Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression.

Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology.

Exploring the potential link between ΔFosB and -acetylcysteine in craving/relapse dynamics: can -acetylcysteine stand out as a possible treatment candidate?

From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that -acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.

Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence.

Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex.

Materials And Methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose.

Doxycycline diminishes the rewarding and psychomotor effects induced by morphine and cocaine.

Few pharmacological treatments are available for substance use disorders (SUDs). Neuroplastic changes induced by increased activity of metalloproteinase (MMP) enzymes in the brain are among the several molecular processes that may play a role in drug addiction. Doxycycline, a widely used tetracycline that crosses the blood-brain barrier, inhibits MMPs and has been investigated as a potential treatment for brain disorders.

Endocannabinoid signaling and epigenetics modifications in the neurobiology of stress-related disorders.

Stress exposure is associated with psychiatric conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD). It is also a vulnerability factor to developing or reinstating substance use disorder. Stress causes several changes in the neuro-immune-endocrine axis, potentially resulting in prolonged dysfunction and diseases.

CB1 Receptor Silencing Attenuates Ketamine-Induced Hyperlocomotion Without Compromising Its Antidepressant-Like Effects.

The antidepressant properties of ketamine have been extensively demonstrated in experimental and clinical settings. However, the psychotomimetic side effects still limit its wider use as an antidepressant. It was recently observed that endocannabinoids are inolved in ketamine induced reward properties.

Roles of cannabinoid CB1 and CB2 receptors in the modulation of psychostimulant responses.

Addiction to psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, is a public health issue that substantially contributes to the global burden of disease. Psychostimulant drugs promote an increase in dopamine levels within the mesocorticolimbic system, which is central to the rewarding properties of such drugs. Cannabinoid receptors (CBR and CBR) are expressed in the main areas of this system and implicated in the neuronal mechanisms underlying the rewarding effect of psychostimulant drugs.

Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice.

Rationale: Cannabis sativa is the most widely used drug by adolescents globally. The recreational use of synthetic cannabinoids by teenagers has also grown in recent years. Despite the wrong perception that exposure to these drugs does not cause harm, repeated exposure to cannabinoids at early stages of life compromises important maturation processes and brain development.

Co-administration of cannabidiol and ketamine induces antidepressant-like effects devoid of hyperlocomotor side-effects.

Background And Purpose: Although useful as a rapid-acting antidepressant drug, ketamine is known to induce psychotomimetic effects, which may interfere with its therapeutic use. Cannabidiol (CBD) is a non-psychostimulant compound from Cannabis sativa, which has shown promising antidepressant effects without inducing hyperlocomotion. AMPA receptor activation is involved in the antidepressant effect induced by ketamine, but its relevance for the effects of CBD is not known.

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence.

Following exposure to drugs of abuse, long-term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2-AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations.

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation.

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving.

Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies ("incubates") during abstinence and is believed to contribute to persistent relapse vulnerability. Changes in gene expression often govern perpetual behavioral abnormalities, but epigenetic plasticity during prolonged abstinence from drug exposure is poorly understood. We examined how E3 ubiquitin ligase TRIM3 dysregulates chromatin remodeler INO80 to mediate cocaine craving during prolonged abstinence.

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc.

Attenuation of glutamatergic and nitrergic system contributes to the antidepressant-like effect induced by capsazepine in the forced swimming test.

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects.

E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking.

Background: Substance use disorder is a neurobiological disease characterized by episodes of relapse despite periods of withdrawal. It is thought that neuroadaptations in discrete brain areas of the reward pathway, including the nucleus accumbens, underlie these aberrant behaviors. The ubiquitin-proteasome system degrades proteins and has been shown to be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which conjugate ubiquitin to substrates, is unknown.

A high-refined carbohydrate diet facilitates compulsive-like behavior in mice through the nitric oxide pathway.

Unlabelled: Obesity is characterized by abnormal adipose tissue expansion and is associated with chronic inflammation. Obesity itself may induce several comorbidities, including psychiatric disorders. It has been previously demonstrated that proinflammatory cytokines are able to up-regulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) release, which both have a role in compulsive related behaviors.

Opposing roles of CB and CB cannabinoid receptors in the stimulant and rewarding effects of cocaine.

Background And Purpose: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) bind to CB and CB cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB receptor antagonism and CB receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately.

N-arachidonoyl-serotonin, a dual FAAH and TRPV1 blocker, inhibits the retrieval of contextual fear memory: Role of the cannabinoid CB1 receptor in the dorsal hippocampus.

Anandamide, an endocannabinoid, inhibits aversive responses by activating the CB cannabinoid receptor. At high concentrations, however, anandamide may exert pro-aversive activities mediated by the transient receptor potential vanilloid type-1 channel (TRPV1). Accordingly, N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the anandamide-hydrolysing enzyme fatty acid amide hydrolase (FAAH) and the TRPV1 channel, induces anxiolytic-like effects.

Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey.

2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks.

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release.

Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, have remained unclear.

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli.

Neuroinflammation as a possible link between cannabinoids and addiction.

Objective: Substance dependence disorder is a chronically relapsing condition characterised by neurobiological changes leading to loss of control in restricting a substance intake, compulsion and withdrawal syndrome. In the past few years, (endo)cannabinoids have been raised as a possible target in the aetiology of drug addiction. On the other hand, although the exact mechanisms of the genesis of addiction remain poorly understood, it is possible that neuroinflammation might also play a role in the pathophysiology of this condition.

The antipsychotic aripiprazole selectively prevents the stimulant and rewarding effects of morphine in mice.

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favorable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine.

Inhibition of endocannabinoid neuronal uptake and hydrolysis as strategies for developing anxiolytic drugs.

The endocannabinoid system comprises the CB1 and CB2 receptors (the targets of the Cannabis sativa compound delta-9-tetrahydrocannabinol), the endogenous ligands (endocannabinoids) arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, their synthesizing machinery and membrane transport system, and the hydrolyzing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The endocannabinoids may act on demand to confer protection against aversive stimuli, which suggests that increasing their brain levels may represent an approach for treatment of anxiety-related disorders. Thus, this article reviews the profile of endocannabinoid reuptake and hydrolysis inhibitors in experimental tests predictive of anxiolytic activity.