Impairment of glutamate homeostasis in the nucleus accumbens core underpins cross-sensitization to cocaine following chronic restraint stress.

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.

Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation.

Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders.

CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context.

Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 µl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 µl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.

Endogenous enkephalin is necessary for cocaine-induced alteration in glutamate transmission within the nucleus accumbens.

Altered glutamate transmission within the nucleus accumbens (NAc) has been proposed as a central mechanism underlying behavioural sensitisation associated with repeated cocaine exposure. In addition to glutamate, enkephalin, an endogenous opioid peptide derived from proenkephalin, is necessary for the neuroadaptations associated with chronic cocaine. However, the influence of enkephalin on long-term changes in glutamate transmission within the NAc associated with cocaine-induced sensitisation has not been described. This study used knockout proenkephalin mice (KO) to study the influence of endogenous enkephalin on the adaptations in glutamate neurotransmission associated with repeated cocaine treatment. Wild-type (WT) and KO mice were treated with daily cocaine injections for 9 days to induce sensitisation. On days 15 and 21, the animals received a cocaine challenge and locomotor sensitisation was evaluated, and microdialysis was performed to determine accumbens glutamate content on day 21. No expression of behavioural sensitisation to cocaine was evidenced in the KO mice. Consistently, these showed no changes in glutamate transmission in the NAc associated with repeated cocaine. This study reveals the central role of enkephalin in regulating the glutamate mechanisms associated with cocaine sensitisation.

Enkephalin as a Pivotal Player in Neuroadaptations Related to Psychostimulant Addiction.

Enkephalin expression is high in mesocorticolimbic areas associated with psychostimulant-induced behavioral and neurobiological effects, and may also modulate local neurotransmission in this circuit network. Psychostimulant drugs, like amphetamine and cocaine, significantly increase the content of enkephalin in these brain structures, but we do not yet understand the specific significance of this drug-induced adaptation. In this review, we summarize the neurochemical and molecular mechanism of psychostimulant-induced enkephalin activation in mesocorticolimbic brain areas, and the contribution of this opioid peptide in the pivotal neuroadaptations and long-term behavioral changes underlying psychostimulant addiction. There is evidence suggesting that adaptive changes in enkephalin content in the mesocorticolimbic circuit, induced by acute and chronic psychostimulant administration, may represent a key initial step in the long-term behavioral and neuronal plasticity induced by these drugs.

NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats.

Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP.