Effects of Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 on the Reinstatement of Cocaine-Mediated Conditioned Place Preference in Mice

A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

Nociceptive stimuli activate the hypothalamus-habenula circuit to inhibit the mesolimbic reward system

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch decreased extracellular DA release in the nucleus accumbens ventrolateral shell, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 50-kHz ultrasonic vocalizations and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement.

The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.

Behavioural Pharmacology of Novel Kappa Opioid Compounds

<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>

Behavioural Pharmacology of Novel Kappa Opioid Compounds

<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>