Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core
Introduction
Drug addiction and dependence are major public health issues. There are currently few efficacious treatments for drug addiction due, in part, to an incomplete understanding of the neurobiology of the disease. While the mechanisms by which drugs of abuse drive behavior are complex and involve a diverse network of brain circuits, it is clear that increased release of the neurotransmitter dopamine plays a critical role in the reinforcing properties of abused drugs [1], [2]. Synchronous burst firing of ventral tegmental area (VTA) dopamine-containing neurons results in brief, high concentration (phasic) increases in nucleus accumbens (NAc) dopamine concentration [3], [4], [5]. These transient increases have been shown to be associated with reward based learning, motivation and reinforcement [6], [7], [8], [9] – all of which are central to the neurobiology of addiction. Cocaine, a highly abused drug with a well-investigated mechanism of action, augments NAc dopamine concentration by binding to and blocking dopamine reuptake by the dopamine transporter [10], [11]. However, cocaine also increases the frequency of dopamine release events [12], a key property for the development of addiction [13]. The increased frequency of dopamine release events would not be predicted by reuptake blockade alone but rather suggests increased burst firing of dopamine neurons which has gained empirical support [14]. Suppression of these cocaine-evoked transients represents a potential therapeutic approach to treating cocaine addiction.
Metabolic state and its proxies have been shown to bidirectionally modulate reward-driven behavior, whether directed at natural (e.g. food; see [15] for review) or artificial (e.g. cocaine; see [16] for review) rewards. The ability of metabolic state to potentiate or suppress drug seeking behavior has been demonstrated with multiple gut-derived peptides and across many classes of drugs of abuse [17], [18], [19], [20], [21], [22]. For example, exogenous administration of the orexigenic peptide ghrelin augments conditioned place preference for cocaine [23], while blockade of ghrelin signaling attenuates conditioned place preference for cocaine, amphetamine, and nicotine [21], [24]. Conversely, anorectic signals like the adiposity hormone leptin reduce food-deprivation induced heroin seeking [19]. Hormonal communicators of hunger and satiety that defend energy balance are therefore sufficient to alter drug reward-driven behavior.
A powerful modulator of food and drug reward is the incretin hormone glucagon-like peptide-1 (GLP-1), which suppresses food intake and body weight in rodents and humans by its actions on central and peripheral GLP-1Rs [25], [26], [27]. Much of the existing work on the anorectic effects of GLP-1 is heavily focused on GLP-1 signaling through metabolic control nuclei including nuclei of the hypothalamus and the nucleus of the solitary tract [28], [29], [30]. Recent work, however, has demonstrated that GLP-1 also decreases food intake by reducing the rewarding value of food [31], [32], [33], [34], implicating a physiological role for the peptide beyond energy balance regulation. Importantly, neurons in the NAc and VTA of the mesolimbic circuit express GLP-1Rs and receive direct projections from central GLP-1 producing neurons [32], [33]. Intra-VTA or NAc infusion of the GLP-1R agonist, Exendin-4, reduces palatable food intake [32], [33] and goal-directed behavior for food [31]. Interestingly GLP-1R agonists also suppress goal-directed behavior for cocaine reward [35], [36], [37], [38], [39], likely by attenuating dopamine signaling in the NAc [35], [39]. However, suppression of cocaine-evoked NAc dopamine release was demonstrated utilizing microdialysis, which lacks the spatiotemporal resolution to allow for investigation of phasic dopamine release patterns as well as potential regional differences. Importantly, the two subregions of the NAc (shell and core) respond differently to cocaine [40], [41] and are postulated to contribute in unique ways to the neurobiological basis of reward- directed behavior and drug addiction [42], [43], [44], [45], [46], [47], [48].
The studies here use fast-scan cyclic voltammetry (FSCV) to measure the pharmacological effects of Exendin-4 (a GLP-1R agonist) on intravenous cocaine-evoked phasic dopamine signaling in the NAc core and shell of rats. We replicate findings that non-contingent cocaine increases dopamine signaling in both the NAc core and shell [49], [50]. We show, for the first time, that central GLP-1R activation suppresses cocaine-evoked dopamine signaling but only within the NAc core. We also demonstrate that in cocaine-treated animals, Exendin-4 has no effect on the magnitude of electrically stimulated dopamine release or the rate of dopamine reuptake. This work suggests that GLP-1R agonism could curb cocaine-directed behavior, in part, by suppressing dopamine signaling in the NAc core. While future studies are needed to establish a causal relationship, GLP-1R targeted pharmacotherapies remain a promising approach for decreasing the reinforcing value of abused drugs like cocaine.
Section snippets
Subjects
Male Sprague-Dawley rats (n = 39; 350–425 g at the time of testing) were housed individually and maintained on a 12:12-h light-dark cycle (on at 7:00 AM). Rats were provided with ad libitum laboratory chow (LabDiet 5012) until post-operative recovery of body weight. Following recovery from the second surgery, animals were fed enough chow to maintain 85% of their ad libitum body weight. Experimental sessions were conducted after 4 days of restricted food access. Animals were treated in accordance
Intravenous cocaine evokes phasic dopamine release in the NAc
Fig. 1 illustrates representative dopamine transients evoked by intravenous cocaine infusion. The color plot (Fig. 1A) and associated concentration trace (Fig. 1B) were acquired from the NAc core of a rat with 15 previous cocaine infusions. Experiments utilizing CV Matches as an index of dopamine signaling used linear regression to compare cyclic voltammograms taken across the recording session to a cyclic voltammogram template for dopamine (Fig. 1C). Cyclic voltammogram templates were
Discussion
Cocaine is highly reinforcing, in part, because it induces phasic dopamine signaling in the NAc. We captured these phasic events using FSCV and examined the hypothesis that central GLP-1R agonism would suppress them. Indeed, the GLP1R agonist Exendin-4 suppressed dopamine signaling but only in the NAc core and not in the NAc shell. The central effects of Exendin-4 on cocaine-induced phasic dopamine signaling and its regional sensitivity is novel. Given the role of the NAc core dopamine in the
Conflict of interest
The authors have no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
The authors gratefully acknowledge the support of The National Institutes of Health (DA025634 to MFR) and the University of Illinois at Chicago (University Fellowship to SMF). The authors would like to thank Dr. Robert Wheeler and Mykel Robbie for their assistance with jugular vein catheterization.
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