KOR Control over Addiction Processing: An Exploration of the Mesolimbic Dopamine Pathway

Ohnishi

International Journal of Neuropsychopharmacology

et al. 2021

Background Dopamine neurotransmission plays a critical role in reward in drug abuse and drug addiction. However, the role of dopamine in the recognition of drug-associated environmental stimuli, retrieval of drug-associated memory and drug-seeking behaviors is not fully understood. Methods Roles of dopamine neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in the cocaine conditioned place preference (CPP) paradigm were evaluated using in vivo microdialysis. Results In mice that had acquired cocaine CPP, dopamine levels in the PFC, but not in the NAc, increased in response to cocaine-associated cues when mice were placed in the cocaine-chamber of an apparatus with two-separated chambers. The induction of the dopamine response and the development of cocaine CPP were mediated through activation of glutamate NMDA/AMPA receptor signaling in the PFC during conditioning. Activation of dopamine D1 or D2 receptor signaling in the PFC was required for cocaine-induced locomotion, but not for the induction of the dopamine response or the development of cocaine CPP. Interestingly, dopamine levels in the NAc increased in response to cocaine-associated cues when mice were placed at the center of an apparatus with two-connected chambers, which requires motivated exploration associated with cocaine reward. Conclusions Dopamine neurotransmission in the PFC is activated by the exposure to the cocaine-associated cues, whereas dopamine neurotransmission in the NAc is activated in the process of motivated exploration of cues associated with cocaine reward. Furthermore, the glutamate signaling cascade in the PFC is suggested to be a potential therapeutic target to prevent the progression of drug addiction.

Section: Discussioncontrasting

confidence: 55%

Distinct Role of Dopamine in the PFC and NAc During Exposure to Cocaine-Associated Cues

Ohnishi

International Journal of Neuropsychopharmacology

et al. 2021

Front. Behav. Neurosci.

“…Interestingly, the fact that norBNI did not increase CeA GABA release after Pentylone and MDMA self-administration may suggest a loss of tonic dynorphin signaling in the CeA at first sight, but it could also stem from alternative or non-canonical KOR signaling cascades resulting from repeated drug exposure ( Nguyen et al, 2017b , 2021 ). Indeed, KOR signaling has been shown to be highly sensitive to stressful events ( Polter et al, 2017 ; Estave et al, 2020 ; Przybysz et al, 2021 ) and recent studies show constitutive activity of KOR at GABAergic synapses in the ventral tegmental area in response to brief cold-water swim stress leading to altered effects of KOR antagonism ( Polter et al, 2017 ). Moreover, KOR activation is coupled to several distinct intracellular signaling cascades involving G-protein coupled Receptor Kinases (GRK) and members of the mitogen-activated protein kinase (MAPK) family or β-arrestin-dependent pathways, amongst other classical G-protein mediated mechanisms ( Bruchas and Chavkin, 2010 ; Lovell et al, 2015 ; Ho et al, 2018 ; Uprety et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

Khom

Nguyen

Vandewater

et al. 2021

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

“…[53,54] A "final common pathway" that may link alterations in pain perception and response to the "psychic pain" is altered functioning of endogenous opioid receptors in the brain, though the exact receptors and pathways involved remain unclear. [55,56] In addition, certain substance use disorders, such as alcoholism, are genetically linked to depression; [45] in these cases, mechanisms similar to those described above for the "anxiety-depressive spectrum" may be relevant.…”

Section: Psychiatric Diagnoses In Male Patientsmentioning

confidence: 98%

Psychiatric comorbidities in dermatitis artefacta: A systematic review and meta-analysis

Rajkumar¹

2021

CSDM

Dermatitis artefacta, also known as factitious or factitial dermatitis, is a rare and difficult-to-treat condition characterized by self-inflicted skin lesions. Despite the well-documented psychological disturbances that characterize this condition, little is known about the relative frequency of specific psychiatric disorders in this patient group. The current systematic review was undertaken to address this gap in our knowledge and was conducted in accordance with PRISMA guidelines. The PubMed and Scopus databases were searched using the terms “dermatitis artefacta,” “factitious dermatitis,” and “factitial dermatitis” in combination with “psychiatry,” “psychiatric diagnosis,” “psychiatric disorder,” “mental illness,” “depression,” and “anxiety.” After screening a total of 215 citations, a total of 11 papers were included in the final review. All the included studies were of low to very low quality as per the GRADE guidelines, and there was substantial heterogeneity among them (I2 = 50.4). It was observed that 46.2% of patients (95% CI: 35.4–57.4%) with dermatitis artefacta had a comorbid psychiatric disorder, with the most common diagnoses being depression, somatoform disorders, anxiety disorders, substance use disorder, and intellectual disability. About 20.1% of patients refused a psychiatric evaluation, while 40.9% reported a significant stressful life event. These results suggest that a significant proportion of patients with dermatitis artefacta suffer from psychiatric disorders, which may be related to their self-infliction of lesions either biologically or psychologically. Treatment of these disorders may lead to a partial or complete improvement in their dermatological condition. A sensitive, non-confrontational approach is essential when evaluating these patients to minimize the chances of refusal and improve patient compliance.