Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the CNS. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g. cannabis) and endogenous cannabinoids affect behavior. As behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, while remarkably similar at various synapses, is controlled by an array of regulatory influences which we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.

Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1–triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.

The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brain.

Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

Identification of neural circuit changes contributing to behavioral plasticity has routinely been conducted on candidates that were preselected based on past results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles. Using rabies virus monosynaptic tracing we mapped cocaine-induced global input changes onto ventral tegmental area (VTA) neurons. Cocaine increased rabies labeled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus previously not known to participate in behavioral plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labeling. Inhibition of GPe activity revealed its vital role in two different forms of cocaine-triggered behavioral plasticity, at least in part via GPe-mediated disinhibition of VTA dopamine neuron activity. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioral adaptations.

CA1 ͉ CB1 ͉ hippocampus ͉ inhibition ͉ LTD S ynaptic plasticity is characterized as presynaptic or postsynaptic depending on whether neurotransmitter release or a target neuron's sensitivity to the transmitter is modified. Neural and behavioral adaptations likely involve both types of plasticity, yet our understanding of presynaptic mechanisms lags far behind what we know about the postsynaptic side. This discrepancy is particularly evident when considering synaptic learning rules. As a prime example, the associative properties of LTP and LTD at the Schaffer collateral-CA1 pyramidal cell (Sch-CA1) synapse result from coincidence detection by postsynaptic NMDA receptors (NMDARs), Ca 2ϩ influx, and the subsequent activation of kinase and phosphatase networks (1). For most forms of presynaptic plasticity, it is unknown whether they possess associative properties, let alone the identity of the molecular pathways involved.Perhaps the most prevalent form of long-term presynaptic plasticity is endocannabinoid-mediated LTD (eCB-LTD), occurring in multiple brain areas at both excitatory and inhibitory synapses (for a recent review, see ref.2). In the hippocampus, brief repetitive stimulation of Schaffer collaterals activates group I metabotropic glutamate receptors (mGluR-I) on CA1 PCs, promoting eCB release. The retrograde release of eCBs targets type 1 cannabinoid receptors (CB1Rs) on presynaptic GABAergic terminals, inducing a heterosynaptic LTD at inhibitory synapses

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.