Exercise as a Novel Treatment for Drug Addiction: A Neurobiological and Stage-Dependent Hypothesis

2.3. Initiation of drug use: neurobiological basis for the efficacy of exercise

As mentioned above, exercise may function as an alternative non-drug reward that competes with the drug and decreases the likelihood of its use. The effects of exercise on dopaminergic signaling in the reward pathway as a mechanism for its efficacy is an obvious possibility given the critical role that dopamine plays at this stage of the addiction process. Indeed, the ability of exercise to function as a reinforcer is believed to occur through a similar process (for review see Knab and Lightfoot, 2010). Acute bouts of forced running on a treadmill increase serum levels of calcium that are transported into the brain where they then activate the synthesis of dopamine (Sutoo and Akiyama, 1996). Chronic voluntary and forced running increase levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis, as well as dopamine in several areas of the brain including the reward pathway (Droste et al., 2006; Greenwood et al., 2011; for review see Dishman et al., 1997; Foley and Fleshner, 2008; Sutoo and Akiyama, 2003). Voluntary wheel running in rats is also associated with burst activation of dopamine neurons in the VTA (Wang and Tsien, 2011). Animals selectively bred for high levels of wheel running have higher basal and exercise-induced concentrations of dopamine in the NAc as compared to controls (Mathes et al., 2010). Collectively, these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation.

Exercise also produces neuroadaptations that may influence an individual’s vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). Like the behavioral effects of exercise, the neurobiological effects of exercise also differ with access conditions. For example, the ability of voluntary wheel running in the context of an enriched environment to prevent the development of a heroin- and cocaine-induced place preference is not mediated via dopamine signaling in the NAc (El-Rawas et al., 2009). In contrast, Greenwood et al. (2011) showed that chronic high levels of voluntary running produced neuroadaptive changes in the reward pathway that were similar to the effects observed following chronic exposure to drugs of abuse. Specifically, 6 weeks of voluntary wheel running increased levels of ΔFosB and tyrosine hydroxylase mRNA in the NAc, and decreased the number of dopamine D2-receptors, a neuro-adaptive effect that is associated with an enhanced vulnerability to drugs of abuse (Dalley et al., 2007; Martinez et al., 2004; 2012; Morgan et al., 2002; Nader et al., 2005; Voisey et al., 2012; Volkow et al., 1999). Chronic high levels of exercise may also lead to an upregulation of dopamine D1 receptor-signaling, another marker of enhanced vulnerability to addiction (e.g., Lynch et al., 2007; Worsley et al., 2000; Zhang et al., 2006), with recent findings showing that direct manipulation of D1 receptors in the NAc attenuates wheel running in high, but not low runners (Roberts et al., 2012a). These findings are important because they suggest that although moderate levels of exercise produce changes in the reward pathway that may protect against later drug use, chronic high levels of exercise, like chronic exposure to drugs of abuse, may sensitize the reward pathway. Support for this idea is provided by findings showing that a history of unlimited access to a running wheel enhances subsequent vulnerability to acquire methamphetamine self-administration and to develop a preference for a drug-associated environment (Eisenstein and Holmes, 2007; Mustroph et al., 2011; Smith et al., 2008; Engelmann et al., 2013). There is also a growing literature in humans on exercise addiction with evidence to suggest that it produces many of the same behavioral and neurochemical changes in the brain as chronic exposure to drugs of abuse (for review see Berczik et al., 2012).

Exercise also produces structural adaptations in the brain at the chromatin level that may alter an individual’s susceptibility to drug use. In this sense, gene expression changes can occur in the absence of altering the underlying DNA sequence through epigenetic regulation, which can either activate or repress gene transcription through chromatin modifications. These include post-translational histone modifications and covalent modifications of genomic DNA (for review see Takizawa and Meshorer, 2008). Such epigenetic effects, and the role these changes play in addiction, have only recently been explored, but it is becoming apparent that such adaptations may mediate long-lasting changes in vulnerability (e.g., Botia et al., 2012; Damez-Werno et al., 2012; Freeman et al., 2008; Gozen et al., 2013; Pascual et al., 2012; Schwarz et al., 2011; Repunte-Canonigo et al., 2013; Tomasiewicz et al., 2012; for review see Feng and Nestler 2013; Nielsen et al., 2012). In particular, emerging evidence implicates brain-derived neurotrophic factor (BDNF) and epigenetic regulation of the BDNF gene, a gene critically involved in synaptic plasticity, as associated with both initial and later vulnerability to addiction (Chase and Sharma, 2012; Im et al., 2010; Jia et al., 2011; Kumar et al., 2005; McGough et al., 2004; Meng et al., 2012; Greenwald et al., 2012; Sadri-Vakili et al., 2010; Schmidt et al., 2012; Vassoler et al., 2013; Wan et al., 2011; for review see Schmidt et al., 2013; McGinty et al., 2010). For example, recent results show that male rats with a history of cocaine self-administration passed on a cocaine-resistant phenotype to their male offspring that was characterized by low rates of acquisition of cocaine self-administration and increased H3 histone acetylation of Bdnf exon IV in the PFC (Vassoler et al., 2013). Exercise increases BDNF in both humans and animal models (for review see Zoladz and Pilc, 2010), and recent work suggests that it promotes stable changes in gene expression through epigenetic regulation of chromatin containing the BDNF gene at the same exon region that is associated with vulnerability to addiction (exon IV). Specifically, Gomez-Pinilla and colleagues (2011) found that chronic voluntary wheel running increased histone H3 acetylation and decreased DNA methylation of the promoter IV region, thereby increasing the expression of Bdnf exon IV mRNA. Together, these findings suggest that exercise may serve as a substitute for drugs of abuse by increasing dopaminergic signaling and may alter vulnerability by producing persistent adaptations in dopaminergic signaling and chromatin remodeling. However, more work is needed to determine the causal effects of these proposed mechanisms of exercise on the initial vulnerability to addiction.

3.3 Progression from use to addiction: neurobiological basis for the efficacy of exercise

Exercise affects both dopaminergic and glutamatergic signaling—neurotransmitter signaling pathways implicated in excessive drug intake and the development of addiction. Specifically, chronic exposure to drugs of abuse leads to mesolimbic hypofunction, which may promote drug use to compensate for its decreased effect on dopamine release (Koeltzow and White, 2003; Maisonneuve et al., 1995; Paulson et al., 1991; Schmidt et al., 1996; for review see Melis et al., 2005), with results showing that escalation of cocaine self-administration can be augmented by further suppression of dopaminergic signaling (Ahmed and Koob, 2004). The ability of exercise to increase dopaminergic signaling, particularly in the reward pathway, may protect against excessive drug use. However, as mentioned earlier, it is also possible that chronic high levels of exercise may mimic the effects of chronic drug exposure and increase vulnerability to developing an addicted phenotype. Escalation of drug self-administration and the development of an addicted phenotype is also associated with a dysregulation of glutamatergic signaling in the reward pathway (Allen et al., 2007; Ben-Shahar et al., 2009; 2012; 2013; Fischer-Smith et al., 2012; Ghasemzadeh et al., 2011; Hao et al., 2010; Lu et al., 2007; Madayag et al., 2007; McCutcheon et al., 2011; for review see Pickens et al., 2011; Loweth et al., 2013; Wolf and Tseng, 2012). Although most of the evidence in this regard has been observed for cocaine, similar findings have also been observed for other drugs of abuse including methamphetamine, heroin, and alcohol (Bauer et al., 2012; Bossert et al., 2012; Kufahl et al., 2011; 2013; Meinhardt et al., 2013; Okvist et al., 2011; Schwendt et al., 2012; Sidhpura et al., 2010). Most of the results on the effects of exercise on glutamatergic signaling have been obtained from animal models of cerebral ischemia, which results in the excessive release of glutamate and overstimulation of its receptors, and these findings show that forced running on treadmill for 2 weeks prior to the ischemia can normalize glutamate levels and improve functioning (Jia et al., 2009; Yang et al., 2012; Zhang et al., 2010). These results are important because they suggest that exercise may protect against overstimulation of glutamate receptors, which also occurs following chronic drug exposure. In “normal” animals, forced and voluntary running decrease glutamate concentrations in the striatum (Guezennec et al., 1998) and hippocampus (Biedermann et al., 2012). There is also evidence suggesting that exercise promotes plastic changes in glutamate receptors with results showing that forced treadmill running increases striatal mGluR2/3 expression, which dampens glutamatergic signaling (Real et al., 2010). Forced running also increases striatal fos expression, a marker of functional activity, and this effect can be blocked by concurrent activation of glutamate NMDA and dopamine D1 receptors (Liste et al., 1997), raising the possibility that the effects of exercise on excessive drug self-administration and the development of addiction may require modulation of both dopaminergic and glutamatergic signaling. Recent work has also shown that the length of training on a treadmill (3 versus 30 days) differentially affects glutamate receptor plasticity (Real et al., 2010), raising the possibility that the amount of exercise training may also determine its efficacy for reducing vulnerability during the transition from regular use to addiction.

4.3 Drug withdrawal: neurobiological basis for the efficacy of exercise

During an early withdrawal period there is decreased dopaminergic activity throughout the reward pathway, and withdrawal symptoms including anhedonia, negative affect, and craving have been linked to this decreased activity (Orsini et al., 2001; Rossetti et al., 1992; Weiss et al., 1992; 1996; for review see Hatzigiakoumis et al., 2011; Koob and Volkow, 2010; Melis et al., 2005). In addition to the ability of forced and voluntary running to increase dopaminergic signaling in normal animals, it can also increase abnormally low levels that are characteristic of certain disease models (e.g., hypertension and epilepsy; for review see Sutoo and Akiyama, 2003). These findings are important because they suggest that exercise may normalize the hypofunctioning in the mesolimbic system that occurs following chronic drug exposure during early withdrawal. This idea is further supported by recent findings showing that voluntary wheel running attenuates methamphetamine-induced damage to dopamine and serotonin terminals in the striatum (O’Dell et al., 2012). Its efficacy may also be related to its ability to normalize overall neuronal activity in the reward pathway, and these effects may depend on the drug self-administered. For example, withdrawal from chronic ethanol exposure is associated with upregulation of glutamatergic excitatory neurotransmission (Bauer et al., 2013; Rosetti et al, 1999). Given the ability of exercise to normalize high levels of glutamate in other disease models, and upregulate mGluR2/3 expression in normal animals, it is possible that its efficacy at reducing ethanol withdrawal symptoms is through a similar mechanism. Although withdrawal from other drugs of abuse including psychostimulants and opioids is also associated with an upregulation in glutamatergic signaling, these effects are typically observed following protracted abstinence (Fischer-Smith et al., 2012; Ghasemzadeh et al., 2011; Hao et al., 2010; Lu et al., 2007; Bossert et al., 2012; Kufahl et al., 2011; Schwendt et al., 2012; Sidhpura et al., 2010), with the opposite occurring during early withdrawal periods (Baker et al., 2003; Ben-Shahar et al., 2012; Hotsenpiller et al., 2001; Pierce et al., 1996; for review see Schmidt et al., 2010). Thus, it is possible that exercise will produce different effects during early versus later stages of withdrawal from psychostimulants and opioids. Taken together, these results suggest that exercise may potentially serve as an intervention during withdrawal due its ability to upregulate dopaminergic signaling and normalize glutamatergic signaling (perhaps particularly for alcohol).

5.3 Relapse to drug use: neurobiological basis for the efficacy of exercise

Exercise may modulate drug-induced neuroadaptations in dopaminergic and glutamatergic signaling that are implicated in relapse to drug use. Evidence from studies primarily with cocaine show that chronic exposure produces neuroadaptations in the dopamine system, such as an upregulation of D1 receptors and a downregulation of D2 receptors, with evidence to suggest that dopamine signaling in the reward pathway may become sensitized over extended periods of abstinence (Casanova et al., 2013; Henry et al., 1988; Puig et al., 2012; Unterwald et al., 1994). Thus, it is also possible that exercise beginning later during abstinence may lead to further increases in dopaminergic signaling and enhance rather than attenuate drug-seeking. An upregulation in glutamatergic signaling in the reward pathway also develops following repeated drug exposure and abstinence which may be critical for the enduring drive to seek drugs of abuse (e.g., Bauer et al., 2013; Bossert et al., 2012; Fischer-Smith et al., 2012; Hotsenpiller et al., 2001; Kufahl et al., 2011; 2013; McFarland et al., 2003; Meinhardt et al., 2013; Okvist et al., 2011; Schwendt et al., 2012; Sidhpura et al., 2010). As mentioned earlier, forced running on a treadmill decreases glutamate in the striatum (Guezennec et al., 1998) and thus may protect against this enhanced vulnerability by blocking enhanced glutamatergic signaling following prolonged abstinence. Additionally, as with excessive drug use, the development of a subsequent addicted phenotype and relapse vulnerability may require the activation of both dopaminergic and glutamatergic signaling. Drug-induced neuroadaptations that initially suppress drug-seeking during early withdrawal dissipate over prolonged abstinence, and are associated with time-dependent increases, or “incubation”, in drug-seeking (Pickens et al., 2011). Presentation of drug-associated cues increases PFC extracellular regulated kinase (ERK) signaling, which requires coincident activation of dopamine and glutamate NMDA receptor signaling, following 30 days, but not 1 day, of withdrawal. Lynch et al. (2010) showed that wheel running beginning during early abstinence not only prevents an increase in cocaine-seeking in response to drug-associated cues, but also prevents an increase in ERK signaling within the PFC. Thus, exercise may ablate preservation of drug-seeking and reduce vulnerability to relapse following extended abstinence through interactions with both dopaminergic and glutamatergic signaling by attenuating time-dependent increases in ERK activity. These results also suggest that the timing of exercise availability is also critical. Specifically, exercise that begins during protracted abstinence, as opposed to during early abstinence, may produce a different pattern of changes and result in either a non-efficacious or detrimental response.

Exercise also affects epigenetic mechanisms, and these effects may provide long-term protection during relapse. As discussed earlier, both wheel running and drugs of abuse modify chromatin containing the BDNF gene. BDNF is one of the few markers that positively associates with the incubation of drug-seeking over abstinence, and although most of evidence in this regard has focused on animal models of cocaine relapse (Grimm et al., 2003; Li et al., 2013; Sadri-Vakili et al., 2010; Schmidt et al., 2012; for review see Pickens et al., 2011), similar findings have also been observed in humans and for other drugs including alcohol and methamphetamine (Corominas-Roso et al., 2012; Costa et al., 2011; Hilburn et al., 2011; D’sa et al., 2011; but see Theberge et al., 2013 for heroin). Results from these studies show that during early abstinence, when levels of drug-seeking are low, markers of BDNF, including the activity of its intracellular pathways (e.g., ERK), are decreased in several brain regions including the PFC and NAc (Angelucci et al., 2007; Chen et al., 2013; Whitfield et al., 2011; Grimm et al., 2003; for review see McGinty et al., 2010). As abstinence increases, BDNF protein and phosphorylated ERK levels increase progressively and are thought to sensitize the excitatory synapses in these regions and contribute to the incubation effect (Lu et al., 2010). Several studies have also shown that infusion of BDNF into the VTA, NAc, or PFC profoundly affects drug-seeking (Berglind et al., 2007; 2009; Lu et al., 2004; Whitfield et al., 2011). For example, infusion of BDNF into the PFC immediately following cocaine self-administration, but not following protracted abstinence, attenuates subsequent cue-induced cocaine-seeking and normalizes ERK and glutamatergic signaling in the PFC and NAc (Berglind et al., 2007; 2009; Whitfield et al., 2011). Voluntary wheel running independently elevates BDNF gene expression through acetylation of histone 3 and reduction of DNA methylation in the BDNF promoter IV region (Gomez-Pinilla et al., 2011). It is therefore possible that exercise, if available during early withdrawal, may offset the initial decrease in BDNF expression thereby preventing the subsequent increase in BDNF expression that occurs following protracted withdrawal. As such, exercise may lead to chromatin modifications that suppress drug-seeking. In support of this idea, recent data show that wheel running beginning during early abstinence session length-dependently reduced cocaine-seeking and attenuated BDNF promoter IV mRNA expression in the PFC (Peterson et al., 2013). In conjunction, D’Sa and colleagues (2011) reported that elevated BDNF serum levels predicted shorter subsequent time to relapse and higher total cocaine use in recovering cocaine dependent individuals. Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes. These effects may vary with the timing of exercise availability, by drug self-administrated, and with type of exercise (e.g., level of intensity, forced versus voluntary).