-
Frontiers in Cellular Neuroscience 2023N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist...
N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.
PubMed: 37066076
DOI: 10.3389/fncel.2023.1152248 -
The International Journal of... Sep 2022Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal...
BACKGROUND
Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.
METHODS
We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.
RESULTS
Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.
CONCLUSIONS
ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.
Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Guanidines; Isoquinolines; Male; Memory Disorders; Methamphetamine; Mice; Mice, Knockout; Phencyclidine; Rats; Rats, Transgenic; Receptors, Serotonin; Scopolamine; Serotonin; Serotonin Antagonists
PubMed: 35882205
DOI: 10.1093/ijnp/pyac041 -
Forensic Chemistry (Amsterdam,... Jul 2023With the sustained prevalence and introduction of new emerging drugs throughout the world there is a need for continued development and maintenance of platforms that...
With the sustained prevalence and introduction of new emerging drugs throughout the world there is a need for continued development and maintenance of platforms that enable rapid identification and characterization of unknown compounds. To complement existing efforts, a collaborative platform between the National Institute of Standards and Technology (NIST) and practicing forensic agencies is being deployed which enables laboratories to leverage techniques and expertise that may not exist at their facilities. Using this approach, unknown compounds are identified and characterized using a suite of analytical tools to obtain (1) a rapid preliminary identification followed by (2) a more complete characterization and confirmation of the preliminary identification. To demonstrate this platform, the characterization of three previously unreported analogs of phencyclidine (PCP) - POXP, PTHP, and P2AP - are described. A preliminary identification of the three substances was obtained using direct analysis in real time mass spectrometry (DART-MS) with confirmation by nuclear magnetic resonance (NMR) spectroscopy, gas chromatography mass spectrometry (GC-MS) and gas chromatography flame ionization detection (GC-FID).
PubMed: 38716063
DOI: 10.1016/j.forc.2023.100505 -
Cureus May 2023Recreational drug use is a significant public health concern in various countries. It is well understood that usage of psychedelics/hallucinogens, such as lysergic acid...
Recreational drug use is a significant public health concern in various countries. It is well understood that usage of psychedelics/hallucinogens, such as lysergic acid diethylamide (LSD), ecstasy, phencyclidine (PCP), and psilocybin-containing mushrooms, has increased significantly over the last few decades, particularly in adolescents and young adults, yet the effects of these recreational drugs are poorly understood. Psilocybin has recently been studied as an alternative to traditional antidepressant therapies with potentially benign side effects. Here, we present the case of a 48-year-old male with a past medical history of attention-deficit/hyperactivity disorder on lisdexamfetamine who presented after a syncopal episode witnessed by his wife at home. He was found to be in ventricular fibrillation and subsequently had an extensive workup with cardiac magnetic resonance imaging (MRI), ischemic evaluation, and electrophysiology, which were unrevealing. He then received an automatic implantable cardiac defibrillator and was incidentally found to have hereditary hemochromatosis on outpatient follow-up. His polypharmacy may have potentially led to catecholamine release, leading to ventricular arrhythmia.
PubMed: 37288212
DOI: 10.7759/cureus.38669 -
Pharmaceuticals (Basel, Switzerland) Nov 2022Ketamine, also called 'K-powder' by abusers, an analog of phencyclidine, primarily acts as an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, therapeutically...
Ketamine, also called 'K-powder' by abusers, an analog of phencyclidine, primarily acts as an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, therapeutically used as an anesthetic agent. Ketamine also stimulates the limbic system, inducing hallucinations and dissociative effects. At sub-anesthetic doses, ketamine also displays hallucinatory and dissociative properties, but not loss of consciousness. These behavioral consequences have elicited its recreational use worldwide, mainly at rave parties. Ketamine is generally a drug of choice among teenagers and young adults; however, the harmful consequences of its recreational use on adolescent central nervous systems are poorly explored. Thus, the aim of the present study was to characterize the behavioral and biochemical consequences induced by one binge-like cycle of ketamine during the early withdrawal period in adolescent female rats. Adolescent female Wistar rats ( = 20) received intraperitoneally administered ketamine (10 mg/kg/day) for 3 consecutive days. Twenty-four hours after the last administration of ketamine, animals were submitted to behavioral tests in an open field, elevated plus-maze, and forced swimming test. Then, animals were intranasally anesthetized with 2% isoflurane and euthanized to collect prefrontal cortex and hippocampus to assess lipid peroxidation, antioxidant capacity against peroxyl radicals, reactive oxygen species, reduced glutathione, and brain-derived neurotrophic factor (BDNF) levels. Our results found that 24 h after recreational ketamine use, emotional behavior disabilities, such as anxiety- and depression-like profiles, were detected. In addition, spontaneous ambulation was reduced. These negative behavioral phenotypes were associated with evidence of oxidative stress on the prefrontal cortex and hippocampus.
PubMed: 36355545
DOI: 10.3390/ph15111373 -
Cells Mar 2022Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this...
Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.
Topics: Animals; Antipsychotic Agents; Clozapine; Hippocampus; Neuronal Plasticity; Prefrontal Cortex; Rats; Rats, Wistar; Risperidone
PubMed: 35406745
DOI: 10.3390/cells11071181 -
Cureus Nov 2022Most patients with advanced cancer experience debilitating pain, which significantly affects their quality of life and has both physical and psychological implications....
Most patients with advanced cancer experience debilitating pain, which significantly affects their quality of life and has both physical and psychological implications. Opioids have been the mainstay of treatment for chronic cancer pain, but some people develop serious adverse effects or may become refractory to opioid use. There is always a need and search for alternative non-opioid analgesics with an acceptable safety profile, and one such drug is ketamine. In this era of evolving analgesic therapeutics, ketamine has been noted to have favourable results. Ketamine, a phencyclidine analogue, is an N-methyl-D-aspartate antagonist (NMDA), and it has been shown to have an analgesic effect at sub-anaesthetic doses by blocking NMDA-induced pain sensitization and enhancing opioid receptor sensitization. This is a case report of a 46-year-old Indian female with recurrent metastatic adenocarcinoma endometrium (International Federation of Obstetrics and Gynecology (FIGO) Grade II) involving the vaginal vault, rectum, and adrenal glands, along with para-rectal, bilateral iliac, and retroperitoneal nodal metastases, in which ketamine infusion was used successfully to alleviate the pain that was initially not controlled with an incremental dose of opioids. The patient presented with progressive pain in the peri-anal region, rated 8/10 on the Numerical Pain Rating Scale (NRS), following which she was treated with escalating doses of intravenous (IV) fentanyl, but with little to no relief. In view of the patient's opioid-resistant pain, she was started on a low-dose ketamine IV infusion (50 mg in 50 ml of 0.9% NS) as "burst therapy," at infusion rates of 0.02 mg/kg/hr-0.08 mg/kg/hr, with adequate pain relief occurring at 0.08 mg/kg/hr. Literature suggests weight-based dosing of ketamine ranging from 0.06 mg/kg/hr to 0.8 mg/kg/hr was previously used to achieve satisfactory results. In this patient, even lower doses were effectively used to achieve optimum long-term analgesia, cause an upliftment in the patient's overall mood and quality of life, and cause a significant reduction in opioid usage. However, further research is required to assess the efficacy of ketamine at such doses and its effect on opioid consumption. This case report will promote further study regarding optimum IV ketamine dosing and administration in the management of opioid-refractory pain in cancer patients, especially in the Indian population.
PubMed: 36545179
DOI: 10.7759/cureus.31662 -
Biomarkers in Neuropsychiatry Jun 2020Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational...
Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-d-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. PCP led to significant increases of ASSR that were further increased in SRKO-/-, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.
PubMed: 34308374
DOI: 10.1016/j.bionps.2020.100019 -
Physiology & Behavior May 2023Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with...
Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.
Topics: Rats; Female; Animals; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Cognition Disorders; Cognition; Disease Models, Animal
PubMed: 36781093
DOI: 10.1016/j.physbeh.2023.114117 -
Drug and Alcohol Dependence Nov 2021Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine,...
BACKGROUND
Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine, are limited. This study assessed the reliability and applicability of DSM-based diagnostic criteria for ketamine use disorder.
METHODS
Participants who used ecstasy were recruited through the Tri-City Study of Club Drug Use, Abuse, and Dependence in St. Louis, Miami, and Sydney. Those who reported using ketamine (lifetime use >5 times) were included in these analyses (n = 205). Participants were interviewed using the computerized Substance Abuse Module for Club Drugs (CD-SAM) at baseline and 7 days later for the reliability of diagnoses and individual diagnostic criteria.
RESULTS
Overall, 29.3% met DSM-5 adopted criteria for ketamine use disorder at Time 1. Moderate to excellent test-retest reliability was observed consistently across study sites for any ketamine use disorder (κ = 0.57, Y = 0.61) and severe ketamine use disorder (κ = 0.62, Y = 0.79). Continued use of ketamine despite knowledge of physical or psychological problems was the most frequently endorsed individual criterion (59.0%), followed by reported withdrawal (30.2%) and physically hazardous use (29.8%). All individual criteria had acceptable reliability estimates (κ ≥ 0.41).
CONCLUSIONS
Diagnoses of ketamine use disorder can be reliably evaluated using this fully structured diagnostic instrument's questions and algorithm. Ketamine-related withdrawal among people who use ketamine should be re-evaluated. Considering that after-effects of this dissociative anesthetic can last for many hours, it is important to explore a different timeframe for possible withdrawal effects.
Topics: Cross-Cultural Comparison; Diagnostic and Statistical Manual of Mental Disorders; Humans; Ketamine; Reproducibility of Results; Substance-Related Disorders
PubMed: 34592704
DOI: 10.1016/j.drugalcdep.2021.109056