Changes in growth factor signaling are hypothesized to be a major factor influencing the structural and behavioral plasticity associated with drug addiction. Human studies are limited. Drug-induced changes in serum BDNF have been observed in humans addicted to cocaine, amphetamine, alcohol, or opiates (Angelucci et al., 2007
; Janak et al., 2006
; Kim et al., 2005
), yet the source of this BDNF, and the relevance of these changes to the onset and maintenance of addiction have remained unclear. It would be interesting in future studies to examine BDNF and its signaling pathways in human postmortem brain tissue.
Over the past decade, work in rodents has established the influence of BDNF on various phases of the addiction process. Early studies showed that local infusion of BDNF into the VTA or NAc augments locomotor and rewarding responses to cocaine, while global loss of BDNF exerts the opposite effects (Hall et al., 2003
; Horger et al., 1999
; Lu et al., 2004
). More recent work has shown that cocaine self-administration increases BDNF signaling in the NAc (Graham et al., 2007
). In addition, an intra-NAc infusion of BDNF potentiates cocaine self-administration and cocaine-seeking and relapse, while infusion of antibodies against BDNF, or local knockout of the bdnf
gene in the NAc (achieved via viral expression of Cre recominase in floxed BDNF mice), blocks these behaviors. Based on these studies, Graham and colleagues (2007)
concluded that BDNF release in the NAc during the initiation of cocaine self-administration is a necessary component of the addiction process.
These data support the view that BDNF is a candidate molecule to mediate the structural changes in NAc neurons produced by chronic exposure to cocaine or other stimulants. According to this hypothesis, stimulant-induced increases in BDNF signaling in the NAc would induce an increase in dendritic arborization of NAc neurons, which would underlie sensitized behavioral responses to the stimulants as well as strong drug-related memories crucial for relapse and addiction. Consistent with this hypothesis are findings from cultured hippocampal neurons, where it has been shown that BDNF secretion induces protein synthesis-dependent enlargement of individual dendritic spines (Tanaka et al., 2008b
). The weakness of this hypothesis is that there has been no direct experimental evidence that enhancement of dendritic spines of NAc neurons per se is necessary or sufficient for sensitized drug responses. In fact, there are data that suggest a more complex relationship between the two phenomena: inhibition of Cdk5 in the NAc blocks the ability of cocaine to increase dendritic spines on NAc neurons, despite the fact that such inhibition potentiates locomotor and rewarding responses to cocaine (Norrholm et al., 2003
; Taylor et al., 2007
). Clearly, further work is needed to study the relationship between this structural and behavioral plasticity.
Another important caveat to this hypothesis is that changes in BDNF signaling may produce profoundly different effects on neuronal morphology and behavior depending on the brain region examined. Recent reports have drawn clear distinctions between BDNF function in the hippocampus versus VTA (Berton et al., 2006
; Eisch et al., 2003
; Krishnan et al., 2007
; Shirayama et al., 2002
): BDNF infusions in the hippocampus are antidepressant-like, whereas infusions of BDNF in the VTA or NAc produce prodepressant-like effects. Similar patterns are emerging in the addiction field. Notably, increased BDNF in the NAc enhances cocaine-induced behaviors (Graham et al., 2007
; Horger et al., 1999
), whereas in the PFC BDNF suppresses these same behaviors (Berglind et al., 2007
). Not surprisingly, the induction of BDNF by cocaine is also differentially regulated in these two brain regions, a pattern which further substantiates the behavioral differences (Fumagalli et al., 2007
Preliminary evidence has implicated NFκB signaling in the regulation of cocaine-induced structural and behavioral plasticity. Although the direct mechanism by which these changes occur is unknown, previous work has shown that the p75NTR, which is upstream of NFκB, is localized at the synapse and that p75NTR activation by BDNF is necessary for LTD. Although BDNF-TrkB interactions have been extensively studied in drug abuse, these data suggest an alternative pathway through NFκB that warrants further investigation. In line with this hypothesis, we have recently observed that viral-mediated overexpression of a dominant negative antagonist of the NFκB pathway in the NAc prevents the ability of chronic cocaine to increase the density of dendritic spines on NAc MSNs. Such inhibition of NFκB signaling also blunts sensitization to the rewarding effects of cocaine (Russo, Soc. Neurosci. Abstr. 611.5, 2007). These data, unlike the situation for Cdk5 cited above, support a link between increased dendritic arborization and behavioral sensitization to cocaine, further emphasizing the complexity of these phenomena and the need for further study.
Although limited work has addressed the relevance of neurotrophic factor signaling in opiate-induced behaviors, work from our laboratory has uncovered a role for BDNF and the downstream IRS2-PI3K-Akt pathway in the regulation of VTA dopaminergic cell size and subsequent reward tolerance (Russo et al., 2007
; Sklair-Tavron et al., 1996
). Specifically, chronic opiate administration in rodents produces a state of reward tolerance and physical dependence during relatively early periods of withdrawal that is thought to contribute to an escalation of drug-taking behavior. Early experiments found that intra-VTA infusion of BDNF prevents the morphine-induced decrease in VTA neuron size (Sklair-Tavron et al., 1996
). More recently, we have shown that the timeline of reward tolerance, as measured by conditioned place preference, parallels the timeline of reduced dopaminergic cell size and that these phenomena are mediated via BDNF signaling cascades (Russo et al., 2007
). As mentioned earlier, the biochemical signaling pathways in the VTA that are downstream of BDNF and the TrKB receptor are differentially regulated by chronic morphine: morphine activates PLCγ(Wolf et al., 2007
; Wolf et al., 1999
), decreases activity of the IRS–PI3K–Akt pathway (Russo et al., 2007
; Wolf et al., 1999
), and produces variable effects on ERK (see above). In light of recent evidence that Akt regulates the size of many cell types in the central nervous system (Backman et al., 2001
; Kwon et al., 2006
; Kwon et al., 2001
; Scheidenhelm et al., 2005
), we utilized viral gene transfer techniques to directly show that morphine produces reward tolerance through inhibition of the IRS2–PI3K–Akt pathway and reduced size of VTA dopamine neurons. These effects were not observed by altering ERK or PLCγ signaling, again pointing to the importance of IRS–PI3K–Akt signaling for this phenomenon. Future studies will address the relevance of BDNF and IRS–PI3K–Akt pathways in the escalation of opiate self-administration, a more clinically relevant paradigm to measure addiction. A greater understanding of the upstream changes in neurotrophic factors or their receptors and downstream targets of Akt will address the specific mechanisms of opiate reward tolerance in addiction models. Moreover, it will be important to understand the role of BDNF signaling in the regulation of VTA function within a neural circuit context. In this regard, it is interesting to note that Pu et al. (2006)
showed that following withdrawal from repeated cocaine exposure, excitatory synapses onto dopamine neurons in the VTA are more responsive to potentiation by weak presynaptic stimuli, an effect requiring endogenous BDNF-TrkB signaling.