Thércia Guedes Viana

Modeling panic disorder in rodents

Panic disorder (PD) is a subtype of anxiety disorder in which the core phenomenon is the spontaneous occurrence of panic attacks. Although studies with laboratory animals have been instrumental for the understanding of its neurobiology and treatment, few review articles have focused on the validity of the currently used animal models for studying this psychopathology. Therefore, the aim of the present paper is to discuss the strengths and limits of these models in terms of face, construct and predictive validity. Based on the hypothesis that panic attacks are related to defensive responses elicited by proximal threat, most animal models measure the escape responses induced by specific stimuli. Some apply electrical or chemical stimulation to brain regions proposed to modulate fear and panic responses, such as the dorsal periaqueductal grey or the medial hypothalamus. Other models focus on the behavioural consequences caused by the exposure of rodents to ultrasound or natural predators. Finally, the elevated T-maze associates a one-way escape response from an open arm with panic attacks. Despite some limitations, animal models are essential for a better understanding of the neurobiology and pharmacology of PD and for discovering more effective treatments.

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. The FAAH inhibitors and the blockers of anandamide transport, in contrast to direct CB1 receptor agonists, induce anxiolytic effects at doses that do not interfere with motor activity. MAGL inhibitors also reduce anxiety-like behavior, although they are more likely to impair motor activity. Regarding their mechanisms, increasing anandamide levels induce responses mediated by the CB1 receptor and occluded by the transient receptor potential vanilloid type-1 channels, whereas the effects of increasing 2-arachidonoyl glycerol depend on both CB1 and CB2 receptors. Their neuroanatomical targets include various structures related to anxiety and fear responses. Understanding the pharmacological properties of FAAH and MAGL inhibitors may contribute toward the development of new anxiolytic interventions based on the endocannabinoid system.

Effects of Aripiprazole, an Atypical Antipsychotic, on the Motor Alterations Induced by Acute Ethanol Administration in Mice

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine receptors. As the effects of most drugs of abuse converge to enhance dopamine‐mediated neurotransmission, the present study was designed to test the hypothesis that aripiprazole would inhibit the acute effects of ethanol, a widely abused substance. Male Swiss mice received acute injections and were evaluated for motor activity in three distinct tests. In the open field, ethanol (1.5, 2.5 and 3.5 g/kg) induced an increase in locomotion in a U‐shaped dose‐related fashion, whereas aripiprazole (0.1, 1 and 10 mg/kg) did not affect this parameter. All the doses of the antipsychotic were able to prevent the stimulant effects of 2.5 g/kg of ethanol. In the rotarod test, ethanol (2.5 and 3.5 g/kg) reduced the latency to fall from the apparatus, an effect also observed with the higher dose of aripiprazole. Contrary to what was observed in the open field, this antipsychotic did not interfere with the effects of ethanol in motor balance. Finally, we tested animals in the wire hang test, in which ethanol, but not aripiprazole, reduced latency to fall at all doses. In this test, aripiprazole did not change ethanol effects. The present data lead to the conclusion that aripiprazole prevents the stimulant effects of ethanol on locomotion, without interfering with the motor impairment induced by this drug.

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. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.