Hippocampal D1-like dopamine receptor as a novel target for the effect of cannabidiol on extinction and reinstatement of methamphetamine-induced CPP.

Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to have the potential to inhibit drug-related behavior. However, the neurobiological mechanisms responsible for the effects of CBD remain unclear. Several studies have proposed that the suppressing effects of CBD on drug-seeking behaviors could be through the modulation of the dopamine system. The hippocampus (HIP) D1-like dopamine receptor (D1R) is essential for forming and retrieving drug-associated memory. Therefore, the present study aimed to investigate the role of D1R in the hippocampal CA1 region on the effects of CBD on the extinction and reinstatement of METH-conditioned place preference (CPP). For this purpose, different groups of rats over a 10-day extinction period were administered different doses of intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl, Saline) as a D1R antagonist before ICV injection of CBD (10 µg/5 µl, DMSO12%). In addition, a different set of animals received intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl) before CBD injection (50 µg/5 µl) on the reinstatement day. The results revealed that the highest dose of SCH23390 (4 µg) significantly reduced the accelerating effects of CBD on the extinction of METH-CPP (P < 0.01). Furthermore, SCH23390 (1 and 4 µg) in the reinstatement phase notably reversed the preventive effects of CBD on the reinstatement of drug-seeking behavior (P < 0.05 and P < 0.001, respectively). In conclusion, the current study revealed that CBD made a shorter extinction period and suppressed METH reinstatement in part by interacting with D1-like dopamine receptors in the CA1 area of HIP.

Blockade of the orexin-2 receptors within the ventral tegmental area facilitates the extinction and prevents the reinstatement of methamphetamine-seeking behavior.

Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 µl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency.

The Dopaminergic System Modulates the Electrophysiological Activity of the Suprachiasmatic Nucleus Dependent on the Circadian Cycle.

The suprachiasmatic nucleus of the hypothalamus (SCN) controls mammalian circadian rhythms. Circadian rhythms influence the dopaminergic system, and dopaminergic tone impresses the physiology and behavior of the circadian clock. However, little is known about the effect of dopamine and dopamine receptors, especially D1-like dopamine receptors (D1Rs), in regulating the circadian rhythm and the SCN neuron's activity. Therefore, the present study aimed to investigate the role of the D1Rs in SCN neural oscillations during the 24-h light-dark cycle using local field potential (LFP) recording. To this end, two groups of rats were given the SKF-38393 (1 mg/kg; i.p.) as a D1-like receptor agonist in the morning or night. LFP recording was performed for ten minutes before and two hours after the SKF-38393 injection. The obtained results showed that diurnal changes affect LFP oscillations so that delta relative power declined substantially, whereas upper-frequency bands and Lempel-Ziv complexity (LZC) index increased at night, which is consistent with rodents' activity cycles. The D1Rs agonist administration in the morning dramatically altered these intrinsic oscillations, decreasing delta and theta relative power, and most of the higher frequency bands and LZC index were promoted. Some of these effects were reversed at the night after the SKF-38393 injection. In conclusion, findings showed that the SCN's neuronal activities are regulated based on the light-dark cycle in terms of population neural oscillatory activity which could be affected by dopaminergic stimulation in a time-dependent way.

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).

The blockade of orexin receptors within the dentate gyrus of the hippocampus attenuated methamphetamine-induced reward learning during conditioning place preference.

Orexins and orexinergic receptors have been shown to play a critical role in reward processing and drug addiction. Previous studies showed that the orexinergic system in the dentate gyrus (DG) region of the hippocampus affects the conditioning (acquisition) and post-conditioning (expression) phases of morphine-induced conditioned place preference (CPP). The action of each orexin receptor within the DG during conditioning and expression phases for methamphetamine (METH)-induced CPP remains unclear. The present study aimed to determine the role of orexin-1 and -2 receptors in the hippocampal DG in METH CPP acquisition and expression. During the 5-day conditioning phase, rats received an intra-DG microinjection of SB334867, a selective orexin-1 receptor (OX1R) antagonist, or TCS OX2-29, a selective orexin-2 receptor (OX2R) antagonist, before injection of METH (1 mg/kg; sc). In different sets of animals on the expression day, rats received each antagonist before the CPP test. The results showed that SB334867 (3, 10, and 30 nmol) and TCS OX2-29 (3, 10, and 30 nmol) significantly decreased the acquisition of METH CPP during the conditioning phase. Furthermore, administration of SB 334867 (10 and 30 nmol) and TCS OX2-29 (3 and 10 nmol) on the post-conditioning day significantly reduced METH-induced CPP expression. The results also indicated that orexin receptors play a more critical role in the conditioning phase than in the expression phase. In summary, the orexin receptors in the DG play a crucial role in drug learning and memory and are essential for METH reward acquisition and expression.

The inhibitory effect of cannabidiol on the rewarding properties of methamphetamine in part mediates by interacting with the hippocampal D1-like dopamine receptors.

Cannabidiol (CBD) is a potential treatment to decrease the rewarding properties of psychostimulants. However, the exact mechanism and distinct neuroanatomical areas responsible for the CBD's effects remain unclear. Indicatively, the D1-like dopamine receptors (D1R) in the hippocampus (HIP) are essential for expressing and acquiring drug-associated conditioned place preference (CPP). Therefore, given that involving D1Rs in reward-related behaviors and the encouraging results of CBD in attenuating the psychostimulant's rewarding effects, the present study sought to investigate the role of D1Rs of the hippocampal dentate gyrus (DG) in the inhibitory effects of CBD on the acquisition and expression of METH-induced CPP. To this end, over a 5-day conditioning period by METH (1 mg/kg; sc), different groups of rats were given intra-DG SCH23390 (0.25, 1, or 4 µg/0.5 µl, saline) as a D1Rs antagonist before ICV administration of CBD (10 µg/5 µl, DMSO12%). In addition, a different set of animals, after the conditioning period, received a single dose of SCH23390 (0.25, 1, or 4 µg/0.5 µl) before CBD (50 µg/5 µl) administration on the expression day. The results showed that SCH23390 (1 and 4 µg) significantly reduced the suppressive effects of CBD on the acquisition of METH place preference (P < 0.05 and P < 0.001, respectively). Furthermore, the highest dose of SCH23390 (4 µg) in the expression phase remarkably abolished the preventive effects of CBD on the expression of METH-seeking behavior (P < 0.001). In conclusion, the current study revealed that CBD's inhibitory effect on rewarding properties of METH partially acts through D1Rs in the DG area of the HIP.

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 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.

Intra-Accumbal D1- But not D2-Like Dopamine Receptor Antagonism Reverses the Inhibitory Effects of Cannabidiol on Extinction and Reinstatement of Methamphetamine Seeking Behavior in Rats.

Introduction: Methamphetamine (METH) is an addictive psychostimulant that facilitates dopamine transmission to the nucleus accumbens (NAc), resulting in alterations in the mesocorticolimbic brain regions. Cannabidiol (CBD) is considered the second most abundant component of cannabis and is believed to decrease the METH effects. Reversing psychostimulant-induced abnormalities in the mesolimbic dopamine system is the main mechanism for this effect. Various other mechanisms have been proposed: increasing endocannabinoid system activity and modulating gamma-aminobutyric acid (GABA) and glutamate neurons in NAc. However, the exact CBD action mechanisms in reducing drug addiction and relapse vulnerability remain unclear. Methods and Results: The present study aimed to investigate the effects of intracerebroventricular (ICV) administrating 5, 10, and 50 µg/5 µL CBD solutions on the extinction period and reinstatement phase of a METH-induced conditioned place preference. This research also aimed to examine the NAc D1-like dopamine receptor (D1R) and D2-like dopamine receptor (D2R) roles in the effects of CBD on these phases, as mentioned earlier, using SCH23390 and sulpiride microinjections as an antagonist of D1R and D2R. The obtained results showed that microinjection of CBD (10 and 50 µg/5 µL, ICV) suppressed the METH-induced reinstatement and significantly decreased mean extinction latency in treated groups compared to both vehicles and/or untreated control groups. In addition, the results demonstrated that administrating intra-accumbal SCH23390 (1 and 4 µg/0.5 µL saline) reversed the inhibitory effects of CBD on extinction and reinstatement phases while different doses of sulpiride (0.25, 1, and 4 µg/0.5 µL; dimethyl sulfoxide 12%) could not alter the CBD effects. Conclusions: In summary, this study showed that CBD made shorter extinction latencies and suppressed the METH reinstatement, in part, by interacting with D1R but not D2R in the NAc.

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.