The Neurobiology of Addiction Research Center (NARC)
BDNF Prevents Cocaine Abstinence-induced Neuroadaptations
Dr. Jacqueline McGinty
Project 2 - BDNF Prevents Cocaine Abstinence-Induced Neuroadaptations.
The primary goal of Project 2 is to characterize novel neurobiological substrates of addiction with a major focus on the role of brain-derived neurotrophic factor (BDNF). We have found that infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) after the last of 10 cocaine self-administration sessions suppresses extinction responding, and cue- and cocaine-induced reinstatement of cocaine-seeking.
Figure 1. Intra-dmPFC BDNF attenuates cocaine-seeking in rats. Top: experimental design. Bottom left: the number of lever presses 6 days after the BDNF infusion administered immediately after the last of 10 cocaine self-administration sessions is reduced. Bottom middle: the number of lever presses elicited by a tone/light conditioned cue after 6 days of extinction training is reduced. Bottom right: the number of lever presses elicited by cocaine prime-induced reinstatement of cocaine-seeking is reduced (adapted from Berglind et al., 2007a).
Although the precise mechanism is unknown, preliminary data suggest that exogenous BDNF is anterogradely transported to the nucleus accumbens (NAc) where it normalizes cocaine-induced alterations in extracellular glutamate (Figure 2-left) and phospho-ERK expression (Figure 2-right).
Figure 2. Left. Intra-dmPFC BDNF infusion prevents basal and cocaine prime-induced increase in dialysis glutamate levels in NAc (left-adapted from Berglind et al., 2007b) and attenuates a cocaine self administration-induced decrease in phospho-ERK MAP kinase in the NAc but not in the CPu (right- from Berglind et al., 2007a).
Our current hypothesis is that infusion of BDNF into the dmPFC suppresses cocaine seeking by preventing cocaine abstinence-induced neuroadaptations in dendritic mRNAs, spine morphology, and relapse-induced alterations in activity genes in the PFC and striatum.
Experimental strategy 1. What is the site of action of intra-PFC BDNF’s suppressive effects on cocaine seeking behavior? Using the BDNF scavenger, TrkB/Fc, the MEK/MAPK inhibitor, U0126, and the PI3K inhibitor, LY294002, we will determine whether BDNF/TrkB signaling in mPFC, NAc, or VTA constitutes an essential component of BDNF-induced behavioral suppression of relapse to cocaine seeking in abstinent rats.
Experimental strategy 2. Will infusion of BDNF into the dmPFC prevent alterations in the expression of dendritic mRNAs, PSD proteins, and dysmorphic dendritic spines in cocaine-abstinent rats?
The expression of a subset of mRNAs that are enriched in dendritic polysomes is altered in the mPFC 22 hr or 3 weeks after the end of cocaine self-administration (McGinty et al., in press). Some of these mRNAs, including BDNF, the protein phosphatase 1 binding protein, spinophilin, protein phosphatase 1 catalytic subunit beta (PP1cb), and the double-stranded RNA-binding protein, staufen 2, are required for the development and maintenance of dendritic spine morphology. Withdrawal from cocaine self-administration alters spine morphology and actin cycling in the mPFC and/or NAc. The molecular mechanisms for these neuroadaptations are thought to include alterations in protein turnover at the postsynaptic density (PSD) in dendritic spines that make excitatory synaptic contacts (see NARC Project 1). Thus, we will investigate whether an intra-PFC BDNF infusion immediately after the last of 10 cocaine self-administration sessions will prevent (a) changes in mRNA expression of gene candidates identified by microarray and confirmed by in situ hybridization in the PFC of abstinent rats, (b) changes in PSD proteins in NAc, and (c) the induction of dysmorphic dendrtic spines in the dmPFC and NAc after 2 weeks of abstinence.
Experimental strategy 3. Will infusion of BDNF into the mPFC prevent alterations in cortical activity markers after contextual relapse? A wide variety of drug-associated stimuli, including the context in which a drug is taken, can gain incentive motivational properties that trigger drug desire and relapse to drug-seeking. Further, both animal and clinical studies suggest that extensive cocaine exposure may induce a transition from cortical to striatal control over decision-making as compulsive drug-seeking emerges. Re-exposure to the environment previously associated with cocaine self-administration following 22 h or 15 d of abstinence produced a significant increase in zif/268 and arc in the PFC, caudate-putamen and nucleus accumbens (Hearing et al., 2007a, 2007b). Thus, we will investigate whether an intra-PFC BDNF infusion immediately after the last of 10 cocaine self-administration sessions will prevent the induction of arc and/or zif268 mRNA in the brains of rats that relapse to cocaine seeking after abstinence.
Figure 3. Activity-regulated cytoskeletal protein (arc) mRNA expression at the end of a 1 h extinction test, 15 d after the last cocaine or yoked-saline administration. Representative coronal hemi-sections illustrating the expression pattern of arc mRNA at PFC (left) and striatal (right) levels. SA=Saline Alternate Environment,SL=Saline Lever Available, SN=Saline No Lever, CA=Cocaine Alternate Environment, CN=Cocaine No Lever, CL=Cocaine Lever Available.
These studies will advance our understanding of the role of BDNF and its neurobiological substrates in addiction and lead to possible novel therapeutic targets in a collaborative environment that would not be possible NARC resources.
Berglind WJ, See RE, Fuchs RA, Ghee SM, Whitfield TW, Miller SW, McGinty JF. A BDNF infusion into the medial prefrontal cortex suppresses cocaine-seeking in rats. Eur J Neurosci 26:757-766, 2007a.
Berglind WJ, LaLumiere RT, Whitfield TW, Kalivas PW, McGinty JF. BDNF infusions into the prefrontal cortex prevent cocaine prime-induced glutamate increase in the nucleus accumbens of rats with a cocaine self-administration history. Soc Neurosci Abstr. 2007b.
Schwendt M, Hearing MC, See RE, McGinty JF. Chronic cocaine reduces RGS4 mRNA in rat prefrontal cortex and dorsal striatum. NeuroReport 18:1261-1265, 2007.
Hearing MC, Miller SW, See RE, McGinty JF. Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology 198:77-91, 2008.
McGinty, JF, Shi XD, Schwendt M, Saylor A, Toda S. Regulation of psychostimulant-induced signaling and gene expression in the striatum. J Neurochem 104:1440-9, 2008.
Hearing MC, See RE, McGinty JF. Relapse to cocaine seeking increases activity-regulated gene expression differentially in the striatum of abstinent rats. Brain Structure & Function (DOI 10.1007/s00429-008-0182-4).
McGinty JF, Matthew C. Hearing MC, Terri L. Schochet TL, William J. Berglind WJ, Saurin D. Jani SD. Activity and dendritic plasticity-related genes are altered in the medial prefrontal cortex after brief or prolonged withdrawal from cocaine self-administration (in press).
Whitfield TW, Berglind WJ, McGinty JF.Infusion of a recombinant human TrkB/Fc chimera into the dorsomedial prefrontal cortex blocks the suppressive effect of BDNF on cocaine-seeking behavior. Soc Neurosci Abstr. 2007.