Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens (original) (raw)
Related papers
Journal of Neuroscience, 2010
Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that following short-term (2d) or long-term (21d) withdrawal from non-contingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or noncontingently. Specifically, the membrane excitability of NAcSh MSNs was decreased at 2d after withdrawal from either 5-day intraperitoneal (i.p.) injections (15 mg/kg) or cocaine selfadministration (SA). At 21d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in i.p.-pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, upon a re-exposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in i.p.-pretreated rats. On the other hand, in SA-pretreated rats, the re-exposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and non-contingent cocaine administration.
Neuropharmacology, 2012
Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 AE 85.9% (n ¼ 5) which further increased by 733.1 AE 157.8% (n ¼ 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 AE 61.0%; n ¼ 4). In contrast to cocaine, IP injection of rats with SP or SP 5e11 (10e100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine's effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine's effects are mimicked by SP.
Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc
Nature Neuroscience, 2009
Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor-dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.
Cocaine Self-Administration Reduces Excitatory Responses in the Mouse Nucleus Accumbens Shell
Neuropsychopharmacology, 2006
Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.
Journal of Neuroscience, 2011
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 non-contingent 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 excitatory postsynaptic currents (mEPSCs) was observed in D1expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPAR to NMDAR ratios, higher spine density and enlarged spine heads were observed in the absence of withdrawal following a long cocaine treatment. These synaptic adaptations expressed in D1-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 D1-expressing MSNs, which although they take time to develop, do not require prolonged cocaine withdrawal.
Neuropharmacology, 2012
Excitatory synapses on dopamine (DA) neurons in the ventral tegmental area (VTA) are modulated following exposure to various addictive drugs, including cocaine. Previously we have shown that cocaine affects GABA(A) receptor (GABA(A)R)-mediated neurotransmission in VTA DA neurons. This finding led us to reexamine the modulation of the excitatory synapse on these neurons in response to cocaine exposure, while the activity of GABA(A)R is uninterrupted. Using rat brain slices, evoked post synaptic currents (ePSC) were monitored and inhibitors of NMDA receptor (NMDAR) and AMPA receptor (AMPAR) were gradually added to inhibitors-free bath solution. Modifications in the efficacy of the excitatory synapses were evaluated by comparing AMPAR-mediated and NMDAR-mediated currents (AMPA/NMDA ratio). The lack of GABA(A)R inhibitors enabled us to examine parallel changes in the relation between GABA(A)R-mediated and NMDAR-mediated currents (GABA(A)/NMDA ratio). First, we found that AMPA/NMDA ratio measured under complete availability of GABA(A)R, is significantly higher than the ratio measured under GABA(A)R blockade. In addition, GABA(A)/NMDA ratio, but not AMPA/NMDA ratio, is augmented a few hours following in vitro acute cocaine exposure. When measured 24 h after in vivo single cocaine injection, no change in GABA(A)/NMDA ratio was observed, however, the AMPA/NMDA ratio was found to be significantly higher. Finally, a decrease in both ratios was detected in rats repeatedly injected with cocaine. Taken together, these results lead to a better understanding of the means by which cocaine modifies synaptic inputs on VTA DA neurons. The parallel changes in GABA(A)/NMDA ratio may suggest an interaction between inhibitory and excitatory neural systems.
Behavioural Brain Research, 2006
Repeated exposure to cocaine leads to behavioral sensitization, which is the augmentation of the locomotor response to a subsequent exposure to the drug. The nucleus accumbens (NAc), a major termination site of dopaminergic neurons, is believed to be involved in behavioral sensitization and studies have demonstrated that the NAc shell can be split into five zones of analysis; the vertex, arch, cone, intermediate and ventrolateral zones [Todtenkopf MS, Stellar JR. Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine. Synapse 2000;38:261-70]. Several reports show cocaine-induced c-fos expression particularly in the intermediate zone after 14, but not 2, drug-free days following repeated cocaine administration, suggesting that this region may be involved in sensitization and particularly in the later phase of expression, versus the earlier phase of sensitization. Bilateral electrolytic lesions of the intermediate zone were made in two groups of rats, which were then repeatedly exposed to cocaine (15 mg/kg, twice/day for 5 days). One group was subsequently given a single cocaine challenge injection (15 mg/kg) after 14 drug-free days, while the other group was challenged after only 2 drug-free days. Two sham surgery groups in which an electrode was lowered but no current was passed served as controls. Results show that lesioned animals as well as sham controls exhibited behavioral sensitization to the drug. However, following a 14-day drug-free period, the lesioned animals showed significant reduction in sensitization, compared to sham controls. Together these findings suggest that the intermediate zone of the NAc shell is indeed involved in the expression phase of behavioral sensitization to cocaine.
Neural mechanisms of tolerance to the effects of cocaine
Behavioural Brain Research, 1997
Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial selfstimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine Dl-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.
PLoS ONE, 2012
We previously showed that the time-dependent intensification (''incubation'') of cue-induced cocaine seeking after withdrawal from extended-access cocaine self-administration is accompanied by accumulation of Ca 2+-permeable AMPA receptors (CP-AMPARs) in the rat nucleus accumbens (NAc). These results suggest an enduring change in Ca 2+ signaling in NAc dendritic spines. The purpose of the present study was to determine if Ca 2+ signaling via NMDA receptors (NMDARs) is also altered after incubation. Rats self-administered cocaine or saline for 10 days (6 h/day). After 45-47 days of withdrawal, NMDAR-mediated Ca 2+ entry elicited by glutamate uncaging was monitored in individual NAc dendritic spines. NMDAR currents were simultaneously recorded using whole cell patch clamp recordings. We also measured NMDAR subunit levels in a postsynaptic density (PSD) fraction prepared from the NAc of identically treated rats. NMDAR currents did not differ between groups, but a smaller percentage of spines in the cocaine group responded to glutamate uncaging with NMDARmediated Ca 2+ entry. No significant group differences in NMDAR subunit protein levels were found. The decrease in the proportion of spines showing NMDAR-mediated Ca 2+ entry suggests that NAc neurons in the cocaine group contain more spines which lack NMDARs (non-responding spines). The fact that cocaine and saline groups did not differ in NMDAR currents or NMDAR subunit levels suggests that the number of NMDARs on responding spines is not significantly altered by cocaine exposure. These findings are discussed in light of increases in dendritic spine density in the NAc observed after withdrawal from repeated cocaine exposure.