Multimodal Neuroimaging x Optogenetics: A Novel Approach to Study Reward Processing Under Pathological Conditions
Final Report Abstract
Cocaine addiction is a brain disease and in the transition from recreational drug use to addicted behavior structural and functional changes occur that contribute to disease progression. The task of this project was to establish a DSM-IV/5 based rat model of cocaine addiction and to perform crosssectional and longitudinal multi-modal neuroimaging studies to pin-down neurochemical changes, structural alterations in white and grey matter, and changes in functional connectivity in the course of the addiction cycle. The expectations of this project were (i) to reveal neuroimaging-based biomarkers for cocaine addiction, (ii) to obtain neuroimaging-retrieved neuropathological mechanisms of addictive behavior, and (iii) to establish new interventions that would target these mechanisms. We established a DSM-IV/5 based animal model of cocaine addiction. Only 15% of the rats become addicted by this longterm cocaine self-administration procedure which mirrors exactly the human situation. By means of FDG-PET we could identify metabolic biomarkers for controlled drug use and loss of control. Specifically, we show that increased glucose metabolism in the caudate putamen and medial prefrontal cortex is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced metabolism in cortical areas are indicative of addictive behavior. Metabolic biomarkers would be of great help for clinical treatment development. Thus an intervention, whether pharmacological, behavioral, or neuromodulatory, should be able to restore metabolic prefrontal activity, which would then be indicative of regaining control of cocaine taking behavior. Future clinical studies should explore whether similar metabolic alterations are observed in recreational vs. addicted cocaine users. Other prognostic findings are related to grey matter volume (GMV) measurements. Our voxel-based morphometry shows that the behavioral differences characterizing addicted versus non-addicted animals are reflected by divergent co-variance with GMV. Thus structural imaging provides specific neuroanatomical correlates of behavioral sub-dimensions of addiction. These preclinical findings may inform future neuroimaging studies in addicted patients that will aim for structural markers that are predictive of behavioral diagnostic criteria given by DSM5. For getting mechanistic insights we constructed a multi-scale cerebral neurochemical connectome of the rat brain that in conjunction with our effective connective maps can retrieve specific neurochemical fingerprints of an addicted vs. nonaddicted brain. That neurochemical fingerprints in experimental rats are of high translational value as demonstrated by our longitudinal spectroscopy studies on glutamate concentrations – in different states of the addiction cycle addicted rats show very similar alterations in regional glutamate content when compared to human addicts. Consequently, we could show that targeting enhanced glutamate levels by activation of metabotropic glutamate 2 (mGluR2) receptors clearly reduces addictive behavior. Therefore, the application of mGluR2 agonists seems to be a new pharmacological intervention strategy for craving and relapse.
Publications
- (2012) Neurocircuitry for modeling drug effects. Addict Biol 17:827-864
Noori HR, Spanagel R, Hansson AC
(See online at https://doi.org/10.1111/j.1369-1600.2012.00485.x) - (2013) The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38:2048-2056
Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R
(See online at https://doi.org/10.1038/npp.2013.106) - (2014) CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects. Front Behav Neurosci 8:212
Bilbao A, Rieker C, Cannella N, Parlato R, Golda S, Piechota M, Korostynski M, Engblom D, Przewlocki R, Schütz G, Spanagel R, Parkitna JR
(See online at https://doi.org/10.3389/fnbeh.2014.00212) - (2014) Incubation of cocaine seeking following brief cocaine experience is enhanced by mGluR1 blockade. J Neurosci 34:1781-1790
Halbout B, Bernardi RE, Hansson AC, Spanagel R
(See online at https://doi.org/10.1523/jneurosci.1076-13.2014) - (2016) Impairment of cocaine-mediated behaviours by clinically relevant Ras-ERK inhibitors. Elife
Papale A, Morella IM, Indrigo MT, Eugene Bernardi R, Marrone L, Marchisella F, Brancale A, Spanagel R, Brambilla R, Fasano S
(See online at https://doi.org/10.7554/elife.17111) - (2017) A multi-scale cerebral neurochemical connectome of the rat brain. Plos Biol
Noori HR, Schöttler J, Ercsey-Ravasz M, Cosa-Linan A, Varga M, Toroczkai Z, Spanagel R
(See online at https://doi.org/10.1371/journal.pbio.2002612) - (2017) Melatonin reduces motivation for cocaine selfadministration and prevents relapse-like behavior in rats. Psychopharmacology
Takahashi TT, Vengeliene V, Spanagel R
(See online at https://doi.org/10.1007/s00213-017-4576-y) - (2017) Persistent strengthening of the prefrontal cortex - nucleus accumbens pathway during incubation of cocaine-seeking behavior. Neurobiol Learn Mem 138:281-290
Luís C, Cannella N, Spanagel R, Köhr G
(See online at https://doi.org/10.1016/j.nlm.2016.10.003) - (2017). In vivo structural imaging in rats reveals neuroanatomical correlates of behavioral sub-dimensions of cocaine addiction. Addict Biol
Cannella N, Cosa-Linan A, Buchler E, Falfan-Melgoza C, Weber-Fahr W, & Spanagel R
(See online at https://doi.org/10.1111/adb.12500)
