Elsevier

Brain Research

Volume 1314, 16 February 2010, Pages 183-193
Brain Research

Research Report
Brain-derived neurotrophic factor and cocaine addiction

https://doi.org/10.1016/j.brainres.2009.08.078Get rights and content

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.

Section snippets

BDNF is a neurotrophic peptide that mediates synaptic plasticity including drug-induced neuroadaptations

BDNF, a member of the neurotrophin polypeptide family that includes nerve growth factor, neurotrophin-3, and neurotrophin 4/5, is the most widely and abundantly expressed neurotrophin in the nervous system (Thoenen, 1995). Like other neuropeptides, BDNF is synthesized as a pro-peptide (32 kDa) that is proteolytically processed into a smaller (13 kDa), mature form. This cleavage is thought by some to occur after secretion by the extracellularly located tissue plasminogen-activated plasmin (Lu,

Addictive drugs alter endogenous BDNF mRNA/protein expression in the mesocorticolimbic system

Key brain areas that are altered by drugs of abuse, particularly psychostimulants, are implicated in the reinstatement of drug-seeking. These structures include the PFC and its downstream target, the NAc. Both of these structures receive dopamine (DA) innervation from the ventral tegmental area (VTA) via the mesocorticolimbic DA (“reward”) pathway. Many cocaine-induced neuroadaptations that are thought to drive reinstatement of cocaine-seeking are manifested by alterations in the plasticity of

BDNF modifies drug-induced behaviors

Ventral midbrain or NAc BDNF infusions enhance motor activity, cocaine reinstatement after extended abstinence, as well as sensitization to cocaine and cocaine-conditioned cues (Altar et al., 1992, Guillin et al., 2001, Martin-Iverson et al., 1994, Martin-Iverson and Altar, 1996, Horger et al., 1999, Lu et al., 2004, Bahi et al., 2008). These reports suggest that elevated BDNF is associated with enhancement of dopamine neurotransmission, motor activation, and goal-directed behavior. Consistent

The effects of exogenous BDNF on drug-seeking are brain region-specific

Infusion of BDNF into subcortical structures, like the NAc and VTA, enhances cocaine- and opioid-seeking (Lu et al., 2004, Graham et al., 2007, Vargas-Perez et al., 2009). Conversely, repeated administration of BDNF antiserum into the NAc during chronic cocaine self-administration attenuates cocaine-induced reinstatement (Graham et al., 2007). Collectively, these studies implicate BDNF activity in the VTA and NAc in long-term modulation of cocaine-induced behavior, possibly by interacting with

BDNF regulates glutamatergic neurotransmission in the prefronto-accumbens pathway

The susceptibility to drug relapse and other addictive behaviors is thought to depend on long-term neuroadaptations in mRNA, proteins, and phospho-proteins in mesocorticobasal ganglia circuitry (Nestler, 2005, Kalivas and Volkow, 2005). These persistent neuroadaptive changes encompass alterations in molecular components at the synapse, changes in gene expression, and altered behavioral output. The PFC, a critical region for goal-directed behaviors and impulse control, is one of the brain

Prefrontal cortical Trk receptor binding is necessary for the expression of BDNF's suppressive effect on cocaine-seeking

Despite the finding that intra-PFC BDNF infusion suppresses cocaine relapse, the specific site(s) of action and molecular–cellular substrates of BDNF's behavioral effects are not fully understood. It is possible that BDNF has local effects at the site of infusion (PFC) as well as distal effects in PFC target areas like the NAc. Infusion of exogenous BDNF into the PFC can have implications for local postsynaptic neuroplasticity in PFC neurons. Interactions between extracellular BDNF and TrkB can

BDNF suppresses cocaine-seeking by altering TrkB-mediated intracellular signaling in the prefrontal cortex

A critical point at which BDNF likely intersects with the effects of psychostimulants is at the level of intracellular signaling. Alterations in TrkB-mediated activation of several distinct intracellular signaling cascades, including the mitogen-activated protein kinase (MAPK), the phospholipase C-γ (PLC-γ), and phosphoinositide 3-kinase (PI3K) cascades, provide a means by which BDNF mediates persistent neuroplasticity (Patapoutian and Reichardt, 2001). These cascades converge on nuclear

Summary

In summary, BDNF expression is associated with neuronal activity and synaptic plasticity. BDNF enhances synaptic transmission and promotes LTP by increasing dendritic protein synthesis and dendritic spine formation. BDNF also regulates drug-induced long-term neuroadaptations that encompass alterations in molecular components at the synapse, changes in gene expression, and modifications of behavioral output. The effects of BDNF on cocaine-seeking are brain region-specific. BDNF may have local

Acknowledgments

Funded by P50DA015369, RO1DA03982, T32DA07288, F31DA023743, and F31DA018500.

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