The role of orexin receptors within the CA1 area in the acquisition and expression of methamphetamine place preference.

Treatment of Methamphetamine (METH) use disorder has become a crucial public health issue. The orexin system manipulation has provided promising evidence to attenuate addictive-like behaviors. This study explored the role of the orexin 1 receptor and orexin 2 receptor (OX1R and OX2R) in the CA1 area of the hippocampal formation in the acquisition and expression of METH-induced place preference. Animals were subjected to bilateral administration of different dosages (1, 3, 10, and 30 nmol/0.5 µl DMSO per side) of a selective OX1R antagonist, SB334867, or selective OX2R antagonist, TCS OX2 29 into the CA1 area throughout the conditioning phase or once on the post-conditioning phase in separate control and experimental groups. Behavioral data revealed that both OX1R (10 nmol; P < 0.01 and 30 nmol; P < 0.001) and OX2R (10 nmol; P < 0.05 and 30 nmol; P < 0.001) antagonism during the conditioning phase could block the formation of METH place preference dose-dependently. In addition, intra-CA1 microinjection of SB334867 on the post-conditioning phase attenuated the expression of METH place preference in a dose-dependent manner (3 nmol; P < 0.05, 10 nmol; P < 0.01 and 30 nmol; P < 0.001) whereas intra-CA1 administration of TCS OX2 29 only at the highest dosage (30 nmol) declined the expression of METH place preference (P < 0.01). It was also indicated that the suppressive effects of orexin receptor blockade on the METH-seeking behavior in the CA1 area were anatomically specific to this area. These findings support the possibility of targeting the orexin system to develop novel and successful pharmacological options for the treatment of METH dependence.

The role of orexin-1 receptors within the ventral tegmental area in the extinction and reinstatement of methamphetamine place preference.

Targeting the orexin system has recently been identified as one of the promising options for treating drug addiction. It may be more feasible and achievable if we investigate the accurate function of the orexin system in brain areas implicated in reward and addiction, such as the ventral tegmental area (VTA) by animal reward models. This study investigated the contribution of the orexin system, mainly the orexin-1 receptors (OX1R) in the VTA, in the extinction and reinstatement of methamphetamine (METH) related memories in the conditioned place preference (CPP) model. Animals after the acquisition of METH place preference were subjected to two separate sets of extinction and reinstatement experiments to receive various concentrations of selective OX1R antagonist, SB334867 into the bilateral VTA before extinction sessions (1, 3, and 10 nmol/0.3 µl DMSO per side) or only on the reinstatement phase (3, 10, and 30 nmol/0.3 µl DMSO per side), respectively. Intra-VTA infusion of SB334867 throughout the extinction phase could remarkably facilitate the extinction process and decrease the maintenance of reinforcing effects of METH at the highest dosage (10 nmol; p < 0.0001). Data also indicated a single microinfusion of SB334867 into the VTA before reinstatement of the METH-seeking behavior could considerably prevent the relapse of previously formed reward-context memories (10 nmol; p < 0.01 and 30 nmol; p < 0.001). The present study provided evidence supporting the potential therapeutic effects of the orexin system modulation, specifically in the VTA, on different stages of METH-induced place preference.

A systematic review of the local field potential adaptations during conditioned place preference task in preclinical studies.

Addiction is a global concern with a high relapse rate and without effective therapeutic options. Developing new effective therapeutic strategies is impossible without discovering the disease's neurobiological basis. The present systematic review aimed to comprehensively recognize and discuss the role of local field potentials from brain areas essential in forming and storing context-drug/food associations following the conditioned place preference (CPP) paradigm as a popular animal model of reward and addiction. Qualified studies were incorporated by a broad search of four databases, including Web of Science, Medline/PubMed, Embase, and ScienceDirect, in July 2022, and they were evaluated via appropriate methodological quality assessment tools. The current study found that drug-seeking behavior in different stages of the CPP paradigm is accompanied by alterations in neural oscillatory activity and adaptations in connectivity among various areas such as the hippocampus, nucleus accumbens, basolateral amygdala, and prelimbic area, intensely engaged in reward-related behaviors. These findings need to be extended by more future advanced studies to finally recognize the altered oscillatory activity patterns of large groups of cells in regions involved in reward-context associations to improve clinical strategies such as neuromodulation approaches to modify the abnormal electrical activity of these critical brain regions and their connections for treating addiction and preventing drug/food relapse in abstinent patients. DEFINITIONS: Power is the amount of energy in a frequency band and is the squared amplitude of the oscillation. Cross-frequency coupling refers to a statistical relationship between activities in two different frequency bands. Phase-amplitude coupling is perhaps the most commonly used method of computing cross-frequency coupling. Phase-amplitude coupling involves testing for a relationship between the phase of one frequency band and the power of another, typically relatively higher, frequency band. Thus, within phase-amplitude coupling, you refer to the "frequency for phase" and the "frequency for power." Spectral coherence has been frequently used to detect and quantify coupling between oscillatory signals of two or more brain areas. Spectral coherence estimates the linear phase-consistency between two frequency-decomposed signals over time windows (or trials).

Distinct suppressing effects of deep brain stimulation in the orbitofrontal cortex on the development, extinction, and reinstatement of methamphetamine-seeking behaviors.

AIMS: The orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats. MAIN METHODS: Electrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high- or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg). KEY FINDINGS: The HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. SIGNIFICANCE: Conclusively, DBS administration in the OFC demonstrated some positive results, including suppressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.

A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder.

Psychostimulant Use Disorder (PUD) is a chronic relapsing disorder with high motivation for drug abuse. In addition to developing PUD, the use of psychostimulants is a growing public health concern because it is associated with several physical and mental health impairments. To date, there are no FDA-confirmed medicines for the treatment of psychostimulant abuse; therefore, clarification of the cellular and molecular alterations participating in PUD is crucial for developing beneficial medications. PUD causes extensive neuroadaptations in glutamatergic circuitry involved in reinforcement and reward processing. These adaptations include both transient and long-lasting changes in glutamate transmission and glutamate receptors, especially metabotropic glutamate receptors, that have been linked to developing and maintaining PUD. Here, we review the roles of all groups of mGluRs,including I,II, and III in synaptic plasticity within brain reward circuitry engaged by psychostimulants (cocaine, amphetamine, methamphetamine, and nicotine). The review concentrates on investigations of psychostimulant-induced behavioral and neurological plasticity, with an ultimate goal to explore circuit and molecular targets with the potential to contribute to the treatment of PUD.

A wide range of Deep Brain Stimulation of the nucleus accumbens shell time independently reduces the extinction period and prevents the reinstatement of methamphetamine-seeking behavior in rats.

Methamphetamine (METH) addiction is a significant public health issue, and standard medical therapies are often not curative. Deep Brain Stimulation (DBS) has recently shown the potential to cure addiction by modulating neural activity in specific brain circuits. Recent studies have revealed that the nucleus accumbens shell (NAcSh) could serve as a promising target in treating addiction. Therefore, the present study aimed to investigate the therapeutic effects of NAcSh high- or low-frequency stimulation (HFS or LFS) in the different time points of application on the extinction and reinstatement of the METH-conditioned place preference (CPP). LFS or HFS (10 or 130 Hz, 150-200 µA, 100 µs) was delivered to the NAcSh for 30 min non-simultaneous (in a distinct non-drug environment) or simultaneous (in a drug-paired context) of the drug-free extinction sessions. The obtained results showed that both non-simultaneous and simultaneous treatments by HFS and LFS notably reduced the extinction period of METH-induced CPP. Furthermore, the data indicated that both non-synchronous and synchronous HFS prevented METH-primed reinstatement, while only the LFS synchronized group could block the reinstatement of METH-seeking behavior. The results also demonstrated that HFS was more effective than LFS in attenuating METH-primed reinstatement, and applying HFS synchronous was significantly more effective than HFS non-synchronous in reducing the relapse of drug-seeking. In conclusion, the current study's results suggest that DBS of the NAcSh in a wide range of frequencies (LFS and HFS) could affect addiction-related behaviors. However, it should be considered that the frequency and timing of DBS administration are among the critical determining factors.

Is Deep Brain Stimulation an Effective Treatment for Psychostimulant Dependency? A Preclinical and Clinical Systematic Review.

Addiction to psychostimulants significantly affects public health. Standard medical therapy is often not curative. Deep brain stimulation (DBS) is a promising treatment that has attracted much attention for addiction treatment in recent years. The present review aimed to systematically identify the positive and adverse effects of DBS in human and animal models to evaluate the feasibility of DBS as a treatment for psychostimulant abuse. The current study also examined the possible mechanisms underlying the therapeutic effects of DBS. In February 2022, a comprehensive search of four databases, including Web of Science, PubMed, Cochrane, and Scopus, was carried out to identify all reports that DBS was a treatment for psychostimulant addiction. The selected studies were extracted, summarized, and evaluated using the appropriate methodological quality assessment tools. The results indicated that DBS could reduce relapse and the desire for the drug in human and animal subjects without any severe side effects. The underlying mechanisms of DBS are complex and likely vary from region to region in terms of stimulation parameters and patterns. DBS seems a promising therapeutic option. However, clinical experiences are currently limited to several uncontrolled case reports. Further studies with controlled, double-blind designs are needed. In addition, more research on animals and humans is required to investigate the precise role of DBS and its mechanisms to achieve optimal stimulation parameters and develop new, less invasive methods.

The Role of Orexin-1 Receptors Within the Hippocampal CA1 Area in the Extinction and Reinstatement of Methamphetamine-Seeking Behaviors.

Psychostimulant addiction is a chronic brain disorder with high relapse rates, requiring new therapeutic strategies. The orexin system is highly implicated in processing reward and addiction through connections with critical areas such as the hippocampus. This study investigated the role of orexin-1 receptors (OX1R) within the CA1 subregion of the hippocampus in the extinction and reinstatement of the methamphetamine-induced conditioned place preference. After cannulae implantation, recovery, and establishing the methamphetamine place preference, 98 male Wistar rats received different doses of bilateral intra-CA1 selective OX1R antagonist, SB334867 (1, 3, 10, and 30 nmol/0.5 µl DMSO per side) during the 10-day extinction period (daily) or after extinction phase, just on the reinstatement day (single dose) in separate experimental and control groups. The findings indicated that bilateral microinjection of SB334867 into the CA1 area during the extinction period could significantly reduce the extinction latency and maintenance of rewarding aspects of methamphetamine dose-dependently (3, 10, and 30 nmol). In another set of experiments, a single dose of bilateral intra-CA1 SB334867 administration on the reinstatement phase prevented the methamphetamine-induced reinstatement of drug-seeking behaviors at the high doses (10, and 30 nmol). The present study provided more evidence for the implication of hippocampal OX1R in the maintenance of rewarding and reinforcing properties of methamphetamine and its role in the relapse of methamphetamine-seeking behavior. Further investigations on the role of the orexin system, including the orexin-2 receptors in treating addiction, are needed to introduce its antagonists as effective therapeutic options for psychostimulant addiction.

Regulatory Role of PFC Corticotropin-Releasing Factor System in Stress-Associated Depression Disorders: A Systematic Review.

Stress has a substantial role in formation of psychiatric disorders especially depression. Meanwhile, impairment of the prefrontal cortex (PFC) is connected to the executive and cognitive deficits induced by the stress. Given the involvement of the corticotropin-releasing factor (CRF) in stress-related processes and knowing the fact that PFC hosts a lot of CRF receptors and CRF neurotransmissions, it can worth to look at the CRF as a potential treatment for the regulation of depression disorders induced by stress within PFC region. Here, for the first time we aimed to systematically review the effectiveness of intra-PFC CRF system in the modulation of depression dysfunction caused by the stress in clinical and preclinical models/studies. Qualified researches were combined utilizing a comprehensive search of six databases including Scopus, Pubmed, Web of Science, Sciencedirect, APA PsycNet, and Embase in April 2021 and were evaluated through proper methodological quality assessment tools. Results indicate that PFC has a remarkable role in the modulation for stress-induced depression and intra-PFC CRF receptors agonist and antagonist are very considerable for regulating these types of impairments. Specifically, elevation of both CRF immunoreactivity and gene expression were observed in human studies. In the animal studies, mostly immunoreactivity or excitatory/inhibitory currents of CRF within the PFC regulated depression dysfunction. In conclusion, reviewed studies show a positive attitude toward the CRF system in regulation of the stress-induced depression; however, obviously further investigations are required to get closer to the best treatment. Prefrontal cortex corticotropin-releasing factor system regulates stress-induced depression. CRFR1, Corticotropin-releasing factor receptor of type1; PFC, Prefrontal cortex; Minus (-) and Plus (+) signs, dysregulation and upregulation, respectively.

Deep brain stimulation for opioid use disorder: A systematic review of preclinical and clinical evidence.

Opioid use disorder (OUD) is a chronic and complex disease characterized by repeated relapses and remissions. Deep brain stimulation (DBS) has been discussed again and again as a potentially helpful neuromodulatory procedure in this context. In this review, for the first time, we intended to systematically identify the positive and negative effects of DBS in human and animal models of opioid dependence to assess the viability of DBS as a treatment of OUD. Eligible studies were incorporated by a comprehensive literature search and evaluated through proper methodological quality assessment tools. Findings showed that the nucleus accumbens was the most stimulated brain target in human and animal studies, and DBS was applied chiefly in the form of high-frequency stimulation (HFS). DBS administration effectively reduced opioid craving and consumption in human and animal subjects dependent on opioids. DBS represents a valuable alternative strategy for treating intractable opioid addiction. Based on our systematic literature analysis, research efforts in this field should be continued.

Preventing morphine reinforcement with high-frequency deep brain stimulation of the lateral hypothalamic area.

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100-microsecond pulse duration and 150 µA) was applied during the morphine-pairing trials (30 minutes daily for 4 days) or drug-free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.