Role In Stress-induced Reinstatement Research Articles

Blockade of orexin receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats.

A major problem managing alcohol use disorder is the high vulnerability to relapse, even after long periods of abstinence. Chronic alcohol use dysregulates stress responsivity, rendering this system hyporesponsive and making individuals vulnerable to relapse. Orexin (hypocretin) plays a role in diverse physiological processes, including stress. Orexin neurons in the hypothalamus, project to the infralimbic cortex. This study asked does infralimbic cortex orexin transmission play a significant role in stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats. Male and female rats were trained to self-administer 10% alcohol (3 weeks) and then made dependent via chronic intermittent alcohol vapour exposure. Following extinction (5 days·week-1 at 8 h abstinence for 10 sessions), rats received an intra- infralimbic cortex microinfusion of the OX1/2 antagonist TCS 1102 (15 μg/0.5 μl per side) and then tested for footshock stress-induced reinstatement of alcohol seeking. In a separate cohort, orexin regulation of infralimbic cortex neuronal activity at the time of reinstatement was investigated using ex vivo electrophysiology. TCS 1102 prevented reinstatement in dependent animals only. Moreover, Hcrtr mRNA expression in the hypothalamus and Hcrtr1/2 in the infralimbic cortex increased in alcohol-dependent animals at the time of testing. Dependence dampened basal orexin/OX receptor influence over infralimbic cortex GABAergic synapses (using TCS 1102) allow for greater stimulated orexin effects. Infralimbic cortex transmission is implicate in stress-induced reinstatement of alcohol-seeking behaviour in subjects with a history of alcohol dependence and show maladaptive recruitment of infralimbic cortex transmission by alcohol dependence.

Blockade of Orexin Receptors in the Posterior Paraventricular Nucleus of the Thalamus Prevents Stress-Induced Reinstatement of Reward-Seeking Behavior in Rats With a History of Ethanol Dependence.

Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOHD and SCMD) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOHND and SCMND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOHD/ND and SCMD/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOHD and SCMD). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOHD and SCMD groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.

Stress-Induced Reinstatement of Nicotine Preference Requires Dynorphin/Kappa Opioid Activity in the Basolateral Amygdala.

The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine's high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos expression in the basolateral amygdala (BLA), which was reduced in mice pretreated with norBNI. We then used several distinct but complementary approaches of locally disrupting BLA KOR activity to assess the role of KORs and KOR-coupled intracellular signaling cascades on reinstatement of nicotine CPP. norBNI injected locally into the BLA prevented yohimbine-induced nicotine CPP reinstatement without affecting CPP acquisition. Similarly, selective deletion of BLA KORs in KOR conditional knock-out mice prevented foot-shock-induced CPP reinstatement. Together, these findings strongly implicate BLA KORs in stress-induced nicotine seeking-like behavior. In addition, we found that chemogenetic activation of Gαi signaling within CaMKIIα BLA neurons was sufficient to induce nicotine CPP reinstatement, identifying an anatomically specific intracellular mechanism by which stress leads to reinstatement. Considered together, our findings suggest that activation of the DYN/KOR system and Gαi signaling within the BLA is both necessary and sufficient to produce reinstatement of nicotine preference. Considering the major impact of nicotine use on human health, understanding the mechanisms by which stress triggers reinstatement of drug-seeking behaviors is particularly pertinent to nicotine. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in stress-induced reinstatement of drug seeking for other commonly abused drugs. However, the specific role, brain region, and mechanisms that this system plays in reinstatement of nicotine seeking has not been characterized. Here, we report region-specific engagement of the DYN/KOR system and subsequent activation of inhibitory (Gi-linked) intracellular signaling pathways within the basolateral amygdala during stress-induced reinstatement of nicotine preference. We show that the DYN/KOR system is necessary to produce this behavioral state. This work may provide novel insight for the development of therapeutic approaches to prevent stress-related nicotine relapse.

A critical role for the melanocortin 4 receptor in stress‐induced relapse to nicotine seeking in rats

Tobacco addiction is characterized by a lack of control over smoking and relapse after periods of abstinence. Smoking cessation leads to a dysphoric state that contributes to relapse to smoking. After the acute withdrawal phase, exposure to stressors increases the risk for relapse. Blockade of melanocortin 4 (MC4 ) receptors has anxiolytic and antidepressant-like effects in animal models. The aim of these studies was to investigate the role of MC4 receptors in the dysphoria associated with nicotine withdrawal and stress-induced reinstatement of nicotine seeking. To study stress-induced reinstatement, rats self-administered nicotine for 16 days and then nicotine seeking was extinguished by substituting saline for nicotine. Nicotine seeking was reinstated by intermittent footshock stress. The intracranial self-stimulation (ICSS) procedure was used to assess the negative mood state associated with nicotine withdrawal. Elevations in the ICSS thresholds are indicative of a dysphoric state. The selective MC4 receptor antagonists HS014 and HS024 prevented stress-induced reinstatement of extinguished nicotine seeking. Drug doses that prevented stress-induced relapse did not affect responding for food pellets, which indicates that the drugs did not induce sedation or motor impairments. In the ICSS experiments, the nicotinic acetylcholine receptor antagonist mecamylamine elevated the ICSS thresholds of the nicotine-dependent rats. Pre-treatment with HS014 or HS024 did not prevent the elevations in ICSS thresholds. These studies indicate that MC4 receptors play a critical role in stress-induced reinstatement of nicotine seeking, but these receptors may not play a role in the dysphoria associated with acute nicotine withdrawal.

Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine-withdrawn adolescent rats

Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the glutamatergic synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28-42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the glutamatergic synapse. Conversely, in cocaine-treated animals, stress dynamically altered the glutamatergic synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC glutamatergic synapses to stress. It is suggested that changes in glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.

Antagonism of the dopamine D1‐like receptor in mesocorticolimbic nuclei attenuates acute food deprivation‐induced reinstatement of heroin seeking in rats

The neurotransmitter dopamine (DA) plays a critical role in both priming-and cue-induced reinstatement of extinguished drug-seeking behavior, but its role in stress-induced reinstatement is less clear. Our laboratory has recently demonstrated that systemic administration of the DA D1-like receptor antagonist, SCH 23390, attenuates acute food deprivation (FD) stress-induced reinstatement. The current study was designed to elucidate the brain regions critical to the effect of SCH 23390 on FD stress-induced reinstatement. Rats were trained to press a lever to self-administer heroin (0.1 mg/kg/inf) over a period of 10 days. Following training, heroin was removed leading to an extinction of lever pressing. Next, rats were tested for reinstatement twice, under extinction conditions: once following 21-48 h FD; and once under sated conditions. Prior to testing, SCH 23390 was administered into the nucleus accumbens (NAc) shell (0.0, 0.3, 0.6 μg/side), NAc core (0.0, 0.3, 0.6 μg/side), dorsomedial prefrontal cortex (dmPFC; 0.0, 0.2, 2.0 μg/side), ventromedial prefrontal cortex (vmPFC; 0.0, 2.0 μg/side) or basolateral amygdala (BLA; 0.0, 1.0, 2.0 μg/side). An attenuation of FD-induced reinstatement of heroin seeking was seen in rats injected with SCH 23390 into the NAc shell, dmPFC or BLA, but not into the NAc core or the vmPFC. These findings support the hypothesis that DA transmission through the DA D1-like receptors plays a critical role in stress-induced reinstatement of heroin seeking.

The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking

A major problem in treating alcohol use disorders (AUDs) is the high rate of relapse due to stress and re-exposure to cues or an environment previously associated with alcohol use. Stressors can induce relapse to alcohol-seeking in humans or reinstatement in rodents. Delta opioid peptide receptors (DOP-Rs) play a role in cue-induced reinstatement of ethanol-seeking; however, their role in stress-induced reinstatement of ethanol-seeking is not known. The objective of this study was to determine the role of DOP-Rs in yohimbine-stress-induced reinstatement of ethanol-seeking. Male, Long-Evans rats were trained to self-administer 10% ethanol in daily 30-minute operant self-administration sessions using a FR3 schedule of reinforcement, followed by extinction training. Once extinction criteria were met, we examined the effects of the DOP-R antagonist, SoRI-9409 (0-5 mg/kg, i.p.) on yohimbine (2 mg/kg, i.p.) stress-induced reinstatement. Additionally, DOP-R-stimulated [(35) S]GTPγS binding was measured in brain membranes and plasma levels of corticosterone (CORT) were determined. Pre-treatment with SoRI-9409 decreased yohimbine stress-induced reinstatement of ethanol-seeking but did not affect yohimbine-induced increases in plasma CORT levels. Additionally, yohimbine increased DOP-R-stimulated (35) [S]GTPγS binding in brain membranes of ethanol-trained rats, an effect that was inhibited by SoRI-9409. This suggests that the DOP-R plays an important role in yohimbine-stress-induced reinstatement of ethanol-seeking behavior, and DOP-R antagonists may be promising candidates for further development as a treatment for AUDs.

Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking

A central problem in the treatment of drug addiction is high rates of relapse to drug use after periods of forced or self-imposed abstinence. This relapse is often provoked by exposure to stress. Stress-induced relapse to drug seeking can be modeled in laboratory animals using a reinstatement procedure. In this procedure, drug-taking behaviors are extinguished and then reinstated by acute exposure to stressors like intermittent unpredictable footshock, restraint, food deprivation, and systemic injections of yohimbine, an alpha-2 adrenoceptor antagonist that induces stress-like responses in humans and nonhumans. For this special issue entitled “The role of neuropeptides in stress and addiction”, we review results from studies on the role of corticotropin-releasing factor (CRF) and several other peptides in stress-induced reinstatement of drug seeking in laboratory animals. The results of the studies reviewed indicate that extrahypothalamic CRF plays a critical role in stress-induced reinstatement of drug seeking; this role is largely independent of drug class, experimental procedure, and type of stressor. There is also limited evidence for the role of dynorphins, hypocretins (orexins), nociceptin (orphanin FQ), and leptin in stress-induced reinstatement of drug seeking.

Blockade of Stress-Induced But Not Cocaine-Induced Reinstatement by Infusion of Noradrenergic Antagonists into the Bed Nucleus of the Stria Terminalis or the Central Nucleus of the Amygdala

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of β-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5–7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the β₁- and β₂-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 μl) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala.

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of beta-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5-7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the beta(1)- and beta(2)-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 microliter) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

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Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of β-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5–7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the β₁- and β₂-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 μl) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.