Cocaine-Induced Plasticity in the Nucleus Accumbens Is Cell Specific and Develops without Prolonged Withdrawal

Abstract

Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different noncontingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature EPSCs was observed in D 1 -expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPA receptor-to-NMDA receptor ratios, higher spine density, and enlarged spine heads were observed in the absence of withdrawal after a long cocaine treatment. These synaptic adaptations expressed in D 1 -containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D 1 -expressing MSNs, which, although they take time to develop, do not require prolonged cocaine withdrawal.

Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

“…Similar to cocaine, repeated morphine augmented synaptic strength and AMPAR-mediated transmission exlcusively in D1R-MSNs of the NAc shell (14). On the other hand, morphinedependent increases in mEPSC frequency and reductions in paired-pulse ratios suggest an increase in release probability at D1R-MSNs, contrasting with cocaine studies, which have directly observed increases in glutamate release probability in the NAc core, but not shell (21)(22)(23)(24).…”

“…In the present study, no significant adaptations in synaptic strength (A/N ratios) or glutamate release probability were observed in either D1R-or D2R-MSNs of the NAc core. Although repeated exposure to cocaine produces enduring increases in synaptic strength in both NAc shell and core, we recently demonstrated NAc synaptic plasticity following repeated amphetamine (22,24,(32)(33)(34), which raises a question of whether cocaine, rather than morphine, may be unusual in regards to plasticity in the NAc core. That said, given that the behavioral and neurochemical effects of opiates are dependent on activation of mu opioid receptors (2,35), the regional differences in morphine-induced plasticity demonstrated here may be related to the higher prevalence of mu opioid receptors in the NAc shell compared with the core (36,37).…”

“…It is worth noting, however, that reductions in NAc core A/N ratios due to up-regulation of NR2B-containing NMDAR currents have been reported following heroin self-administration in rats, and that this adaptation drives reinstatement of heroin seeking (24). The mechanisms underlying this apparent discrepancy in plasticity are unclear; however, morphine and heroin have been shown to differentially modulate synaptic strength (44).…”

Erratum: Repeated Binge-Like Ethanol Drinking Alters Ethanol Drinking Patterns and Depresses Striatal GABAergic Transmission

“…A short and a long abstinence period was investigated because of the extensive literature on the effects of other drugs of abuse such as cocaine on spine density in the striatum observed after 4 weeks of the last exposure (Robinson and Kolb, 1999;Lee et al, 2006;Dobi et al, 2011;Waselus et al, 2013). Sparse fluorescent labeling of MSNs was achieved using the DiOlistic technique in fixed brain slices of ethanol drinking and controls water drinking mice at the two time points (Figure 4e).…”

The Interactional Approach in the Treatment of Cocaine Addicts

“…Indeed, the prolonged use of cocaine produces changes at the neurobiological level (Huang et al, 2009;Dobi et al, 2011, for review see Belin et al, 2009), which likely involves the formation of a long-term memory trace (Lee & Dong, 2011) about the pleasurable effects caused by cocaine, even after a single exposure (Ungless et al, 2001). Thus, working on meta-cognition it becomes possible to act on the mechanisms of impulsivity that may promote relapse in cocaine addiction.…”