Atypical neuroleptic properties ofl-stepholidine : Electrophysiological and behavioral studies
https://sci-hub.do/10.1007/bf03183593
SPD has high affinity to dopamine (DA) Dl and D2 subtypes with preference to Dl, while its affinity to other receptors is low
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Biochemical experiments show that SPD significantly blocks presynaptic D2 receptor-mediated feedback regulation in the striatum so that it increases levodopa accumulation in the striatum, facilitates the release of DA from nerve terminals
Chronic administration of SPD for 21 d elicited upregulation of Dl and D2 receptors, supporting the viewpoint that SPD is an antagonist to both Dl and D2 subtypes.
https://sci-hub.do/1...015907782793649
SPD has been shown to possess dual D1 agonistic and D2 antagonistic effects in both the nigrostriatal and mesocorticolimbic DAergic pathways. Thus, SPD potentially reverses hyperactivity of subcortical D2 receptors and restores PFC dysfunctional D1 receptors in patients with schizophrenia, which would result in the recovery of functional linkage between D1 and D2 receptors. SPD not only treats the positive symptoms of schizophrenia, but also alleviates the negative symptoms. In addition, SPD also potentially relieves the motor symptoms of PD due to its D1 agonistic and D3 antagonistic effects. Furthermore, SPD exhibits neuroprotective effects by scavenging hydroxyl free radicals, and consequently, results in the slowing down of neuronal degeneration in the SN of patients with PD. Considering its features, such as being wellabsorbed in the digestive tract, can be widely distributed in body tissues, and can easily penetrate the blood-brain barrie [85], as well as its dual pharmacological effects on D1 and D2 receptors, SPD is a unique, novel and promising drug for the treatment of schizophrenia and/or PD.
https://sci-hub.do/1...0213-008-1172-1
Whether this translates into clinically meaningful precognitive benefits remains to be studied in future clinical studies, but clearly prefrontal hypofunctionality has been implicated in specific deficits in attentional control and working memory in schizophrenia, and appropriate modulation via D1 receptors is thought to have beneficial outcomes (Robbins 2005). Furthermore, the finding that l-stepholidine promotes neurogenesis (Guo et al. 2002) and protects against cortical neuronal neurotoxicity could theoretically translate in better long-term outcomes in schizophrenia (Zhang et al. 2005). In summary, the preclinical assessment of l-stepholidine as an antipsychotic and its side effect profile seems promising to target the positive and negative symptoms of schizophrenia, and it will in all likelihood be an excellent addition to the therapeutically useful atypical antipsychotic drugs
More attractive, considerable results have proposed that the hypofunction in the D1 receptor activity in the mPFC is involved in schizophrenia: (a) the D1 receptors are implicated in the control of working memory, and its dysfunction resulted in the prominent feature of schizophrenic patients (19); (b) D1 receptors are reduced in the mPFC of schizophrenia, and this reduction is related to the severity of the negative symptoms (1); © the D1 antagonist would worsen the status of schizophrenics (7); (d) D1-specific drugs have already revealed their promising beneficial effects on the negative symptoms of schizophrenia (20). It has, thus, suggested that future antipsychotic drugs should be designed with D1 agonistic-D2 antagonistic dual action to DA receptors, i.e. to optimize stimulation of cortical D1 sites as well as to antagonize D2 receptors in subcortex and/or cortex for the amelioration of positive and negative symptoms (2,5). Based on the previous studies and present work, the pharmacological characteristics of SPD have been established with a dual action, i.e. antagonistic to D2 receptors and agonistic to D1 receptors in the meso-mPFC-NAc DA system. Thus, SPD is well correspondent with the current opinion for new antipsychotic drugs, and it has been attempted to try in clinic. In conclusion, SPD possesses agonist actions on D1 receptors in the mPFC, by which it exerts an excitatory influence on the firing activity of NAc neurons.
https://sci-hub.do/1...3205(00)00729-3
Chronic SPD treatment (sc, 20 mg.kg-1.d-1 x 21 d) upregulated both striatal D1 and D2 receptor density. As compared to vehicle-treated rats, SPD increased D1 and D2 receptors by 41.5% and 43.7%, respectively SPD also altered the turnover of both D1 and D2 receptors. The degradation rate constant (k = 0.0082.h-1) and the synthesis rate (r = 2.65 pmol.h-1/g protein) of D2 receptors in SPD-treated rats were significantly increased vs vehicle-treated rats (k = 0.0049.h-1; r = 1.10 pmol.h-1/g protein). The degradation rate constant (k = 0.0059.h-1) and the synthesis rate (r = 3.1 pmol.h-1/g protein) of D1 receptors was also increased in SPD-treated rats vs vehicle-treated rats (k = 0.0048.h-1; r = 1.8 pmol.h-1/g protein), but the alteration of degradation rate constant missed significance (P > 0.05). As a result, receptor recovery following EEDQ was accelerated. The half time for D1 and D2 receptors recovery in SPD group were 117.5 h and 84.5 h, respectively, shorter than 144.4 h and 141.4 h in vehicle-treated rats.
https://pubmed.ncbi....ih.gov/9863137/
In conclusion, SPD activated the VLPO neurons, increased the amount of NREM sleep, and shortened sleep latency in mice. Unlike often-used sleep pills such as benzodiazepines, SPD did not alter the EEG power density, indicating that SPD induces NREM sleep similar to that seen in physiological sleep and may be potentially used for the treatment of insomnia.
https://sci-hub.do/1...pbb.2009.06.018
More:
https://pubmed.ncbi....h.gov/26539912/
Edited by gintrux, 07 January 2021 - 09:13 PM.
