RESUMO
BACKGROUND: ß-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB2 receptor (CB2R). OBJECTIVE: The study aims to investigate BCP's potential as a new drug for the treatment of substance use disorders by reviewing preclinical studies with animal models. RESULTS: BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB2R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor. CONCLUSION: Preclinical studies have reported promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action.
Assuntos
Canabinoides , Transtornos Relacionados ao Uso de Substâncias , Humanos , Animais , Canabinoides/farmacologia , Sesquiterpenos Policíclicos , Receptores de Canabinoides , Modelos AnimaisRESUMO
Δ9-THC (the main active compound from Cannabis sativa) and related cannabinoids have been used as drugs of abuse and as medications. They induce a complex set of emotional responses in humans and experimental animals, consisting of either anxiolysis or heightened anxiety. These discrepant effects pose a major challenge for data reproducibility and for developing new cannabinoid-based medicines. In this study, we review and analyze previous data on cannabinoids and anxiety-like behavior in experimental animals. Systematic review and meta-analysis on the effects of type-1 cannabinoid receptor agonists (full or partial, selective or not) in rodents exposed to the elevated plus maze, a widely used test of anxiety-like behavior. Cannabinoids tend to reduce anxiety-like behavior if administered at low doses. THC effects are moderated by the dose factor, with anxiolytic- and anxiogenic-like effects occurring at low-dose (0.075-1 mg/kg) and high-dose (1-10 mg/kg) ranges, respectively. However, some studies report no effect at all regardless of the dose tested. Finally, motor impairment represents a potential confounding factor when high doses are administered. The present analysis may contribute to elucidate the experimental factors underlying cannabinoid effects on anxiety-like behavior and facilitate data reproducibility in future studies.
Assuntos
Agonistas de Receptores de Canabinoides , Canabinoides , Humanos , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Teste de Labirinto em Cruz Elevado , Reprodutibilidade dos Testes , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Canabinoides/farmacologiaRESUMO
The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis. In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models. This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice's chronic consumption of a high-refined carbohydrate (HC) diet. BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF). The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet. Our data reinforced the harmful effects of the HC diet's chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.
Assuntos
Canabidiol , Camundongos , Masculino , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Camundongos Endogâmicos BALB C , Comportamento Compulsivo/induzido quimicamente , Comportamento Compulsivo/tratamento farmacológico , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , CarboidratosRESUMO
Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes for memory consolidation related to place preference behavior underlying cocaine administration in mice. Conditioned place preference (CPP) is a protocol extensively used to study the rewarding and/or aversive motivational effects of drug abuse in rodents, reproducing cocaine-seeking behavior in humans. Besides the variety of apparatus used in the CPP protocol, whether different types of apparatus are able to induce the same conditioned behavior response and neurobiological changes remains to be fully explored. We hypothesize that the immune response is involved in the cocaine-induced CPP and that the type of apparatus might influence this response. Herein, two- and three-compartment apparatuses were tested using the behavioral model of CPP. Cocaine-induced CPP was demonstrated in both apparatuses. However, mice injected with cocaine had decreased levels of IL-1ß, IL-6, IL-10, and GDNF in the pre-frontal cortex, and decreased CX3CL1 in the striatum, in the CPP protocol using three compartments compared to controls. While similar levels were seen in the CPP protocol using two compartments. In conclusion, the current study demonstrated that the type of apparatus might influence the investigation of neurobiological mechanisms associated with cocaine-induced CPP. Our data also suggest that the three compartment-apparatus seems to be a more appropriate model to investigate the neuroinflammatory response related to cocaine addiction.
Assuntos
Cocaína , Animais , Camundongos , Encéfalo , Cocaína/farmacologia , Citocinas , Fatores de Crescimento NeuralRESUMO
Drug abuse and addiction can be initiated and reinstated by contextual stimuli previously paired with the drug use. The influence exerted by the context on drug-seeking behaviour can be modelled in experimental animals with place-conditioning protocols. Here, we review the effects of cannabinoids in place conditioning and the therapeutic potential of the endocannabinoid system for interfering with drug-related memories. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) tends to induce conditioned place preference (CPP) at low doses and conditioned place aversion at high doses; cannabidiol is devoid of any effect, yet it inhibits CPP induced by some drugs. Synthetic CB1 receptor agonists tend to recapitulate the biphasic profile observed with THC, whereas selective antagonists/inverse agonists inhibit CPP induced by cocaine, nicotine, alcohol and opioids. However, their therapeutic use is limited by potential psychiatric side effects. The CB2 receptor has also attracted attention, because selective CB2 receptor agonists inhibit cocaine-induced CPP. Inhibitors of endocannabinoid membrane transport and hydrolysis yield mixed results. In targeting the endocannabinoid system for developing new treatments for drug addiction, future research should focus on 'neutral' CB1 receptor antagonists and CB2 receptor agonists. Such compounds may offer a well-tolerated pharmacological profile and curb addiction by preventing drug-seeking triggered by conditioned contextual cues.
Assuntos
Cocaína , Endocanabinoides , Animais , Cocaína/farmacologia , Dronabinol/farmacologia , Receptor CB1 de Canabinoide , Receptor CB2 de CanabinoideRESUMO
The mechanisms involved in the maintenance of cigarette smoking and nicotine reward remain unclear. Immune response might play an important role in this context. Nicotine may induce both central and systemic inflammatory responses as well as changes in the regulation of brain-derived neurotrophic factor (BDNF). The conditioned place preference (CPP) is a method used for the evaluation of nicotine-induced reward, reproducing nicotine-seeking behavior in humans. So far, there are no studies investigating the relationship between neuroinflammation and nicotine-induced CPP. This study aimed to evaluate the levels of inflammatory mediators and neurotrophic factors in key areas of the central nervous system (CNS) of mice subject to nicotine-induced CPP. CPP was induced with an intraperitoneal administration of 0.5â¯mg/kg of nicotine in male Swiss mice, using an unbiased protocol. Control group received vehicle by the same route. The levels of cytokines, chemokines, and neurotrophic factors were measured using Enzyme-Linked Immunosorbent Assay (ELISA) in the brain after CPP test. As expected, nicotine induced place preference behavior. In parallel, we observed increased peripheral levels of IL-6 and IL-10 alongside increased hippocampal levels of NGF but decreased GDNF in mice treated with nicotine compared to controls. In the striatum, nicotine promoted decrease of IL-1ß, IL-10 and GDNF levels, while the levels of all the mediators were similar between groups in the pre-frontal cortex. Our results provide evidence on the role of cytokines and neurotrophic factors in nicotine-induced CPP in mice.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Doenças Neuroinflamatórias/psicologia , Nicotina/administração & dosagem , Recompensa , Tabagismo/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/análise , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/imunologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/imunologia , Hipocampo/patologia , Humanos , Injeções Intraperitoneais , Interleucina-10/análise , Interleucina-10/metabolismo , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Masculino , Camundongos , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/patologia , Nicotina/efeitos adversos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/patologia , Tabagismo/imunologia , Tabagismo/patologiaRESUMO
Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1-0.5 mg/kg) or MAGL (JZL184, 1-10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB1 receptor antagonist (AM251, 1 mg/kg) or a TRPV1 channel blocker (SB366791, 1 mg/kg). Moreover, CB1 receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB1 receptor antagonism, but not by TRPV1 blockage. Remarkably, CB1 receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB1 expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB1 receptor-mediated protection against haloperidol-induced TD in rats. The increased CB1 receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.
Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Endocanabinoides/metabolismo , Haloperidol/efeitos adversos , Animais , Antipsicóticos/efeitos adversos , Ácidos Araquidônicos/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/metabolismo , Endocanabinoides/farmacologia , Glicerídeos/farmacologia , Masculino , Mastigação/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/metabolismoRESUMO
Cocaine addiction is a severe mental disorder for which few treatment options are available. The underlying mechanisms include facilitation of monoamine-neurotransmission, particularly dopamine. Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. Male Swiss mice received injections of (-)-OSU6162 or aripiprazole and cocaine and were tested for cocaine-induced hyperlocomotion, locomotor sensitization, and acquisition and expression of conditioned place preference (CPP). The increase in the distance traveled induced by cocaine (20 mg/kg) was prevented by pretreatment with aripiprazole (1 and 10 mg/kg), whereas (-)-OSU6162 (3 mg/kg) exerted a minor effect. Aripiprazole, however, also impaired spontaneous locomotion. Neither (-)-OSU6162 nor aripiprazole interfered with the locomotor sensitization and expression of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 (3 mg/kg), but not aripiprazole, prevented the acquisition of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction.
Assuntos
Aripiprazol/farmacologia , Cocaína/farmacologia , Locomoção/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Aripiprazol/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Camundongos , Piperidinas/administração & dosagemRESUMO
This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and "transient receptor potential cation channel, subfamily V, member 1" (TRPV1) channel blockers in epilepsy treatment. The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies. Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 ("vanilloid") channel, a possible anandamide target in the brain, have also been investigated. In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications. This article is part of the Special Issue "NEWroscience 2018".
Assuntos
Canabidiol , Canabinoides , Cannabis , Epilepsia , Animais , Canabidiol/uso terapêutico , Canabinoides/uso terapêutico , Dronabinol , Epilepsia/tratamento farmacológico , HumanosRESUMO
Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.