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

The consumption of Cannabis sativa 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. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.

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). In turn, copulation activates mesolimbic dopamine neurons and repeated copulation produces the continuous activation of the MSL system. Sustained sexual activity leads to the achievement of sexual satiety, which main outcome is the transient transformation of sexually active male rats into sexually inhibited animals. Thus, 24 h after copulation to satiety, the sexually satiated males exhibit a decreased sexual motivation and do not respond to the presence of a sexually receptive female with sexual activity. Interestingly, blockade of cannabinoid receptor 1 (CB1R) during the copulation to satiety process, interferes with both the appearance of the long-lasting sexual inhibition and the decrease in sexual motivation in the sexually satiated males. This effect is reproduced when blocking CB1R at the ventral tegmental area evidencing the involvement of MSL eCBs in the induction of this sexual inhibitory state. Here we review the available evidence regarding the effects of cannabinoids, including exogenously administered eCBs, on male rodent sexual behavior of both sexually competent animals and rat sub populations spontaneously showing copulatory deficits, considered useful to model some human male sexual dysfunctions. We also include the effects of cannabis preparations on human male sexual activity. Finally, we review the role played by the ECS in the control of male sexual behavior expression with the aid of the sexual satiety phenomenon. Sexual satiety appears as a suitable model for the study of the relationship between eCB signaling, MSL synaptic plasticity and the modulation of male sexual motivation under physiological conditions that might be useful for the understanding of MSL functioning, eCB-mediated plasticity and their relationship with motivational processes.

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

ABSTRACT The consumption of Cannabis sativa 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. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.

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. There are no studies exploring NAcc DA levels during this sexual inhibitory state. OBJECTIVES: To characterize changes in NAcc DA and its metabolites' levels during sexual satiety development, during the well-established sexual inhibitory state 24 h later, and during its pharmacological reversal. METHODS: Changes in NAcc DA and its metabolites were measured in sexually experienced male rats, using in vivo microdialysis, during copulation to satiety, when presented to a new sexually receptive female 24 h later, and during the pharmacological reversal of the sexual inhibition by anandamide. RESULTS: NAcc DA levels remained increased during copulation to satiety. DA basal levels were significantly reduced 24 h after copulation to satiety, as compared to the initial basal levels. Presenting a receptive female behind a barrier 24 h after satiety did not induce the typical NAcc DA elevation in the sexually satiated males but there was a decrease that persisted when they got access to the female, with which they did not copulate. Anandamide injection slightly increased NAcc DA levels coinciding with sexual satiety reversal. CONCLUSIONS: Reduced NAcc DA concentrations coincide with the inhibition of an instinctive, natural rewarding behavior suggesting that there might be a DA concentration threshold needed to be responsive to a rewarding stimulus.

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

DAT-Cnr2 mice are conditional knockout (cKO) animals that do not express cannabinoid CB2 receptors (CB2R), in midbrain dopamine neurons. The hyperactivity phenotype of DAT-Cnr2 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). Results showed that both male and female adolescent DAT-Cnr2 mice displayed significant increases in distance traveled in the OF test compared with WT mice. However, 2 mg/kg dose of amphetamine reduced the distance traveled by the DAT-Cnr2 but was increased in the WT mice. In the EPM test of anxiety-like behavioral responses, DAT-Cnr2 spent more time in the open arms of the maze than the WT mice, suggesting a reduction in anxiety-like response. DAT-Cnr2 mice showed significant increase in the number of unprotected head dips in the maze test and in the cliff avoidance reaction (CAR) test demonstrating impulsivity and risky behavior. DAT-Cnr2 mice also exhibited deficient response in the delay decision making (DDM), with impulsive choice. Both DAT-Cnr2 and WT were able to recognize the new object in the NOR task, but the exploration by the DAT-Cnr2 was less than that of the WT mice. Following the administration of 2 mg/kg of amphetamine, the similarities and differential performances of the DAT-Cnr2 and WT mice in the EPM test and NOR task was probably due to increase in attention. Microglia activation detected by Cd11b immunolabelling was enhanced in the hippocampus in DAT-Cnr2 cKO than in WT mice, implicating neuro-immune modulatory effects of CB2R. The results demonstrates that DAT-Cnr2 cKO mice with cell-type specific deletion of CB2R in midbrain dopaminergic neurons may represent a possible model for studying the neurobiological basis of ADHD.

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. We hypothesized that AEA's sexual facilitative effects might be exerted at the MSL circuit. Therefore, in this work different AEA doses were bilaterally infused into the VTA of sexually experienced or sexually exhausted animals and their copulatory behavior recorded. Results showed that the lowest AEA dose tested lacked an effect, intermediate doses facilitated specific sexual parameters, and the highest dose inhibited copulation of sexually experienced males. In sexually exhausted animals low AEA doses reversed the sexual inhibition that characterizes sexual satiety, but this effect was lost at higher doses. Together, these data show that the VTA is a target for AEA's biphasic sexual effects suggesting a role of the MLS system in the actions of endocannabinoids on male rat sexual behavior.

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. The aim of this mini-review is to outline the recent literature on the biphasic nature of the behavioural actions of anandamide, with particular focus on male rat sexual behaviour, and to examine whether dose-related activation of distinct receptors plays a role in the biphasic effects of this prototypical endocannabinoid.

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. AIM: To establish if the endocannabinoid anandamide was able to induce sexual behavior expression in male rats classified as noncopulators. METHODS: NC male rats were intraperitoneally (i.p.) injected with anandamide or vehicle and tested for copulatory behavior with a receptive female during 120 minutes. Fourteen days after anandamide or vehicle injection, the animals were subjected to a second sexual behavior test during 60 minutes. MAIN OUTCOME MEASURES: The percentage of rats showing male sexual behavior responses: mount, intromission, ejaculation, and copulation resumption after ejaculation and the specific sexual behavior parameters were quantified. RESULTS: Anandamide injection induced sexual behavior expression in 50% of previously NC rats, while the NC animals injected with vehicle did not show sexual behavior. The responding animals executed several successive ejaculatory series and were still capable of showing sexual behavior 14 days after anandamide injection. Copulation in these rats (the first copulatory series) was characterized by a large number of mounts and intromissions preceding ejaculation, as well as by statistically significant increases in the latencies to mount, intromit, and ejaculate when compared with the sexual performance of sexually naïve animals copulating for the first time. CONCLUSION: The endocannabinoid anandamide transforms previously NC rats into sexually active animals, capable of showing sexual behavior in a long-lasting manner. Only half of the NC population responds to anandamide injection, suggesting that different mechanisms underlie the sexual inhibition of NC rats. The endocannabinoid system seems to play a role in the regulation of male rat sexual behavior expression.