The role of D1-like dopamine receptors within the ventral tegmental area in the cannabidiol's inhibitory effects on the methamphetamine-induced conditioned place preference in rats.

Cannabidiol (CBD) is a non-psychoactive drug extracted from marijuana. It is well established that CBD attenuates the reinforcing effects of drugs of abuse, although its mechanism of action is not fully understood. The current study tries to clarify the role of D1-like dopamine receptors (D1R) in the ventral tegmental area (VTA) in the inhibitory effects of the CBD on the acquisition and expression of methamphetamine (METH)-conditioned place preference (CPP). In the CPP training, adult male Wistar rats were conditioned with subcutaneous administration of METH (1 mg/kg) for five days. Three groups of animals were treated with multiple doses of SCH23390 (as a D1R antagonist; 0.25, 1, and 4 µg/0.3 µl saline) in the VTA, respectively, before intracerebroventricular (ICV) injection of CBD (10 µg/5 µl DMSO) in the acquisition phase. In the second experiment of the study, rats received SCH23390 in the VTA before ICV administration of CBD (50 µg/5 µl DMSO) in the expression of METH CPP. Here, the current study demonstrated that CBD inhibits the acquisition and expression of METH CPP, while microinjection of D1R antagonists (1 and 4 µg) into the VTA significantly reduced CBD's suppressive effect on the acquisition and expression of METH place preference. Furthermore, this research demonstrated that either SCH23390 or CBD alone does not lead to place preference in the CPP paradigm. Based on these data, this study suggests that pharmacological manipulations of D1R may alter the CBD's effect on METH-conditioned preference.

The scheduling of adolescence with Netrin-1 and UNC5C.

Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells - disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner - delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.

Acupuncture in the treatment of cocaine addiction: how does it work?

Cocaine is a frequently abused and highly addictive drug that damages brain health and imposes substantial social and economic costs. Acupuncture has been used in the treatment of cocaine addiction and has been shown to improve abnormal mental and motor states. This article mainly focuses on the neurobiological mechanisms involving the central nervous system (CNS) and peripheral nervous system (PNS) that underlie the effects of acupuncture in the treatment of cocaine addiction. The central dopamine system is a key player in acupuncture treatment of cocaine addiction; the ventral tegmental area (VTA)-nucleus accumbens (NAc) signaling pathway, which has a modulatory influence on behavior and psychology after chronic use of cocaine, is a significant target of acupuncture action. Moreover, acupuncture alleviates cocaine-induced seizures or acute psychomotor responses through the paraventricular thalamus and the lateral habenula (LHb)-rostromedial tegmental (RMTg) nucleus circuits. The data suggest that acupuncture can impact various cocaine-induced issues via stimulation of diverse brain areas; nevertheless, the interconnection of these brain regions and the PNS mechanisms involved remain unknown. In this review, we also discuss the effects of specific acupuncture protocols on cocaine addiction and note that variations in needling modalities, current intensities and traditional acupuncture point locations have led to different experimental results. Therefore, standardized acupuncture protocols (with respect to stimulation methods, point locations and number of sessions) may become particularly important in future studies.

Positron Emission Tomography Imaging of Synaptic Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases with a complex pathogenesis. Aggregations formed by abnormal deposition of alpha-synuclein (αSyn) lead to synapse dysfunction of the dopamine and non-dopamine systems. The loss of dopaminergic neurons and concomitant alterations in non-dopaminergic function in PD constitute its primary pathological manifestation. Positron emission tomography (PET), as a representative molecular imaging technique, enables the non-invasive visualization, characterization, and quantification of biological processes at cellular and molecular levels. Imaging synaptic function with PET would provide insights into the mechanisms underlying PD and facilitate the optimization of clinical management. In this review, we focus on the synaptic dysfunction associated with the αSyn pathology of PD, summarize various related targets and radiopharmaceuticals, and discuss applications and perspectives of PET imaging of synaptic dysfunction in PD.

Arousal, Gray's theory of anxiety, and the etiology of psychopathy.

This paper focuses on Jeffrey Gray's theory of anxiety from the perspective of Fowles' (1980) application of his work to theories of arousal, psychophysiology, and the etiology of psychopathy. Although highly influential, the concept of general arousal failed to find support in terms of between-individuals assessment with multiple physiological measures. Gray's constructs of a behavioral inhibition system (BIS) that mediates anxiety, a behavioral approach or activation system (BAS) that energizes behavior to approach rewards, and a nonspecific arousal system that energizes behavior captured aspects of arousal. Fowles (1980) proposed that the BIS elicits electrodermal activity in response to threats, the BAS increases heart rate in response to reward incentive cues, and psychopathy is associated with a weak BIS. The paper reviews Gray's impact on future research on these topics, including early proposals relevant to the National Institute of Mental Health's Research Domain Criteria. Finally, the paper summarizes the evolution of theories of the etiology of psychopathy since 1980, noting ways in which aspects of Gray's theory are still seen in psychopathy research. Patrick's triarchic model has emerged as a major theory of psychopathy. Beauchaine's trait impulsivity theory of Attention Deficit Hyperactivity Disorder also is relevant.

The potential role of miRNAs in the pathogenesis of schizophrenia - A focus on signaling pathways interplay.

microRNAs (miRNAs) play a crucial role in brain growth and function. Hence, research on miRNA has the potential to reveal much about the etiology of neuropsychiatric diseases. Among these, schizophrenia (SZ) is a highly intricate and destructive neuropsychiatric ailment that has been thoroughly researched in the field of miRNA. Despite being a relatively recent area of study about miRNAs and SZ, this discipline has advanced enough to justify numerous reviews that summarize the findings from the past to the present. However, most reviews cannot cover all research, thus it is necessary to synthesize the large range of publications on this topic systematically and understandably. Consequently, this review aimed to provide evidence that miRNAs play a role in the pathophysiology and progression of SZ. They have also been investigated for their potential use as biomarkers and therapeutic targets.

Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat.

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

Neurodevelopmental Model Explaining Associations between Sex Hormones, Personality, and Eating Pathology.

Clinical scientists have been investigating the relationships between sex hormones, personality, and eating disorders for decades. However, there is a lack of direct research that addresses whether personality mediates or moderates the relationships between sex hormones and eating pathology. Moreover, the neural mechanisms that underlie the interactive associations between these variables remain unclear. This review aims to summarize the associations between these constructs, describe a neural mechanism mediating these relationships, and offer clinical strategies for the early identification and intervention of eating disorders. The gathered evidence shows that aggressiveness, impulsivity, and obsessive-compulsiveness may mediate or moderate the relationships between sex hormones and eating pathology, but only among females. Furthermore, sex hormone receptor density in the mesocorticolimbic dopamine pathway may explain the neural mechanism of these associations. Future research should use more comprehensive personality measurements and assess the mediation and moderation effects of temperament while taking the hormone levels of women across menstrual cycles into account. Additionally, electroencephalography and functional magnetic resonance imaging should be implemented to directly assess brain activity and corroborate these findings.

Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson's disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients with 22q11.2DS, was generated. The behavior of this mouse model was extensively studied and several abnormalities related to the symptoms of 22q11.2DS were found. However, the histological features of their brains have been little addressed. Here we describe the cytoarchitectures of the brains of Del(3.0Mb)/+ mice. First, we investigated the overall histology of the embryonic and adult cerebral cortices, but they were indistinguishable from the wild type. However, the morphologies of individual neurons were slightly but significantly changed from the wild type counterparts in a region-specific manner. The dendritic branches and/or dendritic spine densities of neurons in the medial prefrontal cortex, nucleus accumbens, and primary somatosensory cortex were reduced. We also observed reduced axon innervation of dopaminergic neurons into the prefrontal cortex. Given these affected neurons function together as the dopamine system to control animal behaviors, the impairment we observed may explain a part of the abnormal behaviors of Del(3.0Mb)/+ mice and the psychiatric symptoms of 22q11.2DS.

Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System.

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus-mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF-DA crosstalk in the autistic-like phenotype of BTBR mice.

Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [11C]PE2I, [18F]FE-PE2I and [11C]raclopride PET in healthy individuals.

The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [11C]PE2I (n = 20) and [18F]FE-PE2I (n = 20) and the D2/3 tracer [11C]raclopride (n = 18). Subjects with a [11C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [11C]DASB. Binding potential (BPND) and relative tracer delivery (R1) values were calculated on regional and voxel-level. Striatal R1 and BPND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BPND image. An inter-tracer comparison between [11C]PE2I BPND and [11C]DASB R1 was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BPND and R1 for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [11C]PE2I BPND and [11C]DASB R1. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.

Maternal high-fat diet decreases milk endocannabinoids with sex-specific changes in the cannabinoid and dopamine signaling and food preference in rat offspring.

Introduction: Maternal high-fat (HF) diet during gestation and lactation programs obesity in rat offspring associated with sex-dependent and tissue-specific changes of the endocannabinoid system (ECS). The ECS activation induces food intake and preference for fat as well as lipogenesis. We hypothesized that maternal HF diet would increase the lipid endocannabinoid levels in breast milk programming cannabinoid and dopamine signaling and food preference in rat offspring. Methods: Female Wistar rats were assigned into two experimental groups: control group (C), which received a standard diet (10% fat), or HF group, which received a high-fat diet (29% fat) for 8 weeks before mating and during gestation and lactation. Milk samples were collected to measure endocannabinoids and fatty acids by mass spectrometry. Cannabinoid and dopamine signaling were evaluated in the nucleus accumbens (NAc) of male and female weanling offspring. C and HF offspring received C diet after weaning and food preference was assessed in adolescence. Results: Maternal HF diet reduced the milk content of anandamide (AEA) (p<0.05) and 2-arachidonoylglycerol (2-AG) (p<0.05). In parallel, maternal HF diet increased adiposity in male (p<0.05) and female offspring (p<0.05) at weaning. Maternal HF diet increased cannabinoid and dopamine signaling in the NAc only in male offspring (p<0.05), which was associated with higher preference for fat in adolescence (p<0.05). Conclusion: Contrary to our hypothesis, maternal HF diet reduced AEA and 2-AG in breast milk. We speculate that decreased endocannabinoid exposure during lactation may induce sex-dependent adaptive changes of the cannabinoid-dopamine crosstalk signaling in the developing NAc, contributing to alterations in neurodevelopment and programming of preference for fat in adolescent male offspring.

Structural covariances of prefrontal subregions selectively associate with dopamine-related gene coexpression and schizophrenia.

Evidence highlights that dopamine (DA) system dysregulation and prefrontal cortex (PFC) dysfunction may underlie the pathophysiology of schizophrenia. However, the associations among DA genes, PFC morphometry, and schizophrenia have not yet been fully clarified. Based on the brain gene expression dataset from Allen Human Brain Atlas and structural magnetic resonance imaging data (NDIS = 1727, NREP = 408), we first identified 10 out of 22 PFC subregions whose gray matter volume (GMV) covariance profiles were reliably associated with their DA genes coexpression profiles, then four out of the identified 10 PFC subregions demonstrated abnormally increased GMV covariance with the hippocampus, insula, and medial frontal areas in schizophrenia patients (NCASE = 100; NCONTROL = 102). Moreover, based on a schizophrenia postmortem expression dataset, we found that the DA genes coexpression of schizophrenia was significantly reduced between the middle frontal gyrus and hippocampus, in which 21 DA genes showed significantly unsynchronized expression changes, and the 21 genes' brain expression were enriched in brain activity invoked by working memory, reward, speech production, and episodic memory. Our findings indicate the DA genes selectively regulate the structural covariance of PFC subregions by their coexpression profiles, which may underlie the disrupted GMV covariance and impaired cognitive functions in schizophrenia.

Studying the Brain Monoaminergic Systems and Neurotrophic Factors in Minipigs with High and Low Tolerance to the Presence of Human.

Here, we present the first evidence for brain adaptation in pigs tolerant to the human presence, as a behavioral trait favoring domestication. The study was carried out on minipiglets from population bred at the Institute of Cytology and Genetics (Novosibirsk, Russia). We compared the behavior, metabolism of monoaminergic neurotransmitter systems, and functional activity of the hypothalamic-pituitary-adrenal system, as well as neurotrophic markers in the brain of minipigs differing by tolerance to human presence (HT and LT - high and low tolerance). The piglets did not differ in the levels of activity in the open field test. However, the concentration of cortisol plasma was significantly higher in minipigs with a low tolerance to the presence of humans. Moreover, LT minipigs demonstrated a decreased level of serotonin in the hypothalamus and augmented levels of serotonin and its metabolite 5-HIAA in the substantia nigra as compared to HT animals. In addition, LT minipigs showed increased content of dopamine and its metabolite DOPAC in the substantia nigra and decreased dopamine level in the striatum as well as reduced content of noradrenaline in the hippocampus. Increased mRNA levels of two markers of the serotonin system - TPH2 and HTR7 genes - in the raphe nuclei and in the prefrontal cortex, respectively, were associated in minipigs with a low tolerance to human presence. However, the expression of genes regulating a dopaminergic system (COMT, DRD1, and DRD2) in HT and LT animal groups varied depending on brain structure. In addition, a decrease in the expression of genes encoding BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) was revealed in LT minipigs. The results may contribute to our understanding of the initial stage of domestication in pigs.

Restraint stress induced the antinociceptive responses via the dopamine receptors within the hippocampal CA1 area in animal model of persistent inflammatory pain.

It has been declared that dopamine receptors within the hippocampal formation are involved in emotion, memory, and pain processing. Remarkably, both CA1 and dentate gyrus (DG) areas of the hippocampal formation are involved in persistent peripheral nociceptive perception. A prior study showed that dopamine receptors within the hippocampal DG have a critical role in antinociception induced by forced swim stress (FSS), as a physical stressor, in the presence of formalin irritation. The present experiments were designed to assess whether dopaminergic receptors within the CA1 have any role in antinociceptive responses induced by restraint stress (RS) as a psychological stressor after applying the formalin test as an animal model of persistent inflammatory pain. The D1- and D2-like dopamine receptor antagonists, SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.5 µl), were injected into the CA1 areas of ninety-six male albino Wistar rats 5 min before a 3-h period of restraint stress. Ten min after stress termination, a 50-µl formalin 2.5 % was subcutaneously injected into the plantar surface of the rat's hind paw to induce persistent inflammatory pain. Nociceptive behaviors in both phases of the formalin test were analyzed in the 5-min blocks for a 60-min period. The obtained results demonstrate that although RS could induce an antinociceptive response in both phases of the formalin test, microinjection of D1- and D2-like dopamine receptors, antagonists attenuated RS-induced analgesia. These results support the hypothesis that acute restraint stress could induce analgesia via dopaminergic projection to the CA1 region of the hippocampal formation.

Dysregulation of striatal dopamine D2/D3 receptor-mediated by hypocretin induces depressive behaviors in rats.

BACKGROUND: The dysregulation of the dopamine system contributes to depressive-like behaviors in rats, and the neurological functions regulated by hypocretin are severely affected in depression. However, whether suvorexant plays a role in alleviating depression by affecting the dopamine system is unclear. METHODS: To preliminarily explore the mechanism of suvorexant (10 mg/kg) in the treatment of depression, the mRNA and protein expression of TH, Drd2, Drd3, GluN2A, DAT, and GluN2B in the striatum of rats was quantified by qPCR and western blotting. The plasma hypocretin-1 and dopamine levels and the striatal dopamine levels were determined by ELISA. RESULTS: i) Compared to those of the control group, chronic unpredictable mild stress (CUMS) rats showed depressive-like behaviors, which were subsequently reversed by treatment with suvorexant. ii) The mRNA and protein expressions of TH, Drd2, Drd3, GluN2A, and GluN2B in the striatum of CUMS were significantly increased compared with those in the controls, but decreased after suvorexant treatment. iii) Compared with those in the control group, the plasma and striatal dopamine levels of CUMS decreased while plasma hypocretin-1 levels increased, which was reversed after suvorexant treatment. LIMITATIONS: i) The suvorexant is a dual hypocretin receptor antagonist; however, the responsible receptor is unclear. ii) We only focused on related factors in the striatum but did not explore other brain regions, nor did we directly explore the relationship among these factors. CONCLUSION: Depressive-like behaviors induced by CUMS can be reversed by suvorexant, and the therapeutic effects of suvorexant may be mediated by affecting the dopamine system.

Maternal organophosphate flame retardant exposure alters the developing mesencephalic dopamine system in fetal rat.

Organophosphate flame retardants (OPFRs) have become the predominant substitution for legacy brominated flame retardants but there is concern about their potential developmental neurotoxicity (DNT). OPFRs readily dissociate from the fireproofed substrate to the environment, and they (or their metabolites) have been detected in diverse matrices including air, water, soil, and biota, including human urine and breastmilk. Given this ubiquitous contamination, it becomes increasingly important to understand the potential effects of OPFRs on the developing nervous system. We have previously shown that maternal exposure to OPFRs results in neuroendocrine disruption, alterations to developmental metabolism of serotonin (5-HT) and axonal extension in male fetal rats, and potentiates adult anxiety-like behaviors. The development of the serotonin and dopamine systems occur in parallel and interact, therefore, we first sought to enhance our prior 5-HT work by first examining the ascending 5-HT system on embryonic day 14 using whole mount clearing of fetal heads and 3-dimensional (3D) brain imaging. We also investigated the effects of maternal OPFR exposure on the development of the mesocortical dopamine system in the same animals through 2-dimensional and 3D analysis following immunohistochemistry for tyrosine hydroxylase (TH). Maternal OPFR exposure induced morphological changes to the putative ventral tegmental area and substantia nigra in both sexes and reduced the overall volume of this structure in males, whereas 5-HT nuclei were unchanged. Additionally, dopaminergic axogenesis was disrupted in OPFR exposed animals, as the dorsoventral spread of ventral telencephalic TH afferents were greater at embryonic day 14, while sparing 5-HT fibers. These results indicate maternal exposure to OPFRs alters the development trajectory of the embryonic dopaminergic system and adds to growing evidence of OPFR DNT.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

BACKGROUND AND HYPOTHESIS: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. STUDY RESULTS: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. CONCLUSIONS: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

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.