Amygdala circuitry mediating reversible and bidirectional control of anxiety

Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)—achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA—exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA–CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease

MDMA attenuates THC withdrawal syndrome in mice

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Δ9-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC, and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration. Both, chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.This study was supported by grants from Spanish MCYT (SAF 2004/568; BFU 2004/920BFI), Generalitat de Catalunya (2005SGR00131), European Communities (GENADDICT LSHM–CT–2004–005166) and NIH (Extra-mural research project #DA016768). CT has a fellowship supported by the Department of Education and Universities from Generalitat de Catalunya and by the Social European Fund. Ms Dulce Real in this work is kindly acknowledged for her excellent technical assistance in the in vivo microdialysis experiments

Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB 2 receptors

The potential involvement of the cannabinoid CB 2 receptors (CB 2 r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB 2 r (CB 2 xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB 2 r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and-opioid and cannabinoid CB 1 receptors in the NAcc were also studied in both genotypes. CB 2 xP mice showed decreased motor response to acute administration of cocaine (10-20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB 2 xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB 2 r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and-opioid receptor gene expression was lower in CB 2 xP than in WT mice. However, both genotypes showed similar changes in TH and-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB 2 xP than in cocaine-pretreated WT mice. These results revealed that CB 2 r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction. © 2012 American College of Neuropsychopharmacology.Peer Reviewe