LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Compounds that activate the 5-HT2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT2A receptors in rats. We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D2/D3 receptor antagonist raclopride (0.1 mg/kg, s.c). The effect of LSD on PPI is mediated by the 5-HT2A receptor, whereas activation of the 5-HT2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT2A agonist

Oxygen-Glucose Deprivation Induced Glial Scar-Like Change in Astrocytes

It has been demonstrated that cerebral ischemia induces astrocyte reactivity, and subsequent glial scar formation inhibits axonal regeneration during the recovery phase. Investigating the mechanism of glial scar formation will facilitate the development of strategies to improve axonal regeneration. However, an in vitro model of ischemia-induced glial scar has not yet been systematically established.In the present study, we at the first time found that oxygen-glucose deprivation (OGD) in vitro can induce rat cortical astrocytes to present characteristics of glial scar. After OGD for 6 h, astrocytes showed a remarkable proliferation following 24 h reperfusion, evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and BrdU immunocytochemistry. Meanwhile, the expression of glial fibrillary acidic protein significantly increased, so did the expression of neurocan, which is a hallmark of the glial scar. In further experiments, neurons were co-cultured with astrocytes, which had been exposed to OGD, and then the immunostaining of class III β-tubulin was carried out to assess the neurite growth. When the co-culture was performed at 48 h reperfusion of astrocytes, the neurite growth was obviously inhibited, and this inhibition could be reversed by chondroitinase ABC, which digests glycosaminoglycan chains on CSPGs, including neurocan. However, the processes of neurons were elongated, when the co-culture was performed immediately after OGD.Our results indicated that after conditioned OGD the astrocytes presented the characteristics of the glial scar, which are also comparable to the astrocytes in acute and chronic phases after cerebral ischemia in vivo. Therefore, the present system may be used as an in vitro model to explore the mechanisms underlying glial scar formation and the treatments to improve axonal regeneration after cerebral ischemia

Astrocyte scar formation aids central nervous system axon regeneration

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration

Development of nitric oxide synthase expression in the superficial dorsal horn of the rat spinal cord

Development of nitric oxide synthase (NOS) expression in the superficial dorsal horn of the rat spinal cord was studied using NADPH diaphorase histochemistry. At birth, no positive staining was seen in the superficial laminae of the cord. A week later, a few small positive neurons and fibers were seen in presumptive lamina II. The adult pattern of NOS expression was evident by the end of the third postnatal week.link_to_subscribed_fulltex