Chapter 4 - Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior

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Abstract

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.

Section snippets

Introduction: Ensembles in Addiction

According to classic theory, neuronal networks adapt during brain plasticity, modifying firing probability within the network (Hebb, 1949, Josselyn et al., 2017). As a result, all of the neurons included in a specific network will respond to the same stimulus. One of the first proofs of this theory was found in brain slices from the developing rat neocortex where measures of calcium signaling revealed functional domains formed by neurons activated in synchrony (Yuste et al., 1992, Yuste et al.,

Constitutive Changes Induced by Drugs of Abuse

Abused drugs share the property of modifying the extracellular levels of three behaviorally important monoamines: noradrenalin, serotonin, and dopamine. This modulation is achieved either by blocking neurotransmitter plasmalemmal transporters (e.g., psychostimulants (Balster and Schuster, 1973, Crespi et al., 1997) or via disinhibition of synaptic release (e.g., opioids: Khachaturian and Watson, 1982). However, the release of dopamine in the NAc by all drugs of abuse (Di Chiara and Imperato,

Glutamate Spillover and Transient Synaptic Plasticity, Common to All Drugs of Abuse

Glutamate release is increased in the NAc of cocaine-sensitized animals in response to a cocaine challenge (Pierce et al., 1996) and following presentation of a cue paired with noncontingent cocaine exposure (Hotsenpiller et al., 2001). A large body of work has established that elevated synaptic glutamate spillover from prelimbic cortical afferents is measured in the accumbens during drug seeking for cocaine, heroin, alcohol, or nicotine, but not sucrose seeking (Gass et al., 2011, Gipson et

Could the t-SP Be Embedded in a Neuronal Network Specific to Drug Seeking?

The results described earlier on how t-SP drives drug seeking do not distinguish subpopulations of MSNs in the NAcore and in particular do not specifically identify an engram activated by reinstated drug seeking. Indeed, the A/N ratio and spine density measurements to date have been made indiscriminately from all the MSNs in the NAcore (Gipson et al., 2013a). Interestingly, according to the available studies on engrams and responses to drugs (Carelli et al., 2000, Koya et al., 2009), the

Concluding Remarks

Changes in NAc plasticity after drug exposure are critical to seeking behaviors. Particularly, the transient deregulation of glutamate homeostasis observed in NAcore tetrapartite synapses (constituted by pre- and postsynaptic elements, astroglial end feet, and extracellular matrix encompassing the synapse) has been shown to be necessary to initiate drug seeking during cue-induced reinstatement. Although dissecting the different types of neurons in the NAc and their respective projections has

Acknowledgments

A.-C.B. was funded by a postdoctoral study grant from the French Fyssen Foundation; C.D.G. by NIH R00 DA036569; C.D.F. by NIH DA032543; P.J.K. by NIH DA025983; and P.W.K. was funded by NIH DA003906, DA12513, and DA015369. The authors would like to thank all the members of the Kalivas lab for helpful discussions and comments on this manuscript. Thank you also to the Servier Medical Art for providing free open source designed medical elements used in the illustrations.

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