BDNF Signaling in the VTA Links the Drug-Dependent State to Drug Withdrawal Aversions

Abstract

Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosinreceptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction.

Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

“…3). The incubation effect, wherein relapse is amplified after longer periods of abstinence, involves the VTA-accumbens pathway (Bahi et al, 2008; Graham et al, 2007; Grimm et al, 2003; Li et al, 2013; Lu et al, 2004a), at least for cocaine and perhaps also opiates, though there are conflicting reports (Koo et al, 2012; Vargas-Perez et al, 2009, 2014). Some evidence supports the importance of accumbens subregions in BDNF’s effects, with the shell being pro-relapse, but the core being capable of both pro-relapse and pro-extinction functions (Horger et al, 1999; Li et al, 2013).…”

“…However, these data stand in stark opposition with earlier work from Vargas-Perez et al (2009), who found that VTA BDNF neither opposes nor facilitates morphine reward, but rather switches the mechanism for opiate reward from a dopamine-independent to a dopamine-dependent one. This occurs through BDNF’s reversal of GABA currents in VTA neurons from inhibitory to excitatory, and this effect is thought to underlie the negative aversive state associated with opiate withdrawal (Vargas-Perez et al, 2014). …”

“…Interestingly, BDNF infusions directly into the VTA do not alter expression of ethanol CPP, but do convert the underlying mechanism for this CPP from a dopamine-dependent to a dopamine-independent one (Ting-A-Kee et al, 2013). As with opiates, this simulates the endogenous switch that occurs during withdrawal, despite the fact these dopamine contingencies are opposite for ethanol and opiates (Ting-A-Kee et al, 2013; Vargas-Perez et al, 2009, 2014; but see Koo et al, 2012). By contrast, loss of BDNF in the dorsolateral striatum impairs both ethanol CPP memory and free consumption (Bahi and Dreyer, 2013), as well as intake in a self-administration model (Jeanblanc et al, 2009).…”

Formation of aversive memories associated with conditioned drug withdrawal requires BDNF expression in the amygdala in acute morphine-dependent rats

“…Multiple lines of evidence have demonstrated that BDNF plays an important role in learning and memory in different brain regions [14,15,33] . Moreover, recent studies have found that the BDNF signaling pathway contributes to cocaine seeking [22,23,25,34,35] . Whether the BDNF signaling pathway participates in the formation of aversive memories associated with morphine withdrawal remains unknown.…”

Therapies and Mechanisms of Opioid Withdrawal

“…Hence, brain regions associated with reward and affective behaviors have also been implicated [13]. It has been shown that chronic opioid administration in rodents promoted GABA-mediated excitation [14] and loss of neuronal inhibition via reduction of KCC 2 currents in the ventral tegmental area [15]. Furthermore, acute morphine withdrawal in rats increased c-Fos expression in dopaminergic neurons within nucleus accumbens shell in mice [16], and phosphorylation of NMDARs in the accumbens [17].…”