Hippocampal plasticity may drive cocaine relapse

Premature deaths related to illicit drug use are at an all-time high in the United States (1). Over 72,000 people died from drug overdose in 2019, and this number is expected to increase dramatically in 2020, in no small part because of the COVID-19 pandemic (2). Indeed, March through May of 2020 saw a sharp increase in overdose deaths, which coincided with state-mandated lockdown orders. Numbers of individuals testing positive for cocaine also increased dramatically over this same period. This is important because one-third of overdose deaths involve the use of cocaine or other psychostimulant drugs. Undoubtedly, drug addiction is one of the foremost public health crises of our times. Nevertheless, there are currently no therapeutics approved by the US Food and Drug Administration for the treatment of cocaine addiction. This dearth of medications reflects, in part, an imperfect understanding of the brain mechanisms responsible for the remarkable persistence of cocaine use despite the strenuous efforts by users to quit the habit. Perhaps the greatest challenge in overcoming cocaine addiction is avoiding relapse during periods of attempted sobriety. This challenge is exacerbated by the fact that craving for cocaine can progressively intensify as periods of abstinence become more extended, a phenomenon termed “incubation of craving” (3). In PNAS, Werner et al. (4) uncover a molecular mechanism in the hippocampus that may contribute to relapse vulnerability during periods of extended abstinence.

The dorsal hippocampus (DH) is thought to encode information important for learning about, and successfully navigating, your environment, especially the ability to recognize objects and their location in specific contexts. Emerging evidence has implicated the DH in relapse to cocaine seeking during abstinence. Specifically, the DH is thought to form associations between cocaine use and the environments in which such use occurred (4, 5). These DH-mediated associations can then trigger intense craving for the drug when encountering contexts in which cocaine consumption had previously occurred (4, 5). Whether the DH plays a role in the incubation of cocaine craving that emerges during extended periods of abstinence is currently unknown. Werner et al. (4) set out to determine whether the DH regulates incubation of cocaine craving and if so, to define the molecular mechanisms that may be involved.

Previous work from the same group had established that expression of activin A, a member of the transforming growth factor-β superfamily of cytokines, was increased in the nucleus accumbens (NAc) region of the brain after 7 d but not 1 d of withdrawal from cocaine in rats that had volitionally consumed the drug by means of intravenous (i.v.) self-administration (6). In the self-administration procedure, rats are prepared with jugular catheters and permitted to emit an action, typically a lever press, in order to earn i.v. infusions of the drug. In addition to demonstrating cocaine-induced increases in activin expression in the NAc, the authors found that disrupting activin signaling in the NAc attenuated cocaine-seeking behaviors during periods of abstinence (6). Based on these observations, Werner et al. (4) investigated whether activin expression was similarly increased in the DH of rats with a prior history of cocaine self-administration behavior. They found that activin protein and transcript levels in the DH were, indeed, increased in cocaine-experienced rats but only in those animals that had experienced 30 d of withdrawal from cocaine, and not in those that experienced just 1 d of withdrawal. Notably, they also found that activin levels in the DH were increased by cocaine withdrawal in both neurons and microglia, suggesting that cocaine impacts both of these cell types in the DH to promote activin expression.

Based on these observations, the authors next explored whether activin signaling in the DH can influence cocaine-seeking behaviors. They found that infusion into the DH of an antibody directed against activin or infusion of the glycoprotein Follistatin, both of which that can bind activin to disrupt its activity, reduced cocaine-seeking responses in rats that had experienced 30 d of withdrawal. By contrast, these manipulations had no effects on cocaine seeking in rats that had experienced only 1 d of withdrawal. Conversely, virus-mediated overexpression of ACVR2A in the DH, the gene that encodes activin A receptor type 2a, increased cocaine-seeking responses in rats after 30 d of withdrawal. These findings suggest that activin acts in the DH to promote cocaine-seeking behaviors in rats but only after extended periods of cocaine abstinence. This, in turn, suggests that activin in the DH may contribute to the enduring vulnerability to relapse that represents a cardinal feature of cocaine addiction.

Previously, it was shown that activin enhances the phosphorylation of N-methyl-d-aspartate (NMDA) glutamate receptors containing 2B subunits (GluN2B) in the hippocampus, which facilitates their translocation to the cell surface (7). This is important because GluN2B-containing NMDA receptors play an important role in the synaptic plasticity mechanisms by which information is encoded into hippocampal neurons. Indeed, activin is known to promote long-term potentiation (LTP) in the hippocampus, considered a cellular correlate of learning and memory, in a manner that depends upon enhanced levels of phosphorylated GluN2B subunits (8). Werner et al. (4) found that cocaine-experienced rats demonstrated more robust LTP than cocaine-naïve animals, with this cellular response correlating with increased levels of activin in the cocaine-experienced animals. Moreover, they also detected increased levels of phosphorylated but not total GluN2B protein and enhanced surface expression of GluN2B in the DH of cocaine-experienced rats, and that disruption of activin signaling prevented these cocaine-induced alterations in NMDA receptor expression. Most importantly, the authors found that intra-DH infusion of (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro 25-6981), a selective antagonist of GluN2B-containing NMDA receptors, decreased cocaine-seeking behaviors in rats that had underwent an extended period of withdrawal. Together, these findings suggest that activin promotes excitatory transmission mediated by GluN2B-containing NMDA receptors in the DH, which contributes to vulnerability to cocaine relapse during periods of extended abstinence (Fig. 1).

Fig. 1.

Activin A acts in the hippocampus to regulate cocaine-seeking behaviors. Activin expression is increased in the DH of rats experiencing extended periods of cocaine withdrawal (late withdrawal) compared with cocaine-naïve rats or rats experiencing only short periods of withdrawal (early withdrawal). Activin promotes the phosphorylation of NMDA receptors containing GluN2B subunits, a process enhanced in late withdrawal rats, with increased levels of GluN2B-containing NMDA receptors facilitating synaptic plasticity in the hippocampus. Finally, hippocampal neurons that project to the LS promote cocaine-seeking behaviors and are the likely substrate through which activin acts.

Craving for cocaine can progressively intensify as periods of abstinence become more extended, a phenomenon termed “incubation of craving.” In PNAS, Werner et al. uncover a molecular mechanism in the hippocampus that may contribute to relapse vulnerability during periods of extended abstinence.

Finally, Werner et al. (4) explored the circuit-level mechanisms by which activin-mediated plasticity in the DH can drive relapse-like behaviors in rats. Projections from the DH to the lateral septum (LS) were previously implicated in regulating cocaine-seeking behaviors during abstinence (9). Using an intersectional chemogenetics approach, Werner et al. (4) selectively inhibited the activity of only those DH neurons that project to the LS and found that this manipulation decreased cocaine-seeking behavior in rats after an extended period of abstinence. This finding suggests that increased activin expression in the DH during withdrawal may contribute to the risk of cocaine relapse by progressively strengthening the functional connectivity of neurons in the DH with those in the LS.

In summary, the findings described in PNAS by Werner et al. (4) identify an important role for the hippocampus in regulating the risk of relapse that emerges and progressively increases during the perilous period of abstinence. They also uncover an activin A-mediated molecular mechanism in the hippocampus that may explain this risk of relapse. Furthermore, they identify a circuit-level mechanism involving hippocampal projections to the LS that may serve as the substrate for the actions of activin. This innovative work is likely to catalyze increased attention on the role of the hippocampus–septum circuit in incubation of cocaine craving, which could yield targets for the development of much-needed therapeutics to facilitate long-term abstinence from cocaine use in addicted individuals.