Cannabinoid CB2 receptors and hypersensitivity to methamphetamine: Vulnerability to schizophrenia.

The human cannabinoid receptor 2 (CB2R) gene CNR2 has been associated with schizophrenia development. Inbred mice treated with the CB2R inverse agonist AM630 and challenged with methamphetamine (MAP) showed reduced prepulse inhibition (%PPI) response and locomotor hyperactivity, both behavioral measures in rodents that correlate with psychosis. Mice lacking CB2R on striatal dopaminergic neurons exhibit a hyperdopaminergic tone and a hyperactivity phenotype.

: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin.

The consumption of plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. is the most used illicit drug worldwide; however, its legal status is changing rapidly. regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent .

The endogenous cannabinoid system modulates male sexual behavior expression.

The endocannabinoid system (ECS) plays a key neuromodulatory role in the brain. Main features of endocannabinoids (eCBs) are that they are produced on demand, in response to enhanced neuronal activity, act as retrograde messengers, and participate in the induction of brain plasticity processes. Sexual activity is a motivated behavior and therefore, the mesolimbic dopaminergic system (MSL) plays a central role in the control of its appetitive component (drive to engage in copulation).

The Polypharmacological Effects of Cannabidiol.

Cannabidiol (CBD) is a major phytocannabinoid present in (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ-tetrahydrocannabinol (∆-THC) does. In contrast to ∆-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated.

Crosstalk between the endocannabinoid and mid-brain dopaminergic systems: Implication in dopamine dysregulation.

Endocannabinoids (eCBs) and the expanded endocannabinoid system (ECS)-"endocannabinoidome", consists of the endogenous ligands, eCBs, their canonical and non-canonical receptor subtypes, and their synthesizing and metabolizing enzymes. This system modulates a wide range of body functions and acts as a retrograde signaling system within the central nervous system (CNS) by inhibition of classical transmitters, and plays a vital modulatory function on dopamine, a major neurotransmitter in the CNS. Dopamine is involved in different behavioral processes and contributes to different brain disorders-including Parkinson's disease, schizophrenia, and drug addiction.

The nucleus accumbens dopamine increase, typically triggered by sexual stimuli in male rats, is no longer produced when animals are sexually inhibited due to sexual satiety.

Rationale: Exposure of male rats to an inaccessible receptive female and copulation increases dopamine (DA) levels in the nucleus accumbens (NAcc). Males copulating to satiety become sexually inhibited and most of them do not display sexual activity when presented with a sexually receptive female 24 h later. This inhibitory state can be pharmacologically reversed.

Cell-Type Specific Deletion of CB2 Cannabinoid Receptors in Dopamine Neurons Induced Hyperactivity Phenotype: Possible Relevance to Attention-Deficit Hyperactivity Disorder.

DAT- mice are conditional knockout (cKO) animals that do not express cannabinoid CB2 receptors (CB2R), in midbrain dopamine neurons. The hyperactivity phenotype of DAT- cKO mice were paradoxically reduced by low dose of amphetamine. Here, we report on the locomotor activity analysis in male and female adolescent (PND 30 ± 2) mice in basal conditions and in response to different doses of amphetamine, using the Open Field (OF), Elevated Plus-Maze (EPM) tests and the Novel Object Recognition (NOR) task as a putative model of attention deficit hyperactivity disorder (ADHD).

Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects.

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine.

Involvement of CB2 Receptors in the Neurobehavioral Effects of (Vahl) Endl. (Khat) in Mice.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene.

Endocannabinoids Interact With the Dopaminergic System to Increase Sexual Motivation: Lessons From the Sexual Satiety Phenomenon.

In male rats, copulation to satiety induces a long-lasting sexual inhibitory state, considered to rely on a decreased sexual motivation. Dopaminergic transmission at the mesolimbic system plays a central role in the regulation of male sexual motivation. Endocannabinoids (eCBs) modulate the activity of the mesolimbic system and both dopamine (DA) and cannabinoid receptor activation reverses the sexual inhibition that characterizes sexually satiated rats.

Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons.

Activation of the endocannabinoid system modulate dopaminergic pathways that are involved in the effects of psychostimulants including amphetamine, cocaine, nicotine and other drugs of abuse. Genetic deletion or pharmacological activation of CB2 cannabinoid receptor is involved in the modulation of the effects of psychostimulants and their rewarding properties. Here we report on the behavioral effects of psychostimulants in DAT-Cnr2 conditional knockout (cKO) mice with selective deletion of type 2 cannabinoid receptors in dopamine neurons.

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress.

The alcohol preference model is one of the most widely used animal models relevant to alcoholism. Stressors increase alcohol consumption. Here we present a protocol for a rapid and useful tool to test alcohol preference and stress-induced alcohol consumption in mice.

Sexual interaction is essential for the transformation of non-copulating rats into sexually active animals by the endocannabinoid anandamide.

The endocannabinoid anandamide (AEA) transforms half of the population of previously non-copulating (NC) rats into sexually active animals in a long-lasting manner. The aim of this work was to explore the nature of this transformation. We identified the dose range in which AEA induces mating behavior in previously NC rats, which evidenced a dose-based, biphasic profile for AEA to induce the transformation of NC rats.

Developmental and behavioral effects in neonatal and adult mice following prenatal activation of endocannabinoid receptors by capsaicin.

Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1.

Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference.

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice.

A new role for GABAergic transmission in the control of male rat sexual behavior expression.

GABAergic transmission in the ventral tegmental area (VTA) exerts a tonic inhibitory influence on mesolimbic dopaminergic neurons' activity. Blockade of VTA GABA receptors increases dopamine release in the nucleus accumbens (NAcc). Increases in NAcc dopamine levels typically accompany sexual behavior display.

Intra-VTA anandamide infusion produces dose-based biphasic effects on male rat sexual behavior expression.

Sexual behavior is a natural reward and the mesolimbic (MSL) system is involved in the processing of its motivational component and reinforcing properties. Endocannabinoids control rewarding behaviors through the modulation of MSL system's activity. The endocannabinoid anandamide (AEA), systemically administered, produces dose-based, biphasic effects on male rat copulation, facilitating its expression at low doses in both, sexually experienced and sexually exhausted male rats.

Biphasic effects of anandamide on behavioural responses: emphasis on copulatory behaviour.

Endocannabinoids have emerged as important modulators of different neurotransmitter systems in the brain by acting as retrograde messengers. They are released from postsynaptic cell bodies, travel backwards across the synapsis and bind to their receptors located at the presynaptic terminal to inhibit neurotransmitter release. The fatty acid amide, arachidonoylethanolamide (anandamide), is an important endogenous ligand of the G-protein-coupled cannabinoid receptors CB1 and CB2.

Anandamide reduces the ejaculatory threshold of sexually sluggish male rats: possible relevance for human lifelong delayed ejaculation disorder.

Introduction: The sexually sluggish (SLG) male rat has been proposed as an animal model for the study of lifelong delayed ejaculation, a sexual dysfunction for which no treatment is available. Low endocannabinoid anandamide (AEA) doses facilitate sexual behavior display in normal sexually active and in noncopulating male rats through the activation of CB1 receptors.

Aim: To establish whether low AEA doses reduced the ejaculatory threshold of SLG male rats by acting at CB1 receptors.

Dopamine receptors play distinct roles in sexual behavior expression of rats with a different sexual motivational tone.

Dopamine (DA) plays a central role in the expression of male sexual behavior. The effects of DA-enhancing drugs on copulation seem to vary depending on the dose of the agonist used, the type of DA receptor activated, and the sexual condition of the animals. The aim of the present study was to carry out a systematic analysis of the effects of dopaminergic agonists on the expression of male sexual behavior by sexually competent rats in different sexual motivational states, that is when sexually active (sexually experienced) and when temporarily inhibited (sexually exhausted).

Low anandamide doses facilitate male rat sexual behaviour through the activation of CB1 receptors.

Rationale: Endocannabinoids (eCN) exert biphasic effects on several behaviours; however, they have only been reported to inhibit male sexual behaviour. eCN, the endogenous ligands for CB1 receptors, are released in response to neuronal stimulation and regulate the functioning of the mesocorticolimbic system (MCL), which is activated by male sexual behaviour. We hypothesised that eCN might exert biphasic effects on male rat copulatory behaviour and be released during copulation to satiation as a result of the repeated activation of the MCL system.

Anandamide transforms noncopulating rats into sexually active animals.

Introduction: Noncopulating (NC) male rats are apparently normal and healthy animals that will not mate despite repeated exposure to sexually receptive females. Several lines of evidence suggest the involvement of endogenous opioids in this sexual inhibitory state. Endogenous opioids and endocannabinoids are neuromodulators of neurotransmitter release, although through different mechanisms.