues in cocaine users, but this activation pattern was not evident in subjects without a cocaine history. Study 2 (cue specificity) will help rule out non-specific, unlearned responses as a source of the limbic pattern by testing Cocaine-related vs. Opiate (history-irrelevant) cues in cocaine patients. This study will also constitute a potential replication of findings from both Study 1a and 1b. Study 3 (state specificity) will rule out a common learned response, anxiety, as the source of the limbic findings by measuring the central and subjective response to Anxiety-provoking vs. Opiate (history-irrelevant) cues in cocaine patients. For each patient, functional PET images will be co-registered with an MRI (Magnetic Resonance Image), yielding flow data for limbic and comparison regions. ANOVAs will be used to compare resting rCBF for patients vs. controls, for left vs. right hemispheres, across limbic and non-limbic regions (Study 1a), and will measure the change in rCBF between cue conditions for both limbic and non-limbic regions, for left vs. right hemisphere, in patients (Study 2, Study 3) and in patients vs. controls (Study 1b). Correlations will examine the relationship between subjective symptoms and resting limbic rCBF (Study 1a), and between symptoms and activated rCBF during cocaine cues (Study 1b; Study 2) or anxiety cues (Study 3).
| Young, Kimberly A; Franklin, Teresa R; Roberts, David C S et al. (2014) Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues. J Neurosci 34:5038-43 |
| Suh, Jesse J; Langleben, Daniel D; Ehrman, Ronald N et al. (2009) Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients. Drug Alcohol Depend 99:11-7 |
| Franklin, Teresa R; Acton, Paul D; Maldjian, Joseph A et al. (2002) Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol Psychiatry 51:134-42 |
| Childress, A R; Mozley, P D; McElgin, W et al. (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11-8 |
