COMMENTARY

More Cocaine—More Glutamate—More Addiction Cassandra D. Gipson and Peter W. Kalivas

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ver the last 15 years, animal models of cocaine reinforcement and reinstated drug seeking have pointed to the involvement of nucleus accumbens dopamine and glutamate neurotransmission in regulating drug intake and drug seeking, respectively (1,2). For reinstated drug seeking, evidence supporting glutamate transmission in the core subcompartment of the accumbens (NAcore) is conclusive, including: 1) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists prevent reinstatement of cocaine seeking; and 2) there exist enduring neuroadaptations in glutamate transmission, such as downregulated glutamate transport or upregulated calcium-permeable AMPA receptors, that if normalized prevent reinstated cocaine seeking. In contrast with the clear involvement of glutamate in reinstated drug seeking, self-administration paradigms have been used to show that dopamine transmission in the accumbens is a necessary factor for reinforcing cocaine use. Thus, there is a generally assumed axiom among addiction researchers and clinicians that while dopamine transmission supports the learning and subsequent repeated use of cocaine, glutamate release in the accumbens drives relapse to drug seeking, especially in the NAcore and after periods of drug withdrawal. However, the study by Doyle et al. (3) in this issue of Biological Psychiatry provides important insights into how glutamatergic transmission in the NAcore can also be recruited to contribute to the reinforcing properties of cocaine when animals are allowed access to larger quantities of cocaine. For over a decade, investigators have been showing that if experimental animals are allowed extended daily access to cocaine (⬎4 hours daily), the amount of cocaine infused escalates such that animals self-administer progressively more cocaine per unit time. This escalation has been proposed to model compulsive cocaine use, while the more stable cocaine intake engendered by shorter cocaine access periods (1 to 2 hours daily) may model recreational drug use (4). A finding supporting this conclusion is that when motivation to obtain cocaine is estimated using a progressive ratio schedule of reinforcement (PR), animals trained using extended cocaine access demonstrate a higher PR than short-access subjects. What Doyle et al. (3) discovered is that the number of infusions of cocaine obtained in a PR test from rats showing escalated intake after training on extended cocaine access depends on glutamate transmission in the NAcore. Thus, administration of the AMPA antagonist CNQX into the NAcore just before beginning a PR session reduced the increased intake of cocaine in extended-access animals to the levels of cocaine intake seen in rats trained in the short-access paradigm. Moreover, CNQX did not alter cocaine use in short-access animals. This finding shows that a glutamatergic mechanism is involved in escalated performance in a PR session following extended, but not short-access, sessions of cocaine self-administration. Also, these data nicely complement the authors’ earlier report showing that D1 dopamine receptor antagonism reduced short-access From the Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina. Address correspondence to Peter W. Kalivas, Ph.D., Medical University of South Carolina, Department of Neuroscience, 173 Ashley Avenue, PO Box 250677, Suite BSB-403, Charleston, SC 29425; E-mail: Kalivasp@ musc.edu. Received Aug 13, 2014; accepted Aug 17, 2014.

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motivation for cocaine but had a lesser affect on extended-access subjects (5). Considering these two studies together, the authors have provided an evidence base for concluding that although dopamine supports the reinforcing effect of cocaine, when larger quantities of cocaine are used the motivation to take drug comes to depend more on glutamate transmission in the NAcore. The authors’ primary extrapolation on their data is that increased access to daily cocaine creates a more addicted state than short access and that this state of increased motivation to obtain drug arises from recruiting glutamatergic mechanisms in the accumbens. In support, they correctly note that the substantial evidence supporting a critical role for dopamine transmission in mediating the reinforcing properties of cocaine was largely obtained from animals trained on lower cocaine access paradigms, and they speculate that these short-access paradigms did not addict the animals to cocaine. Although not mentioned by the authors, this conclusion was presaged and nicely complements previous work by the Baker laboratory in 2007 [Madayag et al. (6)]. These authors showed that activating glial glutamate release with N-acetylcysteine prevented the escalation of cocaine use in rats trained on extended drug access but did not alter the self-administration of cocaine in short-access animals. Moreover, these authors provided neurobiological support of their finding by showing that daily N-acetylcysteine administration during cocaine self-administration simultaneously prevented synaptic glutamate spillover in the accumbens and the reinstatement of cocaine seeking elicited by an acute priming injection of cocaine. These data together with the broad literature showing that context-, cue-, or cocaine-induced motivation to seek drug depends on glutamate transmission in NAcore strongly supports the primary conclusion by Doyle et al. (3) that glutamatergic mechanisms are recruited after exposure to addictive drugs. Of greater novelty, both the Madayag et al. (6) and Doyle et al. (3) studies imply that the more a drug is used, the greater the extent of glutamatergic recruitment. As pointed out by Doyle et al. (3), recruitment of glutamatergic mechanisms may also depend on the duration of drug abstinence, even after short-access cocainetraining regimens. Thus, recruiting glutamatergic adaptations in the accumbens contributes to the incubation of context-induced drug seeking in cocaine-abstinent rats (7). In this paradigm, animals show a progressive increase in reinstated drug seeking over increasing durations of cocaine abstinence (the incubation of drug seeking) and show alterations in AMPA receptor subunit composition that is maintained through 70 days of withdrawal (8). Although the authors nicely complement the literature showing that the motivation to seek cocaine depends on glutamate release in the NAcore and explore the less well studied dimension that increasing cocaine access facilitates the recruitment of glutamatergic mechanisms, it is important to not overly anthropomorphize conclusions based on using the short-access and extended-access models. Concluding that the more cocaine used, the greater the motivation to seek and use drug is appropriate. It is also correct to conclude that glutamatergic mechanisms are recruited more effectively by greater amounts of cocaine use and that these mechanisms progressively come to underlie increased motivation to seek drug. However, the literature is clear that when assayed across different drugs of abuse using various reinstatement paradigms, short-access paradigms can also recruit glutamatergic mechanisms to support BIOL PSYCHIATRY 2014;76:765–766 & 2014 Society of Biological Psychiatry

766 BIOL PSYCHIATRY 2014;76:765–766 the motivation to seek drug. Moreover, there is extensive mechanistic evidence using short-access paradigms regarding the cell biology of glutamatergic adaptations that underpin the motivation to seek drug. Examples include the aforementioned recruitment of calcium-permeable AMPA receptors underpinning the greater magnitude of context-induced cocaine seeking and the transient increase in NAcore dendritic spine head diameter and AMPA/Nmethyl-D-aspartate ratio that correlates with cued reinstatement of cocaine seeking (9). Thus, the difference between short and extended access is most appropriately considered on a continuum of glutamatergic recruitment that depends on the dose and duration of cocaine access, as well as the extent of drug withdrawal, and not as a diagnostic criterion separating recreational from compulsive drug use. Nonetheless, in future studies, it will be interesting to employ the two access paradigms to explore this continuum and if there are specific criteria of drug exposure and withdrawal necessary in animal models to trigger glutamate recruitment. However, in our opinion, now that many animal models reveal that recruitment of glutamate transmission underpins the motivation to seek drug, the critical next step is to employ animal models that most efficiently facilitate research to understand the cellular mechanisms of brain plasticity that allow glutamatergic transmission to be recruited. Subsequently, this model can be used as a screening protocol to develop compounds and technologies to interfere with these mechanisms to ameliorate drug addiction. The ideas in this commentary are an outgrowth of funding provided by the National Institute on Drug Abuse, including DA003906, DA012513, and DA015369.

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Commentary The authors have no biomedical financial interests or potential conflicts of interest. 1. Pierce RC, Kumaresan V (2006): The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238. 2. Kalivas PW, Volkow ND (2011): New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16: 974–986. 3. Doyle SE, Ramôa C, Garber G, Newman J, Toor Z, Lynch WJ (2014): A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype. Biol Psychiatry 76:810–815. 4. Piazza PV, Deroche-Gamonet V (2013): A multistep general theory of transition to addiction. Psychopharmacology (Berl) 229:387–413. 5. Ramoa CP, Doyle SE, Lycas MD, Chernau AK, Lynch WJ (2014): Diminished role of dopamine D1-receptor signaling with the development of an addicted phenotype in rats. Biol Psychiatry 76: 8–14. 6. Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Hearing M, et al. (2007): Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 27: 13968–13976. 7. Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, et al. (2008): Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118–121. 8. Wolf ME, Tseng KY (2012): Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: When, how, and why? Front Mol Neurosci 5:72. 9. Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW (2013): Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867–872.

More cocaine-more glutamate-more addiction.

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