Review
Role of BDNF and GDNF in drug reward and relapse: A review

https://doi.org/10.1016/j.neubiorev.2009.11.009Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that are critical for the growth, survival, and differentiation of developing neurons. These neurotrophic factors also play important roles in the survival and function of adult neurons, learning and memory, and synaptic plasticity. Since the mid-1990s, investigators have studied the role of BDNF and GDNF in the behavioral effects of abused drugs and in the neuroadaptations induced by repeated exposure to drugs in the mesocorticolimbic dopamine system. Here, we review rodent studies on the role of BDNF and GDNF in drug reward, as assessed in the drug self-administration and the conditioned place preference procedures, and in drug relapse, as assessed in extinction and reinstatement procedures. Our main conclusion is that whether BDNF or GDNF would facilitate or inhibit drug-taking behaviors depends on the drug type, the brain site, the addiction phase (initiation, maintenance, or abstinence/relapse), and the time interval between site-specific BDNF or GDNF injections and the reward- and relapse-related behavioral assessments.

Introduction

Drug addiction is characterized by compulsive drug use despite adverse consequences and high relapse rates during abstinence periods (Hunt et al., 1971, Wikler, 1973). Results from neurobiological studies in laboratory animals demonstrate that neuronal activity in the mesocorticolimbic dopamine system mediates drug reward (Pierce and Kumaresan, 2006, Wise and Rompre, 1989) and relapse to drug seeking (See, 2002, Shalev et al., 2002); this dopamine system comprises of cell bodies in VTA (ventral tegmental area) that project to several brain areas, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, bed nucleus of stria terminalis (BNST), and hippocampus (Fallon and Moore, 1978, Ungerstedt, 1971). A current popular hypothesis is that compulsive drug seeking and long-term relapse vulnerability are due to drug-induced neuroadaptations in the mesocorticolimbic dopamine system and glutamatergic corticolimbic circuitry in which the dopamine projections are embedded (Kalivas and Volkow, 2005, Nestler, 2001b, Wolf, 1998).

This drug-induced neuroadaptation hypothesis has inspired studies on the role of cellular events and signaling cascades that underlie synaptic plasticity (Box 1) processes of learning and memory in the behavioral effects of drugs (Nestler, 2001a, Thomas et al., 2008, Wolf et al., 2004). Within this framework, since the mid-1990s (Altar et al., 1992, Berhow et al., 1995, Berhow et al., 1996, Martin-Iverson et al., 1994), investigators have explored the effect of exposure to abused drugs on the expression and function of BDNF and GDNF in the mesocorticolimbic dopamine system, and the effect of manipulating their function on the behavioral effects of drugs (Bolanos and Nestler, 2004, Carnicella and Ron, 2009, McGinty et al., 2009, Pierce and Bari, 2001, Ron and Janak, 2005, Russo et al., 2009a).

BDNF and GDNF are well known for their role in growth, survival, and differentiation of developing neurons (Bespalov and Saarma, 2007, Chao, 2003, Chao et al., 2006). Over the last two decades, results from many studies have implicated BDNF and GDNF in the survival and function of adult dopamine neurons, learning and memory, and synaptic plasticity (Airaksinen and Saarma, 2002, Andressoo and Saarma, 2008, Bekinschtein et al., 2008, Chiocco et al., 2007, Lu et al., 2008, Poo, 2001). Here, we review studies on the role of BDNF and GDNF in drug reward, as assessed in the conditioned place preference (CPP, Box 1) (Mucha et al., 1982) and the drug self-administration (Schuster and Thompson, 1969, Weeks, 1962) procedures, and in drug relapse as assessed in the reinstatement procedure (Epstein et al., 2006, Shaham et al., 2003, Stewart and de Wit, 1987). We also review studies on the role of BDNF and GDNF in incubation of cocaine craving (Grimm et al., 2001, Lu et al., 2004b).

The focus of our review is the role of BDNF and GDNF in drug reward and relapse. Thus, we do not discuss results on the role of GDNF and BDNF in the acute effects of drugs on locomotor activity (Airavaara et al., 2004, Airavaara et al., 2007, Gerlai et al., 2001, Martin-Iverson et al., 1994) or drug psychomotor sensitization (for reviews see Carnicella and Ron, 2009, Niwa et al., 2007a, Pierce and Bari, 2001). In Tables S1 and S2 (supplementary online material) we summarize results on the effect of exposure to different regimens of different drugs on BDNF and GDNF expression in different components of the mesocorticolimbic dopamine system. In keeping with the focus of our review, with a few exceptions these results are not discussed, because in many of these studies, investigators did not attempt to connect the drug-induced expression changes of BDNF and GDNF to behavioral measures of drug reward or relapse.

Our review complements previous reviews on the role of neurotrophic factors in psychomotor sensitization (Pierce and Bari, 2001) and signaling pathways underlying their role in drug-induced changes in synaptic plasticity and behavior (Bolanos and Nestler, 2004, Russo et al., 2009a), and GDNF's role in alcohol-taking behavior (Carnicella and Ron, 2009, Ron and Janak, 2005), and methamphetamine sensitization and reward (Niwa et al., 2007b). In Box 1, we provide a glossary of terms that appear in the text in capital letters and in Box 2 and Fig. 1, we provide a general overview of BDNF and GDNF signaling mechanisms.

Section snippets

BDNF

Horger et al. (1999) provided one of the most dramatic illustrations of the role of accumbens BDNF in cocaine's behavioral effects. It is well established that systemic or accumbens injections of psychostimulant drugs potentiate the rat's response to cues previously paired with non-drug rewards (Robbins, 1975, Taylor and Robbins, 1984). Horger et al. (1999) showed that chronic delivery of BDNF into the accumbens (via minipumps) profoundly increased systemic cocaine-induced potentiation of

GDNF

Over the last decade investigators have assessed the role of GDNF in drug reward and relapse, as assessed in animal models. The results from these studies are summarized in Table 2 and are discussed below.

Concluding remarks

We reviewed results from studies on the role of BDNF and GDNF in drug reward and relapse, as assessed in rodent models. Our main conclusion is that whether BDNF or GDNF would facilitate or inhibit drug-taking behaviors is dependent on the drug type, the brain site, the addiction phase (initiation, maintenance, or abstinence/relapse), and the time interval between site-specific BDNF or GDNF injections and the reward- and relapse-related behavioral assessments. This is an unexpected conclusion,

Acknowledgements

This work was supported by the National Basic Research Program of China (2009CB522004) and the Natural Science Foundation of China (No: 30725016) and the Intramural Program of NIDA, NIH.

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