The Role of the Mu Opioid Receptors of the Medial Prefrontal Cortex in the Modulation of Analgesia Induced by Acute Restraint Stress in Male Mice.

Mu opioid receptors (MORs) represent a vital mechanism related to the modulation of stress-induced analgesia (SIA). Previous studies have reported on the gamma-aminobutyric acid (GABA)ergic "disinhibition" mechanisms of MORs on the descending pain modulatory pathway of SIA induced in the midbrain. However, the role of the MORs expressed in the medial prefrontal cortex (mPFC), one of the main cortical areas participating in pain modulation, in SIA remains completely unknown.

Characterizing the dynamic learning process: Implications of a quantitative analysis.

Understanding the neural mechanisms involved in learning processes is crucial for unraveling the complexities of behavior and cognition. Sudden change from the untrained level to the fully-learned level is a pivotal feature of instrumental learning. However, the concept of change point and suitable methods to conveniently analyze the characteristics of sudden change in groups remain elusive, which might hinder a fuller understanding of the neural mechanism underlying dynamic leaning process.

Inhibition of cannabinoid degradation enhances hippocampal contextual fear memory and exhibits anxiolytic effects.

Recent studies have demonstrated the pivotal involvement of endocannabinoids in regulating learning and memory, but the conclusions obtained from different paradigms or contexts are somewhat controversial, and the underlying mechanisms remain largely elusive. Here, we show that JZL195, a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase, can enhance the performance of mice in a contextual fear conditioning task and increase the time spent in open arms in the elevated zero maze (EZM). Although the effect of JZL195 on fear memory could not be inhibited by antagonists of cannabinoid receptors, the effect on the EZM seems to be mediated by CB1R.

Differential Alterations in Striatal Direct and Indirect Pathways Mediate Two Autism-like Behaviors in Valproate-Exposed Mice.

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration.

The Contributions of Mu-Opioid Receptors on Glutamatergic and GABAergic Neurons to Analgesia Induced by Various Stress Intensities.

The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of the major opioid receptors, are expressed widely in subpopulations of cells throughout the CNS. However, the potential roles of MORs expressed in glutamatergic (MOR) and γ-aminobutyric acidergic (MOR) neurons in stress-induced analgesia remain unclear.

Acute cannabinoids impair association learning via selectively enhancing synaptic transmission in striatonigral neurons.

Background: Cannabinoids and their derivatives attract strong interest due to the tremendous potential of their psychoactive effects for treating psychiatric disorders and symptoms. However, their clinical application is restricted by various side-effects such as impaired coordination, anxiety, and learning and memory disability. Adverse impact on dorsal striatum-dependent learning is an important side-effect of cannabinoids.

N-methyladenosine RNA modification of glutamatergic neurons is associated with contextual fear discrimination.

Fear memory overgeneralization is a hallmark of many stress-related disorders, especially posttraumatic stress disorder. The neurobiology of fear memory generalization and discrimination involves a series of interplays between molecular and cellular factors, the mechanisms of which remain largely unexplored. N-methyladenosine (mA) of RNA is a reversible and dynamically regulated posttranscriptional modification with especially high levels in mammalian brain.

Stress Controllability Modulates Basal Activity of Dopamine Neurons in the Substantia Nigra Compacta.

Prolonged stress induces neural maladaptations in the mesolimbic dopamine (DA) system and produces emotional and behavioral disorders. However, the effects of stress on activity of DA neurons are diverse and complex that hinge on the type, duration, intensity, and controllability of stressors. Here, controlling the duration, intensity, and type of the stressors to be identical, we observed the effects of stressor controllability on the activity of substantia nigra pars compacta (SNc) DA neurons in mice.

Single Exposure to Cocaine Impairs Reinforcement Learning by Potentiating the Activity of Neurons in the Direct Striatal Pathway in Mice.

Plasticity in the glutamatergic synapses on striatal medium spiny neurons (MSNs) is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse. Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment. In the present work, we found that the negative reinforcement learning, escaping mild foot-shocks by correct nose-poking, was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.

Abnormal reinforcement learning in a mice model of autism induced by prenatal exposure to valproic acid.

Individuals with autism spectrum disorder (ASD) display dysfunction in learning from environmental stimulus that have positive or negative emotional values, posing obstacles to their everyday life. Unfortunately, mechanisms of the dysfunction are still unclear. Although early intervention for ASD victims based on reinforcement learning are commonly used, the mechanisms and characteristics of the improvement are also unknown.

Loss of control over mild aversive events produces significant helplessness in mice.

Most of the pathophysiology of depression are still unknown because of its numerous disease states of distinct etiology and pathogenesis. Stressful rodent models have been used to test a number of hypotheses regarding the etiology of depression. The learned helplessness rodent model demonstrates that having no control at all over aversive events produces helplessness and depression, but the role of loss of control over aversive events in helplessness is still not reliably modelled or deeply investigated.

5-HT1A autoreceptor in dorsal raphe nucleus mediates sensitization of conditioned place preference to cocaine in mice experienced with chronic pain.

Chronic stress, including chronic neuropathic pain, cannot only induce depressive disorders but also enhance sensitization to addictive drugs. Ample evidence support the implication of the 5-hydroxytryptamine (5-HT) system in the enhanced sensitization to cocaine. However, mechanisms underpinning such an enhancement are still unclear.

Cannabinoids-induced peripheral analgesia depends on activation of BK channels.

The endogenous cannabinoid system is involved in the physiological inhibitory control of pain and is of particular interest for the development of therapeutic approaches for pain management. Selective activation of the peripheral CB1 cannabinoid receptor has been shown to suppress the heightened firing of primary afferents, which is the peripheral mechanism underlying neuropathic pain after nerve injury. However, the mechanism underlying this effect of CB1 receptor remains unclear.

Downregulation of mGluR2/3 receptors during morphine withdrawal in rats impairs mGluR2/3- and NMDA receptor-dependent long-term depression in the nucleus accumbens.

Drugs of abuse modify synaptic long-term potentiation and long-term depression (LTD) in the nucleus accumbens, and the impairment of synaptic plasticity in this brain region may be a universal feature of drug addiction. It is unknown whether metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity induced by drugs such as morphine. The neurochemical, electrophysiological, and Western blotting experiments reported here reveal a novel form of LTD in synapses of the shell region of the nucleus accumbens induced in vivo by low-frequency stimulation of the medial prefrontal cortex.

Cannabinoid-Elicited Conditioned Place Preference in a Modified Behavioral Paradigm.

Cannabinoids are the active ingredients in marijuana, which is among the most widely used addictive drugs despite the well-documented harmfulness related to its abuse. The mechanism underlying cannabinoid addiction remains unclear, which is attributed partially to the difficulty in behavioral testing of high-dose cannabinoids using the conditioned place preference (CPP) model. Here, we optimized conditions for establishing CPP with the synthetic cannabinoid HU210 intraperitoneally administered at a high dose.

Activation of the D1 receptors inhibits the long-term potentiation in vivo induced by acute morphine administration through a D1-GluN2A interaction in the nucleus accumbens.

Dopamine D1-like receptors can modulate glutamate-mediated excitatory synaptic neurotransmission, but the underlying molecular mechanism remains elusive. Here, we report that acute in-vivo morphine administration induces the long-term potentiation (Mor-LTP) of field excitatory postsynaptic potentials at the prefrontal cortex-to-nucleus accumbens shell synapses, and this process requires the activation of GluN2A-containing N-methyl-D-aspartate receptors. This Mor-LTP is completely inhibited by the D1-like receptor agonist SKF81297, but not by the D2-like receptor agonist quinpirole.

Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning.

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses.