Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats

Carelli, Regina M.; Ijames, Stephanie G.

doi:10.1016/s0006-8993(00)02217-4

Cited by 60 publications

(40 citation statements)

References 41 publications

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“…In vivo studies have shown the occurrence of low-frequency (up to 10-15 Hz) cell firing in the NAc (26,27), and that long-term synaptic potentiation can be induced at the cortico-striatal synapses by applying 5-Hz discharge for several minutes (28). We decided to explore the effects of various low-frequency stimulations in a slice preparation containing prelimbic cortex-NAc synapses.…”

Section: Resultsmentioning

confidence: 99%

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Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Robbe

Köpf

Rémaury

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

514

502

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Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a longterm depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca 2؉ stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system. E xogenous cannabinoids, such as the active component of Cannabis sativa L, (Ϫ)-transdelta9-tetrahydrocannabinol, as well as endocannabinoids (eCBs; anandamide and 2-arachidonoyl-glycerol) share the same target in the central nervous system: a Gi͞Go-coupled receptor named CB1 (1, 2). Activation of CB1 receptors inhibits both inhibitory and excitatory synaptic transmission in the hippocampus (3, 4), substantia nigra pars compacta (5), the cerebellum (6), the prefrontal cortex (7), and the nucleus accumbens (NAc) (8, 9). Both eCBs and CB1 have been involved in a short-lasting form of synaptic regulation: the ''depolarization-induced suppression'' of both inhibitory (10-15) and excitatory transmission (16). However, the involvement of eCB in long-lasting activity-dependent synaptic plasticity remained to be documented. The mesocorticolimbic dopaminergic system, and particularly the NAc, is essential to the reinforcing properties of addictive drugs (17, 18). Cannabinoids activate mesolimbic dopamine neurons (19) and increase NAc dopamine levels (20), similarly to other drugs of abuse. Our finding that CB1 are localized at the excitatory afferents to the NAc where exogenous cannabimimetics inhibit glutamatergic synaptic transmission (9) raised two questions: how does synaptic activity lead to the production of eCBs in the NAc, and what are the physiological correlates of eCB release on synaptic transmission? Methods Slice Preparation and Electrophysiology. Whole-cell patch-clamp and extracellular field recordings were made from medium spiny neurons in parasagittal slices of mouse NAc. These methods have been described in detail previously (9). In brief, mice (male C57BL6, 4-6 weeks) were anesthetized with isoflurane and decapitated. The brain was sliced (300-400 m) in the parasagittal plane by using a vibratome and maintained in physiological saline at 4°C. Slices containing the NAc were stored at least 1 h at room temperature before being placed in the recording chamber and superfused (2 ml͞min) with artificial cerebrospinal fluid that contained (in mM): 126 NaCl, 2.5 KCl, 1.2 MgCl 2 , 2.4 CaCl 2, 18 NaHCO 3 , 1.2 NaH 2 PO 4 , and 11 glucose, and was equilibrated with 95% O 2 ͞5% CO 2 . All experiments were done at room temperature. The superfusion medium contained picrotoxin (100 M) to...

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Section: Resultsmentioning

confidence: 99%

“…The fact that eCB-LTD was induced with low-frequency tetanus mimicking naturally occurring frequencies (26)(27)(28) is highly indicative of the existence of eCB-LTD in vivo. Retrograde eCB signaling could be engaged in the adaptive responses of many central glutamatergic synapses.…”

Section: Discussionmentioning

confidence: 99%

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Robbe

Köpf

Rémaury

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

514

502

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“…Notably, these nuclei fall within a well characterized circuit in the basal forebrain, termed the "motive circuit" (Mogenson et al, 1980;Kalivas et al, 1993a). Behavioral responding to biologically relevant stimuli is associated with altered electrophysiological activity and extracellular neurotransmitter levels within many nuclei of the motive circuit (Schultz et al, 1993;Kosobud et al, 1994;Westerink, 1995;Cousins et al, 1999;Bradberry et al, 2000;Carelli and Ijames, 2000;Chang et al, 2000). Furthermore, lesions of the nucleus accumbens (NA), prefrontal cortex (PFC), amygdala, ventral pallidum (VP), or mediodorsal nucleus (MD) have been shown to disrupt responding maintained by food or drugs of abuse as well as responding maintained by stimuli predictive of such reinforcement (Brown and Fibiger, 1993;McAlonan et al, 1993;Baker et al, 1994Baker et al, , 1996Gong et al, 1997;Parkinson et al, 1999;Alderson et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Limbic and Motor Circuitry Underlying Footshock-Induced Reinstatement of Cocaine-Seeking Behavior

McFarland¹,

Davidge²,

Lapish³

et al. 2004

J. Neurosci.

481

474

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The role of limbic, cortical, and striatal circuitry in a footshock reinstatement model of relapse to cocaine seeking was evaluated. Transient inhibition of the central extended amygdala [CEA; including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)], ventral tegmental area (VTA), and motor circuitry [including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)] blocked the ability of footshock stress to reinstate lever pressing previously associated with cocaine delivery. However, inhibition of the basolateral amygdala, mediodorsal nucleus of the thalamus, or the ventral prefrontal cortex had no effect on drug-seeking behavior. These data suggest that footshock stress activates limbic circuitry of the CEA that, via the VTA, activates motor output circuitry responsible for producing lever press responding. Consistent with this notion, the D 1 /D 2 dopamine receptor antagonist fluphenazine blocked footshock-induced reinstatement when infused into the PFCd. Further, inhibition of the NAshell blocked a footshock-induced increase in dopamine within the PFC and concomitantly blocked reinstatement responding. Also supporting the idea of a CEA-VTA-motor circuit in stress-induced reinstatement of cocaine seeking, inactivation of the PFCd was shown to block stress-induced glutamate release within the NAcore while concurrently inhibiting reinstatement responding. Taken together, these data suggest that footshock activates limbic circuitry in the CEA, which in turn activates a VTA dopamine projection to the PFCd. The rise in dopamine within the PFCd initiates reinstatement via a glutamatergic projection to the NAcore.

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“…Similarly, animal models of relapse show that activation of this pathway is necessary and sufficient to reinstate cocaine-seeking behavior (13) and that neuronal activity in pyramidal neurons in prefrontal cortex projecting to medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) region is correlated with cocaine-seeking (14,15). Accordingly, it is thought that prefrontal-to-accumbens synapses undergo enduring potentiation after chronic cocaine use that contributes to relapse vulnerability (4,6,16).…”

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confidence: 99%

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

Moussawi¹,

Zhou

Shen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

162

188

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Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaineinduced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model. C ocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. An enduring cocaine-induced impairment in cognitive control of motivated behavior contributes to the vulnerability to relapse (1, 2). Projections from the frontal cortex to the basal ganglia constitute a primary brain substrate for regulating motivated behavior (3). Cocaine-induced neuropathologies in the projection from the prefrontal cortex to the nucleus accumbens are implicated in cocaine addiction (4), including impaired neuroplasticity and synaptic communication (4,5). For example, prefrontal synapses in the accumbens undergo enduring potentiation (6-9), and the ability of these synapses to increase or decrease synaptic strength is impaired (7, 10). In addition, withdrawal from chronic cocaine use increases both presynaptic release estimated by elevated frequency of miniature excitatory postsynaptic currents (mEPSC) and by postsynaptic strength measured as increases in the surface expression of AMPA glutamate receptors and the ratio of AMPA/NMDA currents at glutamatergic synapses (6,8,11).Neuroimaging in cocaine addicts reveals reduced activity in prefrontal cortex under baseline conditions, but marked hyperresponsiveness in the prefrontal cortex and accumbens that is correlated with a desire for drug upon exposure to drug-associated stimuli (12). Similarly, animal models of relapse show that activation of this pathway is necessary and sufficient to reinstate cocaine-seeking behavior (13) and that neuronal ac...

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Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats

Cited by 60 publications

References 41 publications

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Limbic and Motor Circuitry Underlying Footshock-Induced Reinstatement of Cocaine-Seeking Behavior

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

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