The Bermuda Triangle of cocaine-induced neuroadaptations

Abstract

Activation of medium spiny neurons (MSNs) of the nucleus accumbens is critical for goal-directed behaviors including cocaine seeking. Studies in cocaine-experienced rodents have revealed three major categories of neuroadaptations that influence the ability of glutamate inputs to activate MSNs: changes in synaptic AMPA receptor levels, changes in extracellular non-synaptic glutamate levels and changes in MSN intrinsic membrane excitability. Most studies have focused on one of these adaptations. This review will consider the possibility that they are causally related and speculate about how time-dependent changes in their interactions may regulate MSN output during early and late withdrawal from repeated cocaine exposure.

Figure 1. Three major cocaine-induced neuroadaptations that influence the functional output of medium spiny neurons (MSN) of the nucleus accumbens (NAc)

Left: AMPA receptor (AMPAR) surface expression (GluA1A2), AMPA/NMDA ratios, and GluA1 and GluA2 levels in synaptic membrane fractions are increased in the NAc of rodents sensitized with non-contingent cocaine injections [–15]. This occurs during the first week of withdrawal and persists for many weeks. In contrast, Ca²⁺-permeable AMPARs (CP-AMPARs), which lack the GluA2 subunit [–21], are added to NAc synapses in association with the incubation of cocaine craving after extended-access cocaine self-administration [18,22,24]. Due to the higher conductance of CP-AMPARs and their ability to couple to Ca²⁺-dependent signaling pathways, they may enhance MSN output more than upregulation of GluA1A2 receptors. Center: The intrinsic membrane excitability of MSN is decreased after withdrawal from a sensitizing regimen of cocaine [,,–51]. This effect may differ between the core and shell subregions of the NAc [51; Box 1], and its duration is determined by whether cocaine exposure is contingent or non-contingent [7]. Decreased intrinsic excitability is due to decreased Na⁺ and Ca²⁺ conductances, and increased K⁺ conductances [,–48,51], secondary to homeostatic synapse-driven membrane plasticity (hSMP) [5] and alterations in protein kinase and phosphatase cascades [45,46,48,49]. Right: Repeated cocaine exposure decreases extracellular non-synaptic glutamate levels in the NAc, altering mechanisms that regulate glutamate synaptic transmission [31]. Synaptically released and extracellular non-synaptic glutamate pools are segregated (e.g., by glutamate transporters that limit diffusion of synaptically released glutamate). Microdialysis samples the extracellular non-synaptic pool (“extracellular glutamate”). This pool is derived mainly (~60%) from the cystine-glutamate (Cys-Glu) exchanger, which operates constitutively to exchange extracellular cystine for intracellular glutamate [36]. It provides glutamate tone on extrasynaptic group II metabotropic glutamate receptors (mGluR) that exert inhibitory control over glutamate neurotransmission [–38]. Activity of the cystine-glutamate exchanger decreases after cocaine exposure and withdrawal, which decreases extracellular non-synaptic glutamate levels [–35]. This decreases glutamate tone on group II mGluRs, removing the “brake” on synaptic glutamate release [38]. Other cocaine-induced neuroadaptations, including decreased G protein coupling, also contribute to decreased group II mGluR transmission [31,39]. Manipulating GLT-1, the glial glutamate transporter responsible for the majority of glutamate uptake, can also affect the glutamate transmission required for reinstatement of cocaine-seeking [35,90,91].

Figure 2. Bermuda “square” depicting the three neuroadaptations that are highlighted in this review (blue ovals) and a relatively unexplored area (brown oval)

An important challenge is to understand how time-dependent changes in their interactions regulate the functional output of nucleus accumbens (NAc) medium spiny neurons during cocaine withdrawal, causing the NAc to enter a new state in which cocaine-related signals have acquired more influence. Lines between ovals are not meant to indicate direct causal relationships.