The astrocyte α1A-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex.

Noradrenaline (norepinephrine) is known to modulate many physiological functions and behaviors. In this study, we tested to what extent astrocytes, a type of glial cell, participate in noradrenergic signaling in mouse primary visual cortex (V1). Astrocytes are essential partners of neurons in the central nervous system. They are central to brain homeostasis, but also dynamically regulate neuronal activity, notably by relaying and regulating neuromodulator signaling. Indeed, astrocytes express receptors for multiple neuromodulators, including noradrenaline, but the extent to which astrocytes are involved in noradrenergic signaling remains unclear. To test whether astrocytes are involved in noradrenergic neuromodulation in mice, we employed both short hairpin RNA mediated knockdown as well as pharmacological manipulation of the major noradrenaline receptor in astrocytes, the α1A-adrenoreceptor. Using acute brain slices, we found that the astrocytic α1A-adrenoreceptor subtype contributes to the generation of large intracellular Ca2+ signals in visual cortex astrocytes, which are generally thought to underlie astrocyte function. To test if reduced α1A-adrenoreceptor signaling in astrocytes affected the function of neuronal circuits in V1, we used both patch-clamp and field potential recordings. These revealed that noradrenergic signaling through the astrocyte α1A-adrenoreceptor is important to not only modulate synaptic activity but also to regulate plasticity in V1, through the potentiation of synaptic responses in circuits involved in visual information processing.

Effects of the cannabinoid CB1-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats.

Evidence suggests the existence of a functional interaction between endogenous cannabinoid (CB) and opioid systems. Thus, targeting CB1 receptors might be a viable approach to develop new medications for opioid use disorders (OUD). The present studies were undertaken to evaluate the effects of the neutral CB1 antagonist AM4113 and the CB1 antagonist/inverse agonist rimonabant in male rats trained to discriminate 0.032 mg/kg fentanyl from saline under a 10-response fixed-ratio (FR-10) schedule of food reinforcement. Results show that the µ-opioid agonists (fentanyl, oxycodone, and morphine) substituted fully and dose-dependently for fentanyl, whereas pretreatment with the µ-opioid antagonist naltrexone antagonized fentanyl's discriminative-stimulus effects. In interaction studies, AM4113 (0.32 or 1.0 mg/kg) was more effective in blocking fentanyl discrimination at 10-fold lower doses that did not modify rates of food-maintained responding, whereas rimonabant (1.0-10 mg/kg) produced some attenuation of fentanyl's discriminative-stimulus effects at the highest dose tested which also significantly decreased response rates. These results extend our recent work showing that AM4113 can effectively block the behavioral effects of heroin without producing rimonabant-like adverse effects. Taken together, these data suggests that CB1 neutral antagonists effectively block the behavioral effects of structurally distinct morphinan (heroin) and phenylpiperidine-based (fentanyl) opioids and may provide a novel therapeutic option for the treatment of OUD.