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Brain-derived neurotrophic factor and cocaine addiction - PubMed

  • ️Fri Jan 01 2010

Review

Brain-derived neurotrophic factor and cocaine addiction

Jacqueline F McGinty et al. Brain Res. 2010.

Abstract

The effects of brain-derived neurotrophic factor (BDNF) on cocaine-seeking are brain region-specific. Infusion of BDNF into subcortical structures, like the nucleus accumbens and ventral tegmental area, enhances cocaine-induced behavioral sensitization and cocaine-seeking. Conversely, repeated administration of BDNF antiserum into the nucleus accumbens during chronic cocaine self-administration attenuates cocaine-induced reinstatement. In contrast, BDNF infusion into the dorsomedial prefrontal cortex immediately following a final session of cocaine self-administration attenuates relapse to cocaine-seeking after abstinence, as well as cue- and cocaine prime-induced reinstatement of cocaine-seeking following extinction. BDNF-induced alterations in the ERK-MAP kinase cascade and in prefronto-accumbens glutamatergic transmission are implicated in BDNF's ability to alter cocaine-seeking. Within 22 hours after infusion into the prefrontal cortex, BDNF increases BDNF protein in prefrontal cortical targets, including nucleus accumbens, and restores cocaine-mediated decreases in phospho-ERK expression in the nucleus accumbens. Furthermore, 3 weeks after BDNF infusion in animals with a cocaine self-administration history, suppressed basal levels of glutamate are normalized and a cocaine prime-induced increase in extracellular glutamate levels in the nucleus accumbens is prevented. Thus, BDNF may have local effects at the site of infusion and distal effects in target areas that are critical to mediating or preventing cocaine-induced dysfunctional neuroadaptations.

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Figures

Figure 1
Figure 1

BDNF expression within the meso-corticolimbic system. BDNF is expressed in glutamatergic pyramidal neurons arising from the PFC as well as dopaminergic neurons arising from the VTA, both of which synapse on GABAaergic medium spiny neurons within the NAc. BDNF itself is transported anterogradely to the striatum where it binds to TrkB receptors on medium spiny neurons. Labeling studies have demonstrated that a majority of BDNF expression within the NAc arises from the PFC, not the VTA. Glu=glutamate, DA=dopamine, GABA=gamma-aminobutyric acid.

Figure 2
Figure 2

In situ hybridization histochemistry performed on frontal sections after the end of cocaine self-administration demonstrates that Bdnf mRNA in the dorsomedial PFC was downregulated after 22 hr (A,B-left), but not after 21 days (B-right), of cocaine abstinence. C. BDNF protein expression was increased in the PFC 21 days after the end of cocaine self-administration in abstinent rats. SA=self-administration condition in which rats received cocaine in response to active lever presses or yoked-saline. Prime=i.p. injection of saline or cocaine given 30 min. before euthanasia. *p<0.05.

Figure 3
Figure 3

An intra-PFC infusion of BDNF attenuated extinction responding, cue- and cocaine-induced reinstatement of cocaine-seeking. (A) After 6 days of abstinence, the BDNF-treated rats exhibited significantly fewer active lever presses during the post-abstinence test than the vehicle-treated rats (***P=0.001). (B) The BDNF-treated rats exhibited significantly fewer active (***P<0.001) lever presses during the cue-induced reinstatement test than vehicle-treated rats. (C) The BDNF-treated rats exhibited significantly fewer active lever presses during the cocaine-induced reinstatement test than the vehicle-treated rats (*P<0.05). Modified from Berglind et al., 2007.

Figure 4
Figure 4

Intra-PFC BDNF infusion suppressed cocaine-seeking behavior (A) and normalized phospho-(p)ERK expression levels in the NAc (B), but not the caudate-putamen (C) of rats after a 30 min extinction test 22 hrs after the final cocaine SA session. *p<0.05. Avg SA 8, 9, 10=average number of active lever presses on the last 3 days of cocaine self-administration; 30 min Ext Test=30 min extinction test 22 hr after the 10th self-administration session; Coc-Veh=cocaine self administration and intra-PFC vehicle infusion; Coc-BDNF= cocaine self administration and intra-PFC BDNF infusion. Modified from Berglind et al., 2007.

Figure 5
Figure 5

A. BDNF normalized basal extracellular glutamate levels in the NAc of rats with a cocaine self-administration history. Intra-PFC BDNF treatment significantly increased the point of no net flux, indicating an increase in the basal extracellular glutamate concentrations in the rats compared with those that received intra-PFC vehicle infusions *p<0.05. B. Average area under the curve (AUC) values before and after a cocaine challenge in rats with a cocaine history. Veh-Base: average baseline AUC value for rats that received an intra-PFC vehicle infusion; Coc- Veh: average AUC value after the cocaine challenge for rats that received a vehicle infusion BDNF-Base: average baseline AUC value for rats that received an intra-dmPFC BDNF infusion; Coc- BDNF: average AUC value after the cocaine challenge for rats that received an intra-PFC BDNF infusion. * p<0.05 vs. Coc- BDNF; # p<0.05 vs. Veh-Base. Modified from Berglind et al., 2009.

Figure 6
Figure 6

BDNF protein expression levels, detected by ELISA, are significantly elevated in the NAc, basolateral amygdala (BLA), and central nucleus of the amygdala (CeA) of naïve rats 22 hrs after infusion of BDNF in to the dorsomedial PFC. N=6 per group.mPFC=medial prefrontal cortex; NAc=nucleus accumbens; lCPu=lateral caudate-putamen; mCPu=medial caudate-putamen. *p<0.05 vs. Vehicle-infused.

Figure 7
Figure 7

Pre-infusion with a BDNF scavenger, TrkB/Fc, prevented the suppressive effect of intra-PFC BDNF on cocaine-seeking during day 1 of extinction responding. V-V=vehicle-vehicle; V-B=vehicle-BDNF; Fc-V=TrkB/Fc-vehicle; Fc-B=TrkB/Fc-BDNF. Avg SA 8,9,10=average number of active lever presses on the last 3 days of cocaine self-administration; 2hr Ext Test= 2hr extinction test 22 hr after the 10th self-administration session. *p<0.05 vs. V-V; ##=p<0.005 vs. V-B; +=p<0.05 vs. Avg SA 8,9,10 within each group.

Figure 8
Figure 8

Schematic of BDNF/TrkB signal transduction. Activation of the TrkB receptor initiates downstream changes in CREB-dependent gene transcription via PI-3K, ERK/MAPK, and PLC-γ signaling.

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