Drug-Primed Reinstatement of Cocaine Seeking in Mice: Increased Excitability of Medium-Sized Spiny Neurons in the Nucleus Accumbens

Abstract

To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…In these experiments, we used a modified internal pipette solution and two different holding potentials to monitor sEPSCs and sIPSCs in the same neuron (Ma et al, 2013). As compared with air controls, CIE-treated mice showed increases in the amplitude (one-way ANOVA: F (3, 39) = 2.889, p = 0.0476; Figure 4a), but not frequency (Figure 4b) of spontaneous excitatory synaptic currents (measured as inward currents at − 70 mV).…”

“…Amplitude (pA) and area (pA/ms) of synaptic events were measured to determine the effects of WD from CIE on evoked AMPA and NMDA EPSCs. In separate set of experiments, a cesium methanesulfonate internal pipette solution (in mM: 125 CsMeSO 3 , 10 CsCl, 5 NaCl, 10 HEPES, 1 EGTA, 2 MgCl 2 , 5 MgATP, 0.3 NaGTP) was used to measure spontaneous EPSCs (sEPSCs) and inhibitory postsynaptic currents (IPSCs) in the same neuron by recording events at a membrane potential at − 70 or 10 mV, respectively (Ma et al, 2013). Spontaneous events were detected using a template matching algorithm and a threshold amplitude of 6 pA for sEPSCs and 10 pA for spontaneous IPSCs (sIPSCs).…”

HIV-1 Transgenic Female Rat: Synaptodendritic Alterations of Medium Spiny Neurons in the Nucleus Accumbens

“…Therefore, we used DiOlistic labeling to explore alterations in dendritic arborization and spine morphology of MSNs in the NAcc of HIV-1 Tg female rats. The MSNs in the NAcc represent an important component of the motivational/reward system mediating substance abuse (Ma et al 2013), which is often co-morbid with HAND in women (Meyer et al 2013; Maki and Martin-Thormeyer 2009). Thus, identification of altered MSN synaptodendritic structures in HIV-1 Tg female animals is a key step in clarifying possible neuropathological substrates of HAND.…”

Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens

“…Thus, natural or psychostimulant conditioned rewarding stimuli can activate MSN neuronal populations recorded in rodents during behavioral reinforcement paradigms (Lansink et al, 2010;Ma et al, 2013). Indeed, Taha and Fields (2005) reported that a plurality of identified MSNs showed excitatory responses associated with sucrose reward exposure in rats.…”