Similar Neurons, Opposite Adaptations: Psychostimulant Experience Differentially Alters Firing Properties in Accumbens Core versus Shell

Abstract

The principal components of neuronal excitability include synaptic and intrinsic membrane parameters. While recent studies indicate that cocaine exposure can induce widespread changes in synaptic function in the neural circuits for reward, intrinsic firing properties have received much less attention. Using whole cell recording in ex vivo brain slices from cocaine-treated mice, we studied the intrinsic firing characteristics of medium-spiny projection neurons of the nucleus accumbens—a key node in the circuit that controls reward-directed behavior. Our data demonstrate that repeated in vivo cocaine (5 × 15 mg/kg i.p. once daily, 5 days) induces opposite changes in neurons of the two main subdivisions of the accumbens, the shell and the core. While shell neurons exhibit an initial depression in firing capacity (1-3 days abstinence) that persists for at least two weeks, core neurons exhibit increased firing capacity during early abstinence (1-3 days) that declines to basal levels within two weeks. Shared adaptations between addictive drugs may mediate core processes of addiction. We find that amphetamine exposure (5 × 5 mg/kg i.p. once daily, 5 days) that induced a similar degree of locomotor sensitization as cocaine also induced an indistinguishable pattern of NAc intrinsic plasticity. Finally, we provided evidence that opposite regulation of A-type potassium current is an important factor in this bidirectional intrinsic plasticity for both cocaine and amphetamine. We propose that a persistent disparity in core/shell excitability might be an important mediator of the changes in reward circuit activity that drive drug-seeking behavior in animal models of addiction.

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

“…The two major subdivisions of the NAc, the shell and core, are distinguished based on anatomic connectivity and their role in reward-related behavior (6,(30)(31)(32)(33). 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.…”

“…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).…”

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…To investigate potential long-lasting effects of repeated amphetamine exposure on glutamatergic synaptic transmission, we treated mice with an amphetamine regimen that produces robust psychomotor sensitization (eg, Kourrich and Thomas, 2009; Figure 3a) and prepared acute sagittal slices containing the NAc shell (Figure 1) or core ( Figure 2) 10-14 days following the final drug (or saline) injection. In two additional groups of amphetamine-sensitized mice, we examined whether re-exposure to amphetamine (AmphAmph) or saline (Amph-Sal) with a challenge injection induced 'depotentiation,' a form of long-term synaptic depression (LTD) that has been observed 24 h following drug re-exposure (Boudreau et al, 2007;Kourrich et al, 2007;Pascoli et al, 2012;Rothwell et al, 2011).…”

“…For example, exposure to cocaine and amphetamine produce a similar set of outcomes at both the behavioral and cellular level. Specifically, both promote development of behavioral sensitization and increase drug self-administration, enhance extracellular dopamine (DA) and glutamate levels in the NAc, and produce parallel adaptations in MSN intrinsic excitability (Kourrich and Thomas, 2009;Reid et al, 1997;Vezina, 2004;Xue et al, 1996). However, more drug-specific effects on NAc plasticity, most notably AMPAR expression, have also been demonstrated.…”

“…These results raise questions of whether amphetamine alters excitatory synaptic strength in the NAc and whether the two major subdivision of the NAc, the core and shell, display similar adaptations. These areas are distinguished based on anatomical connectivity, involvement in reward-related responses, and have been shown to be differentially affected by drugs of abuse (Everitt et al, 1999;Heimer et al, 1991;Kourrich and Thomas, 2009;Zahm and Brog, 1992). Therefore, we investigated how repeated exposure to amphetamine and cocaine may differentially alter excitatory signaling in the NAc, focusing on region-specific changes in synaptic strength and AMPAR-mediated signaling in the core and shell.…”