An endogenous ligand for the sigma opioid binding site

It had been suggested that phencyclidine (PCP) and sigma opioids exert their similar psychotomimetic effects through a common receptor. Recently, however, there have been several reports demonstrating significant differences between the binding of PCP and SKF 10,047, a sigma opioid agonist, which suggests that there may be distinct PCP and sigma opioid receptors. If these differences in binding represent different receptors, then there may be different endogenous ligands for each receptor. Using porcine brains, which have already been used to isolate and purify an endogenous ligand for the PCP receptor, another factor has been isolated that inhibited the binding of [3H]-(+)SKF 10,047 and not the binding of [3H]-PCP. This factor appears to be a peptide or protein because incubation of the active fraction with pronase, a nonspecific peptidase, eliminated the ability of the porcine fractions to inhibit the binding of [3H]-(+)SKF 10,047. These findings suggest the existence of an endogenous ligand for sigma opioid receptors, which is different from the previously identified endogenous ligand for PCP receptors.     

Behavioural and electroencephalographic interactions between haloperidol and PCP/sigma ligands in the rat

Phencyclidine (PCP) and sigma ligands produce a typical excitatory behaviour in rats, characterized by circling and head- and body-weaving. Excitatory amino acid antagonists such as 2-amino 5-phosphonovaleric acid (AP5) or 3-(±)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) also produce a PCP-like excitatory behaviour in rats. In the present paper, the interactions between PCP/sigma drugs or excitatory amino acid receptor antagonists and haloperidol have been investigated in rats. In addition, the influence of two other butyrophenones having a different affinity for the sigma/haloperidol receptors, such as spiperone and 3-(4-(3(4-fluorobenzoyl)-propyl-piperazino-1-ylisoquinolino (HR 375), has been tested on the behavioural and EEG effects of PCP/sigma drugs and excitatory amino acid antagonists. PCP (2.5–5 mg/kg IP), (+) or (–) SKF 10,047 (1–15 mg/kg IP), (+) or (–) cyclazocine (2–8 mg/kg IP) and AP5 (0.5 µmol ICV) dose-dependently and significantly (P<0.01) antagonized the haloperidol-induced catalepsy in the horizontal bar and podium tests in rats. On the other hand, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP) reduced the head-weaving induced by (+) SKF 10,047, PCP, or AP5. On the contrary, HR 375 (6 mg/kg IP) was ineffective in blocking the excitatory effects of these drugs. In addition, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP), but not HR 375 (6 mg/kg IP) reduced the amplitude increase of the fast (20–30 Hz) frequency/low (30–50 µV) voltage background cortical activity elicited by PCP or (+) SKF 10,047. The results demonstrate an interaction between dopamine and excitatory amino acid receptors. At the same time, the data reveal the scarce relevance of the high affinity sigma/haloperidol receptors in the interference between PCP/sigma drugs and butyrophenones.     

SAT-1 -1415T/C polymorphism and susceptibility to schizophrenia

Patients suffering from psychosis show increased blood and fibroblast total polyamine levels. Spermidine/spermine N1-acetyltransferase (SSAT-1) and its coding gene (SAT-1) are the main factors regulating polyamine catabolism. The aim of the present study was to examine the association between the SAT-1 -1415T/C single nucleotide polymorphism (SNP) and schizophrenia. A case-control design was used in order to compare the genotypes for the SNP between schizophrenia patients (n = 180, 83 females and 97 males), other non-psychotic psychiatric patients (n = 413, 256 females and 157 males), and healthy controls (n = 251, 101 females and 150 males).     

Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand

Bi-acetylated l-stepholidine (l-SPD-A), a novel derivate of l-stepholidine (l-SPD), possesses a pharmacological profile of D₁/5-HT_1A agonism and D₂ antagonism. In the present study, we examined the potential antipsychotic effect of l-SPD-A in a phencyclidine (PCP)-induced rat model of schizophrenia. Pretreatment with l-SPD-A blocked acute PCP-induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Chronic l-SPD-A administration (i.p., 10 mg/kg/day for 14 days) improved social interaction and novel object recognition impairments in rats that were pretreated with PCP (i.p., 5 mg/kg/day for 14 days). Moreover, in a conditioned avoidance response (CAR) test, l-SPD-A, with either i.p. or oral administration, significantly decreased active avoidance without affecting the escape response of rats. Importantly, compared to that of the parent compound l-SPD, l-SPD-A showed stronger suppression of CARs. Lastly, using a [³⁵S]GTPγS binding assay, we demonstrated that l-SPD-A improved impaired dopamine D₁ receptor function in the prefrontal cortex (PFC) in chronic PCP-treated rats. Taken together, these results indicate that l-SPD-A was not only effective against the hyperactivity, but also improved the sensorimotor gating deficit, social withdrawal and cognitive impairment in an animal model of schizophrenia. The present data suggest that l-SPD-A, a potential neurotransmitter stabilizer, is a promising novel candidate drug for the treatment of schizophrenia.     

CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity

CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline

BACKGROUND: The N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice. METHODS: Saline (10 ml/kg/day, s.c., once daily on day 1-5, 8-12) or PCP (10 mg/kg/day, s.c., once daily on day 1-5, 8-12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed. RESULTS: PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg). CONCLUSIONS: This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.     

Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study

In a putative model of acute phencyclidine (PCP)-induced psychosis we evaluated effects of the drug on locomotor activity (LMA) and immediate early gene (IEG) induction in the rat using two routes of drug administration, intraperitoneal (i.p.) and subcutaneous (s.c.). Adult male rats received saline or PCP (1.0-5.0 mg/kg) either i.p or s.c. and were assessed for LMA for 60 min. At the end of the LMA testing animals were culled and blood and brain samples were collected for PCP concentration analysis. Separate cohorts of animals received 5.0 mg/kg PCP (i.p. or s.c.) and were used to investigate (1) the pharmacokinetics of PCP or (2) induction of IEG (Arc, c-fos, BDNF, junB, Krox-20, sgk-1, NURR1, fra-2, Krox-24, and egr-3) mRNA expression in the prefrontal cortex (PFC). Administration of PCP resulted in locomotor hyperactivity which was more robust and longer-lasting in animals dosed s.c. compared to i.p.-treated-animals. Differences in hyperlocomotion were paralleled by higher concentrations of PCP in the blood and in the brain of s.c.-treated animals compared to i.p.-treated animals. The differences in the concentration of PCP between the two routes of administration were detected 30 min after dosing and persisted for up to 4 h. Administration of PCP via the s.c. route resulted in induction of more IEGs and consistently larger magnitudes of induction than that via the i.p. route. Therefore, we have outlined the dosing conditions to induce rapid and robust effect of acute PCP on behaviour, gene induction, and pharmacokinetic profile, to allow investigation of this as a potential animal model of acute psychosis.     

G试验水平对艾滋病合并肺孢子菌肺炎机械通气患者脱机结局的预测价值

目的 探讨G试验能否预测艾滋病合并肺孢子菌肺炎(PCP)机械通气患者的撤机.方法 回顾性分析北京佑安医院感染科监护病房2010年5月至2017年5月收治的艾滋病合并重症PCP且行机械通气治疗患者的临床资料,根据患者脱机成功与否将患者分为两组,比较两组患者G试验水平.结果 共入选49例患者,脱机成功组9例,失败组40例.两组患者基线资料比较结果显示,白蛋白、CD4计数、G试验水平差异均有统计学意义(P均＜0.05).成功组G试验水平显著低于失败组,分别为331.0 ng/L(299.0～488.7 ng/L)和267.0 ng/L(236.0～294.5 ng/L).多因素分析结果显示,血清G试验水平是影响艾滋病合并重度PCP患者能够脱机与否的独立危险因素(0R=0.978,95％CI:0.959～0.998,P=0.032).结论 G试验可以作为一项脱机结局预测指标,用来预测艾滋病合并PCP患者撤机预后.