-
Current Medicinal Chemistry 2016Close to 1% of the world population suffer from schizophrenia. Current medications for this chronic mental disorder have greatly improved treatment over the last half... (Review)
Review
Close to 1% of the world population suffer from schizophrenia. Current medications for this chronic mental disorder have greatly improved treatment over the last half century or more, but, the newer atypical antipsychotics have proven to be disappointing, and enormous challenges remain. The negative symptoms and cognitive dysfunction in schizophrenia which greatly affect overall morbidity call for better treatments. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of schizophrenia, so excessive NO production might contribute to the pathology. This implies that it might be useful to reduce nitrergic activity, so molecules aiming to decrease NO production such as NO synthase (NOS) inhibitors might be candidates. Here, I critically review advances in research on these emerging molecules which hold promise although a note of caution is required on account of their potential neurotoxicity and narrow therapeutic window.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Humans; Ketamine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phencyclidine; Schizophrenia
PubMed: 27776474
DOI: 10.2174/0929867323666160812151054 -
Toxicology and Applied Pharmacology Dec 2022The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early...
The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D receptors.
Topics: Mice; Animals; Phencyclidine; Nicotine; Raclopride; Locomotion; Motor Activity; Receptors, Dopamine
PubMed: 36252887
DOI: 10.1016/j.taap.2022.116282 -
Vaccine Nov 2015Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but... (Review)
Review
Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Cocaine; Female; Heroin; Humans; Immunization, Passive; Immunotherapy; Male; Nicotine; Substance-Related Disorders; Treatment Outcome; Vaccination
PubMed: 26432911
DOI: 10.1016/j.vaccine.2015.09.079 -
International Journal of Molecular... Jul 20211-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho,... (Comparative Study)
Comparative Study
1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.
Topics: Analgesics, Opioid; Animals; Anisoles; Benzene Derivatives; Cells, Cultured; Cricetinae; Hallucinogens; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Models, Animal; Phencyclidine; Psychotropic Drugs; Receptors, Opioid; Tramadol
PubMed: 34299276
DOI: 10.3390/ijms22147659 -
Combinatorial Chemistry & High... 2019Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some...
BACKGROUND
Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both.
AIM AND OBJECTIVE
The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities.
MATERIALS AND METHODS
Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups.
RESULTS
The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site.
CONCLUSION
It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.
Topics: Amines; Animals; Formaldehyde; High-Throughput Screening Assays; Male; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Pain Measurement; Phencyclidine
PubMed: 31622215
DOI: 10.2174/1386207322666191016152157 -
AANA Journal Dec 2019Ketamine, a phencyclidine analog and dissociative anesthetic, has been used in anesthesia since the 1960s. Serial subanesthetic administration has been explored for... (Comparative Study)
Comparative Study Review
Ketamine, a phencyclidine analog and dissociative anesthetic, has been used in anesthesia since the 1960s. Serial subanesthetic administration has been explored for treatment of depression and chronic pain; however, there has been a recent surge in its intraoperative and perioperative use among anesthesia providers. As ketamine becomes an important addition to multimodal acute pain regimens, it important that anesthesia providers review the physiologic underpinnings of ketamine administration. Herein, we review the primary scientific literature and discuss recent studies that have implicated ketamine in inflammation and oxidative stress, inhibition of ion channels in dorsal horn neurons, and in disruption of frontoparietal communication. Also discussed are the potential clinical implications these effects may have for patients.
Topics: Adult; Aged; Aged, 80 and over; Anesthesia, General; Anesthesia, Spinal; Anesthetics, Dissociative; Female; Humans; Ketamine; Male; Middle Aged; Monitoring, Physiologic; Practice Guidelines as Topic
PubMed: 31920203
DOI: No ID Found -
Human & Experimental Toxicology Oct 2014Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a... (Review)
Review
Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.
Topics: Amphetamine-Related Disorders; Amphetamines; Analgesics, Opioid; Animals; Designer Drugs; Humans; Opioid-Related Disorders; Phencyclidine; Phencyclidine Abuse; Poisoning; Risk Factors
PubMed: 24501103
DOI: 10.1177/0960327113514100 -
Cerebral Cortex (New York, N.Y. : 1991) Aug 2022Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like...
Atypical, but Not Typical, Antipsychotic Drugs Reduce Hypersynchronized Prefrontal-Hippocampal Circuits during Psychosis-Like States in Mice: Contribution of 5-HT2A and 5-HT1A Receptors.
Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.
Topics: Animals; Antipsychotic Agents; Clozapine; Haloperidol; Hippocampus; Mice; Phencyclidine; Prefrontal Cortex; Psychotic Disorders; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Risperidone; Serotonin Antagonists
PubMed: 34875009
DOI: 10.1093/cercor/bhab427 -
Seminars in Cell & Developmental Biology Jan 2022Few reports are found in the literature regarding the role of planar cell polarity (PCP) in supporting spermatogenesis in the testis. Yet morphological studies reported... (Review)
Review
Few reports are found in the literature regarding the role of planar cell polarity (PCP) in supporting spermatogenesis in the testis. Yet morphological studies reported decades earlier have illustrated the directional alignment of polarized developing spermatids, most notably step 17-19 spermatids in stage V-early VIII tubules in the testis, across the plane of the epithelium in seminiferous tubules of adult rats. Such morphological features have unequivocally demonstrated the presence of PCP in developing spermatids, analogous to the PCP noted in hair cells of the cochlea in mammals. Emerging evidence in recent years has shown that Sertoli and germ cells express numerous PCP proteins, mostly notably, the core PCP proteins, PCP effectors and PCP signaling proteins. In this review, we discuss recent findings in the field regarding the two core PCP protein complexes, namely the Van Gogh-like 2 (Vangl2)/Prickle (Pk) complex and the Frizzled (Fzd)/Dishevelled (Dvl) complex. These findings have illustrated that these PCP proteins exert their regulatory role to support spermatogenesis through changes in the organization of actin and microtubule (MT) cytoskeletons in Sertoli cells. For instance, these PCP proteins confer PCP to developing spermatids. As such, developing haploid spermatids can be aligned and orderly packed within the limited space of the seminiferous tubules in the testes for the production of sperm via spermatogenesis. Thus, each adult male in the mouse, rat or human can produce an upward of 30, 50 or 300 million spermatozoa on a daily basis, respectively, throughout the adulthood. We also highlight critical areas of research that deserve attention in future studies. We also provide a hypothetical model by which PCP proteins support spermatogenesis based on recent studies in the testis. It is conceivable that the hypothetical model shown here will be updated as more data become available in future years, but this information can serve as the framework by investigators to unravel the role of PCP in spermatogenesis.
Topics: Animals; Cell Polarity; Cytoskeleton; Drosophila; Male; Receptors, Phencyclidine; Spermatogenesis; Testis
PubMed: 34059418
DOI: 10.1016/j.semcdb.2021.04.008 -
Journal of Pharmaceutical and... Sep 2023Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after...
Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after entry into the body. The parent nucleus of phencyclidine-type substances is arylcyclohexylamine, which is easy to modify; therefore, abusers and dealers can readily synthesize substitutes beyond the drug control catalog. An urgent need exists to establish screening methods for phencyclidine-type substances to provide technical support for abuse monitoring. In this study, 20 mg of hair was pulverized in 500 mL of methanol containing 0.5 ng/mL PCP-d. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) operating in the multiple reaction monitoring mode. Phencyclidine-type substances were separated in 13 min on a biphenyl column using a mobile phase gradient composed of A (water, formic acid 0.1%, acetonitrile 5%, 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.25-2 pg/mg and lower limit of quantitation: 0.5-4 pg/mg), linearity (R > 0.994), accuracy, and precision (< 20%), and a dilution effect. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phencyclidine-type substances in hair from 87 authentic forensic cases. Nine analytes were detected: ketamine (10.3-26211.3 pg/mg), 2-F-2-oxo-PCE (11.5-4034.9 pg/mg), 2-FDCK (14.0-43290.2 pg/mg), 2-BrDCK (10.6-21170.0 pg/mg), nor2-FDCK (10.1-16767.4 pg/mg), tiletamine (10.1-3250.8 pg/mg), O-PCE (43.3-166.1 pg/mg), DCK (10.2-90.4 pg/mg), and norDCK (24.9-103.0 pg/mg).
Topics: Phencyclidine; Chromatography, High Pressure Liquid; Chromatography, Liquid; Tandem Mass Spectrometry; Hair; Acetonitriles
PubMed: 37480824
DOI: 10.1016/j.jpba.2023.115577