The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice.

RATIONALE: Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction. OBJECTIVES: Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation. METHODS: Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3-10 mg/kg) or JWH133 (CB2R agonist; 1-10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus. RESULTS: AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals. CONCLUSIONS: CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.

Hypothalamic endocannabinoid signalling modulates aversive responses related to panic attacks.

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB1 and CB2 antagonists (AM251 and AM630, respectively), and mimicked by CB1 and CB2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB1 and CB2 receptors in this brain region.

Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine.

BACKGROUND AND PURPOSE: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine. EXPERIMENTAL APPROACH: Male Swiss mice received i.p. injections of cannabinoid-related drugs followed by cocaine, and were then tested for cocaine-induced hyperlocomotion, c-Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed. KEY RESULTS: The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine-induced hyperlocomotion. The same results were obtained by combining sub-effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine-induced hyperlocomotion and c-Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2-AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine-induced hyperlocomotion when given after a sub-effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine-induced conditioned place preference. CONCLUSION AND IMPLICATIONS: The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction-related effects of cocaine. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Inhibition of the dopamine transporter as an animal model of bipolar disorder mania: Locomotor response, neuroimmunological profile and pharmacological modulation.

Inhibition of dopamine transporter (DAT) by GBR12909 has been proposed as a pharmacological model of mania related to bipolar disorder (BD). Here we tested the hypothesis that GBR12909 injection impairs habituation and induces hyperlocomotion in mice, along with changes in cytokines and neurotrophic factors levels, as observed in BD patients. We also tested if lithium carbonate, sodium valproate and aripiprazole prevent GBR12909-induced locomotion. Male Swiss mice received GBR12909 (15 mg/kg) injections and locomotor responses were quantified in an open field. Cytokines and neurotrophic factors levels were assessed in the prefrontal cortex, striatum and hippocampus 30 min and 24 h after injections. Pre-treatments with lithium, valproate or aripiprazole were performed with single and repeated injection protocols. GBR12909 prevented motoric habituation and increased basal locomotion in habituated mice in the open field. This compound also induced changes in IL-2 and BDNF levels in prefrontal cortex; IL-2, IL-4 and IL-10 in striatum; and IL-10, IL-4, IFN-γ and NGF in hippocampus. GBR12909-induced hyperlocomotion was attenuated by lithium (12.5-100 mg/kg), but not valproate (75-300 mg/kg), and prevented by aripiprazole (0.1-10 mg/kg). Repeated injections of these drugs (twice a day for 3 days), however, failed to inhibit hyperlocomotion. The main limitations of the protocols in this study are the analysis of locomotion as the only behavioral parameter, changes in immune factors that may overlap with other psychiatric disorders and the lack chronic drug injections. Despite of these limitations, this study adds to previous literature suggesting DAT inhibition as a potential animal model of mania related to BD.

Role of endocannabinoid signalling in the dorsolateral periaqueductal grey in the modulation of distinct panic-like responses.

Panic attacks, a major feature of panic disorder, can be modelled in rats by exposing animals to stimuli that induce escape reactions, such as the elevated T-maze or the activation of the dorsolateral periaqueductal grey. Since the cannabinoid CB1 receptor modulates various types of aversive responses, this study tested the hypothesis that enhancement of endocannabinoid signalling in the dorsolateral periaqueductal grey inhibits panic-like reactions in rats. Local injection of the CB1 agonist, arachidonoyl 2-Chloroethylamide (0.005-0.5 pmol), attenuated the escape response from the open arm of the elevated T-maze, a panicolytic effect. The anandamide hydrolysis inhibitor, URB597 (0.3-3 nmol), did not induce consistent results. In the test of dorsolateral periaqueductal grey stimulation with d,l-homocysteic acid, arachidonoyl 2-Chloroethylamide, at the lowest dose, attenuated the escape reaction. The highest dose of URB597 also inhibited this response, contrary to the result obtained in the elevated T-maze. This effect was reversed by the CB1 antagonist, AM251 (100 pmol). The present results confirm the anti-aversive property of direct CB1 receptor activation in the dorsolateral periaqueductal grey. The effect of the anandamide hydrolysis inhibitor, however, could be detected only in a model employing direct stimulation of this structure. Altogether, these results suggest that anandamide signalling is recruited only under certain types of aversive stimuli.