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Neurobiology of Disease Jan 2023Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is...
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.
Topics: Mice; Animals; Cannabinoids; Cyclin-Dependent Kinase 5; Psychotic Disorders; Schizophrenia; Phencyclidine; Cannabinoid Receptor Agonists; Disks Large Homolog 4 Protein
PubMed: 36473591
DOI: 10.1016/j.nbd.2022.105942 -
American Journal of Perinatology May 2024The U.S. opioid epidemic has been characterized by increases in opioid misuse, overdose deaths, and neonatal opioid withdrawal syndrome. Research suggests that...
OBJECTIVE
The U.S. opioid epidemic has been characterized by increases in opioid misuse, overdose deaths, and neonatal opioid withdrawal syndrome. Research suggests that marijuana legalization has contributed to decreased use of opiates, although many studies had methodological weaknesses and failed to address the pregnant population. Implementation of medical cannabis laws has the potential to reduce maternal opioid use and, therefore, neonatal exposure to the drugs. This study aimed to examine the association between Oklahoma's implementation of state medical marijuana laws and the neonatal exposure to opioids.
STUDY DESIGN
Electronic medical records at two sites (Oklahoma City and Lawton) were searched for results of cord, urine, and meconium screens to detect amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, opiates, phencyclidine, and tetrahydrocannabinol (THC). Two study periods were compared: 19 months before Oklahoma's medical marijuana law took effect and 19 months after legalization began.
RESULTS
A total of 16,804 babies were born alive at the two sites during the study period. The rate of positive THC tests per 1,000 liveborn infants significantly increased from 16.2 per 1,000 during the prelaw period to 22.2 per 1,000 during the postlaw period ( = 0.004). Neonatal opioid exposure incidence showed a nonsignificant decrease from 7.6 positive tests per 1,000 liveborn infants to 6.8 per 1,000 from prelaw to postlaw period ( = 0.542). The number of positive tests for THC and concomitant use of opioids doubled from the prelaw period ( = 4) to postlaw ( = 9), but there were too few cases for statistical significance. Infants at the more rural site had significantly higher rates for amphetamines, benzodiazepines, and THC, with a trend toward higher rates for opiates.
CONCLUSION
Marijuana legalization was related to significant increases in positive test rates for THC, but no significant change/association was noted for neonatal exposure to opioids.
KEY POINTS
· Prior studies have not examined neonatal exposure to opioids following marijuana legalization.. · Oklahoma's new law led to higher neonatal marijuana exposure.. · Legalization of medical marijuana did not change Oklahoma's neonatal opioid positivity rate..
Topics: Humans; Oklahoma; Infant, Newborn; Female; Pregnancy; Medical Marijuana; Adult; Analgesics, Opioid; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Male; Dronabinol; Meconium; Substance Abuse Detection; Legislation, Drug; Young Adult
PubMed: 36452967
DOI: 10.1055/a-1990-8311 -
Advances in Clinical Chemistry 2022Traditional clinical toxicology involves the analysis of patient urine samples by immunoassays designed to detect opiates/opioids, amphetamine/methamphetamine,... (Review)
Review
Traditional clinical toxicology involves the analysis of patient urine samples by immunoassays designed to detect opiates/opioids, amphetamine/methamphetamine, benzodiazepines, barbiturates, cocaine metabolite and tetrahydrocannabinol. Expanded drug screens may also include assays for oxycodone, buprenorphine, methadone, 6-monoacetylmorphine, phencyclidine and fentanyl. Patient samples that are positive are commonly reflexed to be run on a liquid chromatography-tandem mass spectrometry confirmatory assay, as are samples that are negative for drugs that are prescribed to the patient. These mass spectrometry assays are targeted and so only detect the drugs or drug metabolites that they were designed to detect. With the explosion of new psychoactive substances in the past decade, it has become necessary for clinical laboratories to reevaluate traditional targeted drug screening approaches. The utility of high-resolution mass spectrometry in this arena has been recognized and this review will discuss the traditional approach to, and the recent advances in clinical toxicology including data collection and interrogation strategies for new psychoactive substances using high-resolution mass spectrometry (HRMS). Various modes of data processing techniques including targeted analysis, suspect screening and non-targeted analysis will also be described using HRMS. Several published methods will be described to demonstrate the utility of various data acquisition and processing techniques using HRMS in NPS analysis specifically.
Topics: Humans; Substance Abuse Detection; Mass Spectrometry; Dronabinol; Methadone; Amphetamine
PubMed: 36427911
DOI: 10.1016/bs.acc.2022.08.001 -
The American Journal of Drug and... Mar 2023Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental...
Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental disorders. However, the use of ketamine and/or its analogues, as well as combinations with other drugs, can be fatal. To outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues, as reported in the scientific literature. To investigate if ketamine is safe in a therapeutic context, particularly in its use as an antidepressant. Electronic searches were performed on three medical databases. Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included. After the removal of duplicates, title analysis and full-text analysis, 34 articles were included in this review. Eighteen articles described fatal cases and sixteen described overdoses. Poly-substance use was mentioned in 53% of the selected articles. Most cases were males and the ages varied from two to 65 years old. A total of 312 overdose cases and 138 deaths were reported. In both death reports and overdose cases, ketamine was preponderant: 89.1% and 79%, respectively. No cases of overdose or death related to the use of ketamine as an antidepressant in a therapeutic setting were found; most of the deaths occurred in the circumstances of polydrug use and overdoses left no sequelae. There is legitimate concern about the risks involving the use of ketamine and its analogues, especially in recreational settings. On the other hand, ketamine as medicine is considered safe and it is listed as an essential medicine by the World Health Organization. Although clinicians must remain vigilant, this should not deter appropriate prescription.
Topics: Male; Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Female; Ketamine; Drug Overdose; Substance-Related Disorders; Analgesics, Opioid
PubMed: 36410032
DOI: 10.1080/00952990.2022.2132506 -
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 -
Journal of Neurosurgery. Case Lessons Mar 2022The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder...
BACKGROUND
The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder (SUD) becomes a chronic, lifelong condition. Health system-level data in recent years indicate a significant increase in patients with coexisting SUD and degenerative disc disease, representing an emerging population. A retrospective electronic medical record review identified seven patients with SUD who underwent elective spine surgery by orthopedic or neurosurgical staff from 2012 to 2021. The authors present two of these illustrative cases and a framework that can be used in the treatment of similar patients.
OBSERVATIONS
Substances used included opioids, benzodiazepines, barbiturates, cocaine, methamphetamines, hallucinogens, lysergic acid diethylamide, phencyclidine, and cannabis. All were abstaining from drug use preoperatively, with four patients in a formal treatment program. Five patients were discharged with an opioid prescription, and two patients deferred opioids. Three experienced a relapse of substance use within 1 year. All patients presented for follow-up, although two required additional contact for follow-up compliance.
LESSONS
Perioperative protocols focusing on patient-led care plans, pain control, communication with medication for opioid use disorder providers, family and social support, and specific indicators of possible poor results can contribute to better outcomes for care challenges associated with these diagnoses.
PubMed: 36273856
DOI: 10.3171/CASE21656 -
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 -
European Journal of Pharmacology Nov 2022N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR signalling can...
N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR signalling can be enhanced by increasing extracellular levels of the NMDAR co-agonist glycine through inhibition of its transporter (GlyT1). This may be one option to improve cognitive deficits or negative symptoms of schizophrenia. In this preclinical study, we aimed at investigating effects of the GlyT1-inhibitor Bitopertin on cognition, social function and motivation. Central target engagement was assessed by Bitopertin-induced changes in glycine levels in rats' cerebrospinal fluid (CSF) and prefrontal cortex (PFC). Behavioural effects of Bitopertin on recognition memory were evaluated using a social-recognition test in rats, while its effects on working memory were tested in a spontaneous alternation task in mice pre-treated with the NMDAR antagonist MK-801. Bitopertin was further investigated using a social interaction test in rats pre-treated with the NMDAR antagonist phencyclidine, and the effects on effortful motivation were explored in progressive ratio tasks in rats. Results show that Bitopertin increased glycine levels in CSF and PFC. Moreover, it enhanced recognition memory and reduced MK-801-induced working memory deficits. By contrast, Bitopertin had no significant effects on PCP-induced social interaction deficits, and it did not alter effort-related responding. Collectively, our data demonstrate that GlyT1 inhibition by Bitopertin increased CSF and extracellular glycine levels and advocated for pro-cognitive effects of GlyT1 inhibition both in intact and NMDAR antagonists-pre-treated rodents. Together, these findings support the use of GlyT1-inhibitors for the treatment of cognitive symptoms in pathologies characterized by NMDR hypofunction, such as schizophrenia.
Topics: Animals; Mice; Rats; Glycine Plasma Membrane Transport Proteins; Dizocilpine Maleate; Rodentia; Receptors, N-Methyl-D-Aspartate; Glycine; Cognition
PubMed: 36183855
DOI: 10.1016/j.ejphar.2022.175306 -
Biochemical and Biophysical Research... Nov 2022Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP)...
Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP) generates metabolites that modulate glutamatergic systems such as kynurenic acid (KA), quinolinic acid (QA), and xanthurenic acid (XA). Kynurenine 3-monooxygenase (KMO) metabolizes KYN to 3-hydroxykynurenine (3-HK), an upstream metabolite of QA and XA. Clinical studies have reported lower KMO mRNA and higher KA levels in the postmortem brains of patients with schizophrenia and exacerbation of symptoms in schizophrenia by PCP. However, the association between KMO deficiency and PCP remains elusive. Here, we demonstrated that a non-effective dose of PCP induced impairment of prepulse inhibition (PPI) in KMO KO mice. KA levels were increased in the prefrontal cortex (PFC) and hippocampus (HIP) of KMO KO mice, but 3-HK levels were decreased. In wild-type C57BL/6 N mice, the PPI impairment induced by PCP is exacerbated by KA, while attenuated by 3-HK, QA and XA. Taken together, KMO KO mice were vulnerable to the PPI impairment induced by PCP through an increase in KA and a decrease in 3-HK, suggesting that an increase in the ratio of KA to 3-HK (QA and XA) may play an important role in the pathophysiology of schizophrenia.
Topics: Animals; Kynurenic Acid; Kynurenine; Kynurenine 3-Monooxygenase; Mice; Mice, Inbred C57BL; Phencyclidine; Prepulse Inhibition; Quinolinic Acid; RNA, Messenger
PubMed: 36116377
DOI: 10.1016/j.bbrc.2022.09.003 -
British Journal of Pharmacology Jan 2023Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an...
BACKGROUND AND PURPOSE
Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis.
KEY RESULTS
Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway.
CONCLUSION AND IMPLICATIONS
This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
Topics: Animals; Rats; Male; Phencyclidine; Schizophrenia; Fingolimod Hydrochloride; Brain-Derived Neurotrophic Factor; Rats, Sprague-Dawley; Cognitive Dysfunction; Cytokines; Disease Models, Animal
PubMed: 36106568
DOI: 10.1111/bph.15954