Psychedelic Drugs, Hallucinogens, and Schizophrenia Lecture Notes PDF

What are psychedelic drugs? Psychedelic drug: psychoactive substance causing perceptual changes, visual hallucinations, altered awareness of the mind and body, and cognitive distortions, without producing a state of toxic delirium Many are synthesized by plants or are based on plant-derived...

What are psychedelic drugs? Psychedelic drug: psychoactive substance causing perceptual changes, visual hallucinations, altered awareness of the mind and body, and cognitive distortions, without producing a state of toxic delirium Many are synthesized by plants or are based on plant-derived compounds Lysergic acid diethylamide (LSD), mescaline, psilocybin, bufotenine, dimethyltryptamine (DMT), 5-methoxy-dimethyltryptamine (5-MeO- DMT), salvinorin (Salvia), and ibogaine  Mescaline Mescaline: in peyote cactus; top is cut off and dried – called mescal button or peyote button; chewed raw or cooked Native Americans use peyote for religious and healing rituals Pure mescaline can be synthesised; became popular in the 1960s Public Domain, https://commons.wikimedia.org/w/index.php?curid=500120  Psilocybin Psilocybin: alkaloid from several mushroom species (magic mushrooms); dried and eaten raw or made into tea After ingestion psilocybin is converted to psilocin, the psychoactive agent Use goes back thousands of years in several parts of the world Harvard Marsh Chapel Experiment: Walter N. Pahnke, Timothy Leary, Richard Alpert Psilocybin given to graduate students at Harvard Divinity School Elicited ‘profound’ religious experiences By Arp - This image is Image Number 6514 at Mushroom Observer, a source for mycological images., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=120663 35  DMT and ayahuasca Dimethyltryptamine (DMT), 5-MeO-DMT, and bufotenine are found in plants indigenous to South America When smoked or snorted DMT can produce a brief (about 30 minutes) but intense hallucinatory experience; orally active synthetic DMT analogs are available Native peoples in the Amazon make a hallucinogenic drink called ayahuasca from plants containing DMT or alkaloids (β-carbolines) that inhibit MAO activity Use of ayahuasca dates to the pre-Columbian era, used in spiritual/religious ceremonies  Lysergic acid diethylamide Lysergic acid diethylamide (LSD): synthetic; based on alkaloids in ergot, a parasitic fungus on rye (1938) Long-term poisoning causes ergotism: convulsions and gangrene Ergot very toxic: produces powerful contractions of the uterus that can help trigger labor and reduce post-birth uterine hemorrhage LSD first synthesised in search for analeptic drugs – circulatory and respiratory stimulants https://aokin.de/products/mycotoxins/ergot_alkaloids/?lang=en By G. Barger - Ergot and Ergotism, Public Domain, https://commons.wikimedia.org/w/index.php?curid=12608659  Lysergic acid diethylamide Some researchers tried LSD as a tool in psychotherapy or psychoanalysis Psycholytic therapy: drug-induced “psycholysis,” meaning psychic loosening or opening Psychedelic therapy: patient was given a high dose of LSD in hopes of gaining insight into his or her problems The CIA investigated LSD as a psychological weapon (illegal human experimentation in Project MKUltra) LSD use exploded with the hippie culture in the 1960s; cultural backlash, as well as anecdotal and scientific reports of LSD-related problems  Ibogaine Ibogaine: from bark and roots of a west African shrub; chewed or made into a powder Low doses are psychostimulant – increasing energy, reducing hunger, producing a euphoric feeling; high doses produce psychedelic effect Under controlled conditions it can have beneficial effects in counteracting opioid withdrawal symptoms and drug craving https://www.theguardian.com/society/2023/jan/23/ibogaine-iboga-drug-addiction- psychedelic-gabon  Salvinorin A and ketocyclazocine Salvinorin A: psychoactive ingredient in Salvia divinorum (sage of the diviners), a mint family plant native to Mexico; historically used in religious rituals by Mazatec shamans Leaves can be chewed or extracts made and absorbed through the mouth or smoked; salvinorin A is inactivated in the GI tract Produces vivid hallucinations, out-of-body experiences, and other feelings resembling those produced by other hallucinogens Ketocyclazocine has a similar mechanism of action, can induce sleepiness, analgesia, and hallucinations Key historical events in research on the classic psychedelic drugs mescaline, psilocybin, and LSD  Basic pharmacology of psychedelic drugs Potency varies widely: from LSD (most potent) to mescaline and ibogaine Effects of drugs taken orally begin 30 – 90 minutes after ingestion; effects last from minutes (DMT and Salvia) to many hours (ibogaine) “Trip:” state of intoxication; four phases: onset, plateau, peak, and comedown http://upload.medbullets.com/topic/107007/images/potency%20efficacy.jpg  Basic pharmacology of psychedelic drugs Users experience vivid visual hallucinations, slowing of the sense of time, feelings of depersonalisation, strong emotional reactions, disruption of logical thought Synesthesia: crossing-over of sensations e.g., colors are “heard” A trip may be experienced either as mystical and spiritually enlightening (a “good trip”) or as disturbing and frightening (a “bad trip”)  Basic pharmacology of psychedelic drugs Altered States of Consciousness (ASC) rating scale has five dimensions: oceanic boundlessness, ego-disintegration anxiety, visionary restructuralisation, reduced vigilance, auditory alterations Divided into subdimensions to provide more detailed information on drug-induced reactions Physiological responses: reflect activation of sympathetic nervous system; dizziness, nausea, and vomiting (more likely with mushrooms and peyote) Subjective effects of psilocybin using the Altered States of Consciousness (ASC) rating scale Altered States of Consciousness (ASC) rating scale has five dimensions: oceanic boundlessness, ego-disintegration anxiety, visionary restructuralisation, reduced vigilance, auditory alterations Subdimensions provide more detailed information on drug-induced reactions Physiological responses: reflect activation of sympathetic nervous system; dizziness, nausea, and vomiting (more likely with mushrooms and peyote)  Chemical structures of psychedelic drugs Serotonin-like (indolamine) molecular structure: LSD, psilocybin, psilocin, DMT, 5-MeO-DMT, ibogaine, synthetic tryptamines Indolamines are a group of monoamines (serotonin, melatonin) Catecholamine-like structure: mescaline and N- benzylphenethylamines (NBOMes; synthetic); amphetamine analogs DOM and TMA (phenethylamine psychedelics) Structures of 5-HT and the indolamine psychedelics Structures of NE and the phenethylamine psychedelics Dose-dependent stimulation of mouse head-twitch response – response to 5-HT2A activation 5-HT2A receptor underlies many hallucinogen activities Indolamine and phenethylamine hallucinogens are 5-HT2A receptor agonists (except ibogaine) 5-HT2A knockout mice and humans given the 5-HT2A antagonist ketanserin show no response to these drugs Brain imaging shows strong relationship between neocortical 5-HT2A receptor occupancy and subjective psychedelic intensity rating (seminar) Extended length of LSD trip: binding to the receptor causes it to be trapped temporarily in the binding pocket by a lid-like structure FIGURE 15.12 Relationship between the intensity of subjective psychedelic effects and neocortical 5-HT2A receptor occupancy in subjects given psilocybin Why doesn’t all 5-HT2A activation induce psychedelic responses? Distinct signalling pathways may underlie gain of psychedelic properties Secondary receptors, like D2, may also be activated and correspond to distinct effects 5-HT2A receptors may form homomers (receptor complexes with itself) and heteromers (multi-receptor complexes) that underlie distinct responses Psychedelic responses may depend on 5-HT2A complex with mGluR2, which alters second messengers  Some hallucinogens act through opioid pathways Salvinorin A and ketocyclazocine are κ-opioid receptor agonists; have little effect on 5-HT receptors Ibogaine and its metabolite noribogaine have very low affinity for the 5-HT2A receptor; partial agonists at κ-opioid and μ-opioid receptors; NMDA receptor antagonist; inhibit 5-HT and DA reuptake  Neurobiology of psychedelic drugs A key component of the neural circuitry is a “trigger population” of glutamatergic pyramidal neurons in the PFC that is activated by stimulation of 5-HT2A, AMPA, and NMDA receptors Trigger population activity initiates neural cascade This disrupts a cortico-striatal-thalamo-cortical loop, leading to decreased gating of sensory and cognitive input from subcortical to cortical areas Subjective and cognitive distortions resulting in a ‘trip’  Simplified model of indolamine and phenethylamine cellular mechanisms Cortex is organised in layers Cell bodies in layers: Tend to receive inputs from identified brain regions Tend to send outputs to identified regions Simplified model of indolamine and phenethylamine cellular mechanisms ‘Trigger’ neurons  Other mechanisms of hallucinogens Reduced activity within the default mode network (DMN) DMN associated with wakeful rest, e.g., daydreaming Functional connectivity changes that decrease thalamic sensory gating and integrative cortical information processing, and increase cortical sensory processing Alves PN, Foulon C, Karolis V, Bzdok D, Margulies DS, Volle E, Thiebaut de Schotten M. An improved neuroanatomical model of the default-mode network reconciles previous neuroimaging and neuropathological findings. Commun Biol. 2019 Oct 10;2:370. doi: 10.1038/s42003-019-0611-3.  Medical uses of psychedelics LSD was explored as a treatment for alcohol dependence prior to US labelling of psychedelics as Schedule I in 1970 (highly addictive/no medical use) Recent research shows long-lasting psychological impacts (sometimes beneficial) of a single psychedelic drug exposure in healthy participants (seminar) Psychedelic drug therapy: the peak experience is the desired subjective state; may be followed by an afterglow lasting days to weeks; being explored to treat depression, OCD, PTSD, etc. Two- and 14-month responses of participants to their experience with a single dose of psilocybin (Psil) or methylphenidate (MPD) Hypothesised time course of the therapeutic effects elicited by psychedelic drugs Rapid structural changes produced by serotonergic psychedelic drugs The best predictor of a good therapeutic response appears to be the intensity of the psychedelic experience Hypothesis: antidepressant actions of classical psychedelics are mediated by rapid glutamate-dependent neural plasticity  Adverse reactions to psychedelics Psychedelics are not dependence forming or addictive for most users; a few meet the DSM-V diagnostic criteria for other hallucinogen use disorder Most 5-HT–acting psychedelic drugs produce tolerance, repeated use linked to 5-HT2A receptor down-regulation Adverse effects include bad trips, flashbacks, and hallucinogen persisting perception disorder (HPPD)  Adverse reactions to psychedelics High doses of a psychedelic can cause toxic reactions involving psychiatric and/or somatic symptoms (think of why plants evolved such compounds!) Psychiatric symptoms resemble those of acutely psychotic patients; more likely with existing psychiatric disorder or preexisting vulnerability for developing psychosis NBOMes (synthetics) are responsible for the most severe reactions  PCP and Ketamine Phencyclidine (PCP) and ketamine are dissociative anesthetics PCP developed in the 1950s as anesthetic but had unusual properties and adverse side effects (1960s, street names “angel dust”, “hog”) Ketamine developed as a safer alternative; used as anesthetic for children and veterinary use Ketamine is often stolen from hospitals and vet clinics as injectable liquid and evaporated to form a powder “K,” “special K,” or “cat Valium” Anaesthetic-range doses produce dissociated state called the “K-hole”  Subjective experiences reported by ketamine users Sensations of light coming through the body and/or of colorful visions Complete loss of time sense Bizarre distortions of body shape or size Altered perception of body consistency (e.g., feeling as though one is made of a strange material such as rubber, plastic, or wood) Sensations of floating or hovering weightlessly in space Feelings of leaving one’s body Sudden insights into the mysteries of existence or of the self Experiences of being “at one” with the universe Visions of spiritual or supernatural beings P. J. Dalgarno and D. Shewan 1996. J Psychoactive Drugs 28: 191–199.  Pharmacology of PCP and ketamine PCP and ketamine are uncompetitive NMDA antagonists – binding site in receptor’s channel, blocking ion flow Competitive: competes with ligand at ligand binding site Noncompetitive: binds to target (allosteric or active) site with or without ligand binding Uncompetitive: requires ligand binding to access target site The drug molecule remains trapped in the channel even after the agonist (glutamate) dissociates from its binding site and the channel closes The NMDA receptor blockade on cortical GABAergic interneurons increases cortical glutamate release FIGURE 15.19 Proposed mechanism of PCP- or ketamine-induced enhancement of cortical glutamate release  PCP and ketamine models of schizophrenia LSD model of schizophrenia: researchers argued for similar symptoms Distinctions between hallucinations: PCP/ketamine primarily visual hallucinations, schizophrenia primarily auditory hallucinations Psychedelics do not reproduce negative symptoms of speech, affect, and social withdrawal PCP/ketamine models of schizophrenia: high doses produce similar symptoms – disordered thought, delusions, motor disturbances, and negative symptoms Glutamate hypothesis of schizophrenia: hypoactivity of the glutamatergic system, particularly with respect to NMDA receptor signaling, is a key factor Supported by reduced NMDA receptor in post-mortem analysis of brains of schizophrenic patients  Recreational use of PCP and ketamine Rodents and non-human primates will self-administer PCP and ketamine, demonstrating the reinforcing properties Both activate midbrain DA cell firing and stimulate DA release in the dorsal striatum, NAc, and PFC In human volunteers without prior exposure to ketamine, researchers found dose-dependent increases in drug liking and desire for more drug IV ketamine administration produces dose-dependent rewarding effects in humans Low dose > high dose  Other uncompetitive NMDA receptor antagonists Dextromethorphan: common in OTC cold medications, is an antitussive, or cough suppressant Methoxetamine (“Mexxy,” “MXE,” or “special M”) – analog of ketamine but effects last longer PCP and ketamine analogs synthesised to avoid positive drug tests; have substantial toxic effects and fatalities 4-F-PCP, 4-keto-PCP, 4-methoxy-PCP, 3-methoxy-PCP, and 2-oxo-PCE  Getting high on cough syrup Dextromethorphan metabolises to dextrorphan, thought to be the psychoactive agent (“Skittles”, “Robo”) Extracts from cough syrup are repackaged as pills or powder; available on the internet – may be called ecstasy; effects resemble those produced by classical psychedelic drugs Repeated use can lead to dependence, withdrawal, and toxic responses Therapeutic uses: treating pseudobulbar affect and depression Dextromethorphan produces similar subjective effects to classical psychedelics  Chronic use of PCP and ketamine PCP induces ΔFosB expression in NAc, leading to addiction Chronic use of ketamine or PCP can lead to urological symptoms, GI disturbances, memory deficits and other cognitive dysfunction, gray and white matter abnormalities Long-term users may develop psychosis similar to schizophrenia Therapeutic uses: ketamine is given for immediate relief of depression, before SSRIs take effect; and as a non-opioid analgesic for acute and chronic pain conditions  Cannabis exhibits properties of multiple drug classes Stimulant effects: alert, energetic, elevated mood Depressant effects: relaxation Marijuana may induce hallucinogen-like effects (portion of plant with significant tetrahydrocannabinol, THC)  Cannabinoid-based medications: THC, CBD, and medical marijuana Four types of therapeutic cannabinoids: Pure synthetic THC: dronabinol (Marinol), nabilone (Cesamet); enhance appetite or combat nausea Cannabis extracts containing both THC and CBD: nabiximols (Sativex) neuropathic pain, muscle spasticity in MS CBD-only extracts: Epidiolex reduce seizures in pediatric epilepsy Medical marijuana: treating a variety of conditions CBD-containing preparations are also available over the counter  Cannabis consumption produces a dose-dependent state of intoxication Subjective and behavioral effects of marijuana use can be separated into four stages: the “buzz,” the “high,” being “stoned,” and the “come-down” Physical responses include increased heart rate and blood pressure, increased hunger Effects of cannabinoid use vary depending on dose, frequency of use, characteristics of the user, the setting in which use occurs, and expectations  Cannabis consumption produces a dose-dependent state of intoxication Effects of marijuana are at least partially mediated by CB1 receptors; intoxication can be significantly inhibited by prior treatment with rimonabant (inverse agonist of CB1) Adverse reactions: high doses can cause anxiety, transient psychotic symptoms, paranoia, violent behavior Acute toxic reaction is manifested as CNS excitation or depression, tachycardia, and GI symptoms; rarely life-threatening Reduction in the subjective and physiological effects of smoked marijuana by rimonabant pretreatment Rimonabant: CB1 cannabinoid receptor inverse agonist Also called antagonist in some literature: some antagonists are reclassified as inverse agonists when new functions are discovered Marijuana use can lead to deficits in memory and other cognitive processes Marijuana affects a variety of cognitive functions, including learning, memory, attention, impulse control, and decision making Animal studies suggest that impairment of hippocampal-dependent learning/memory tasks is related to cannabinoid effects on the glutamatergic system within this brain area Also acutely impairs performance on complex psychomotor tasks; affects driving ability, especially if combined with alcohol Estimated relationship between the driver’s blood THC concentration and the odds ratio of being in a motor vehicle accident Dip is not obviously real! Danger of interpreting ‘optimal’ doses Rewarding and reinforcing effects of cannabinoids in humans and animals THC has less reward and reinforcing properties than opioids in animal tests, with the exception of squirrel monkeys CB1 receptors are involved in the brain’s reward system and interact with the endogenous opioid systems THC is a partial agonist at the CB1 receptor; WIN55,212–2, a full agonist at the CB1 receptor, is self-administered by rodents  Acquisition of THC self-administration by squirrel monkeys Monkeys trained to press lever on fixed-ratio-10 schedule using cocaine as reinforcer Switched to saline Then given THC at two doses Monkeys immediately increase self-administration  Cannabinoid reinforcement acts through mesolimbic system Cannabinoid reinforcement is dependent on CB1 receptor-mediated activation of VTA dopaminergic cell firing and DA release in the NAc Mediated partly by presynaptic CB1 receptors on GABAergic nerve terminals that synapse on the VTA neurons – suppressing GABA- mediated inhibition of cell firing  Chronic use of cannabis can lead to the development of a cannabis use disorder (CUD) Regular cannabis users showed tolerance to the acute intoxicating effects, impairment of cognitive function, feelings of anxiety induced by higher doses, physiological changes such as tachycardia Mechanisms of CUD may include: Desensitisation and down-regulation of CB1 receptors Reduced glutamate levels in anterior cingulate cortex and striatum Impaired striatal dopaminergic functioning Withdrawal symptoms similar to nicotine These changes may partly underlie the cognitive deficits and abnormal mood and motivation observed in CUD  Chronic use of cannabis can lead to the development of a cannabis use disorder (CUD) Withdrawal symptoms are similar to those of nicotine; symptoms can be relieved with smoked or oral THC Absence of symptoms in rodent studies was due to long elimination half-life of THC When rimonabant was used to abruptly block receptors (precipitated withdrawal), withdrawal symptoms were observed Reduced DA cell firing, increased CRF release, and other changes could contribute to symptoms of cannabis withdrawal in human users.  Neurochemical changes related to acute cannabis use, chronic use and the development of cannabis use disorder, and abstinence from use Reduced DA cell firing and increased CRF release may contribute to symptoms of cannabis withdrawal in human user Withdrawal effects are greatest in first 1-2 weeks of abstinence  Long-term cannabis use Long-term cannabis use leads to impairment in many cognitive domains when assessed following 2 weeks of abstinence Persistent deficits are most likely to occur if regular, heavy cannabis use begins early in adolescence Longitudinal studies find a significant relationship between early cannabis use and later educational and/or occupational achievements Drug-related motivational changes may have a negative impact on performance in the classroom (amotivational syndrome) Personality characteristics could be a cause, not a consequence, of marijuana use  Acute and chronic effects of cannabinoid exposure on cognitive processes Acute effects (depend on task, dose, frequency of use, age of first cannabis use) Impaired verbal learning and memory Impaired working memory Impaired attention (task- and dose-dependent) Impaired inhibitory control and (to a lesser extent) other executive functions Impaired psychomotor function Chronic effects Impaired verbal learning and memory Impaired attention; attentional bias Possibly impaired psychomotor function Possibly impaired executive function (depending on frequency of use and age of onset) Recovery of function with abstinence Likely persistent effects on attention and psychomotor function Possibly persistent effects on verbal learning and memory (insufficient and mixed evidence) S. J. Broyd et al. 2016. Biol Psychiatry 79: 557–567.  Changes in brain with long-term cannabis use Lower gray matter volume in some areas – could reflect changes in dendritic arborisation and/or synaptic connectivity (brain imaging) Differential activation of some brain areas (fMRI and EEG) Chronic dosing of adolescent rodents with THC or synthetic cannabinoids results in numerous changes in the glutamatergic, GABAergic, and dopaminergic systems Altered task-dependent functional brain activity in CUD compared to controls Amy, amygdala FC, frontal cortex Hipp, hippocampus MB, midbrain MCN, mesocorticolimbic NAcc, nucleus accumbens OFC, orbitofrontal cortex PFC, prefrontal cortex Str, striatum Chronic treatment of adolescent rats with synthetic cannabinoid reduced PFC dendritic length and impaired LTP at hippocampal–PFC synapses CP-55,940: synthetic cannabinoid  Psychoses and antipsychotic medications Psychoses are conditions that result in difficulty discriminating real and not real Term introduced in 1841 for ‘psychic neurosis’ as an alternative to ‘insanity’ or ‘mania’: a neurosis meant any disturbance of the nervous system Early psychology and psychiatry were heavily influenced by understand such disturbances LSD and other psychedelics (1960s) sometimes called psychotomimetic drugs Medications are therefore termed antipsychotics, particularly for schizophrenia  Characteristics of schizophrenia Schizophrenia is a chronic psychosis; a form of psychiatric diseases known as schizophrenia spectrum, schizoaffective disorders, and other psychotic disorders Individuals demonstrate many different symptoms At this time, it can not be cured or prevented Symptoms most often begin during the late teenage years and early twenties  Sex differences in age at onset (diagnosis!) of schizophrenia Male-centric diagnoses often lead to inaccurate diagnoses in females (e.g., heart attacks) Differences in first presentation may be recognition of symptoms  Schizophrenia is a heterogeneous disorder DSM-V defines schizophrenia with delusions, hallucinations, or disorganized thought Delusions of persecution and auditory hallucinations are common Grossly disorganized or abnormal motor behavior Language, particularly speech, often disorganized or incoherent Negative symptoms: reduced emotional expression, lack of volition, social withdrawal, apathy, cognitive defects  Diagnosing schizophrenia can be challenging No two individuals show the same pattern of symptoms No single symptom occurs in every patient Symptoms increase and decrease over time Type of symptoms may change over time in one individual  Electrically induced hallucinations resemble schizophrenic delusions Stimulation of site behind temporoparietal junction triggers creepy feeling that someone is close by Arzy et al 2006 Induction of an illusory shadow person  Electrically induced hallucinations resemble schizophrenic delusions Stimulation of site behind temporoparietal junction triggers creepy feeling that someone is close by Arzy et al 2006 Induction of an illusory shadow person  Diagnosing schizophrenia can be challenging (and maybe sex-and gender-dependent!) Positive symptoms dominant: delusions and hallucinations, disorganised speech and thinking, bizarre behavior Patients tend to be older at onset, respond well to antipsychotic medication Negative symptoms dominant: reduced speech, flat affect, loss of motivation, social withdrawal Symptoms easily mistaken for other disorders (e.g., depression) Cognitive symptoms: impaired working memory, executive function, etc. Negative and cognitive symptoms are resistant to current treatments Abnormalities of brain structure and function occur in individuals with schizophrenia Brain imaging shows cerebral atrophy and ventricle enlargement Post-mortem studies: reduced brain volume due to small nerve cell somas, reduced dendritic trees and spine density Hippocampal cells disorganized Abnormal myelination and organization of white matter tracts reduces connectivity between brain regions Brain images of twins not concordant for schizophrenia Disorganization of cells in the hippocampus Abnormalities of brain structure and function occur in individuals with schizophrenia Brain function abnormalities: Reduced function of PFC (hypofrontality) – PET scans show less blood flow to the frontal cortex when performing cognitive tasks Some brain areas show more activation, other brain areas show less, than in controls Abnormalities of brain structure and function occur in individuals with schizophrenia Association between immune dysfunction and schizophrenia: Blood levels of pro-inflammatory cytokines are elevated and anti- inflammatory cytokines are reduced; levels return to normal after successful antipsychotic drug treatment. Unclear whether cytokines cause, or are a result of, the symptoms Prenatal inflammation may cause abnormal neurodevelopment that increases the risk for schizophrenia. Twin studies and risk of lifetime schizophrenia development A strong genetic component is shown by family, twin, and adoption studies; but identical twin concordance is not 100% Identification of specific genes difficult – many genes at different loci are involved; 145 loci have been identified as likely sites  Epigenetic modifications and risk for schizophrenia Early life stress produces epigenetic modifications that alter neurodevelopment Reelin, a glycoprotein secreted by neurons, guides neuron positioning during fetal brain development (neurogenesis) Also involved in adult hippocampal neurogenesis Reduced reelin expression is due to methylation of the RELN gene; could explain cell disorganization and morphological abnormalities in schizophrenic brains Genetic polymorphisms contribute to schizophrenia risk Mutations of gene Disrupted in schizophrenia 1 (DISC1) gene may contribute to risk of schizophrenia DISC1 codes for proteins essential in neural development and can be disrupted by a chromosome translocation Roles include cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth Various DISC1 polymorphisms have other clinical implications (autism, bipolar disorder)  Interaction of genetics and development Genetic vulnerability may increase probability that events during perinatal brain development will contribute to risk Exposure to viral infections and ensuing inflammatory response – cytokines can affect neurogenesis Other prenatal assaults can also cause inflammation Behavioral abnormalities apparent in young children who later develop schizophrenia, suggests early developmental errors Developmental errors during adolescence cause twice the cortical cell loss compared with that seen in healthy teens FIGURE 19.6 Cortical gray matter loss The “two-hit” model of schizophrenia development Genetics cause altered perinatal brain development Neurodevelopment errors plus adolescent environmental events produce diagnosable symptoms  Preclinical models of schizophrenia Animal models focus on one aspect of the disorder to experimentally induce similar changes in animal behavior If we do not know causes of dysfunction, it is only possible to develop a model of symptoms! Potential new drugs: models often depend on neurochemically induced behaviors known to respond to currently useful drugs Often fails to identify novel drugs CNS stimulants produce symptoms similar to schizophrenia  Preclinical models of schizophrenia Amphetamine-induced stereotypy: the compulsive repetitions of meaningless behavior seen in schizophrenia Hypoglutamate model: NMDA receptor antagonists PCP and ketamine produce behaviors similar to symptoms of schizophrenia Vacuous chewing movements test: mouth and facial dyskinesias similar to the tardive dyskinesia that occurs in some patients Attentional set-shifting task: ability to change cognitive strategies for task performance on the basis of feedback Prepulse inhibition of startle (PPI): models used to study sensory-filtering deficits, especially gating Neonatal ventral hippocampal lesion model (NVHL): putative model of developmental abnormalities in disorder etiology  The prenatal inflammation model of schizophrenia Rodent models using maternal immune activation: The inflammatory agent polyinosinic:polycytidylic acid (poly I:C) is an immunostimulant: mimics the acute response to viral infection Lipopolysaccharide, a bacterial endotoxin Levels of pro-inflammatory cytokines are elevated in the fetal brain, placenta, and amniotic fluid The agents produce brain structural, neurochemical, cognitive, and behavioral outcomes that resemble components of schizophrenia Cognitive deficits of chronic PCP administration reduced by anti- inflammatory drugs: supports role of immune system  Preclinical models of schizophrenia Genetic models: modifications of schizophrenia susceptibility genes DA reuptake transporter knockout mice show hyperactivity, deficits in PPI, stereotyped movements, and spatial learning impairments Newer models also manipulate environmental factors, prenatal inflammation, postnatal stress, vitamin D deficiency, exposure to drugs of abuse. Dopamine hypothesis of schizophrenia: positive symptoms are caused by excessive mesolimbic DA activity Amphetamine produces positive symptoms in healthy individuals that can be reversed by DA antagonists Amphetamines make symptoms worse in patients with schizophrenia Strong correlation between D2 receptor blockade and reduction of symptoms Schizophrenic individuals show exaggerated DA release after amphetamine challenge as well as in basal conditions Some evidence for increased D2 receptors in schizophrenia Abnormal DA function contributes to schizophrenic symptoms DA imbalance hypothesis: symptoms are due to reduced DA function in mesocortical neurons along with excess DA function in mesolimbic neurons Negative symptoms and impaired thinking explained by impaired PFC function (low mesocortical activity) Positive symptoms improved by reducing DA function in mesolimbic neurons Evidence for DA’s role is inconsistent, possibly highly specific or time- dependent (e.g., development)  The neurodevelopmental model integrates anatomical and neurochemical evidence Hypothesis that schizophrenia arises from altered dopaminergic function and loss of specific nerve cells Negative and cognitive symptoms are associated with reduced frontal lobe function Excessive mesolimbic DA activity following early mesocortical cell loss can explain the positive symptoms Early mesocortical cell loss due to genetics or environmental events that alter brain development are followed by loss of inhibitory control of mesolimbic cells and onset of positive symptoms Glutamate and other neurotransmitters contribute to symptoms Hypoglutamate hypothesis: inadequate glutamate may explain the apparent increase in mesolimbic DA and decrease in PFC Similarities between cognitive deficits induced by D1 and NMDA receptor blockades Descending glutamatergic neurons influence both mesocortical and mesolimbic DA pathways Evidence for the importance of NMDA receptors comes from challenge studies, rodent studies, receptor subunit studies, and genetics – suggesting that NMDA hypofunction is central to schizophrenia FIGURE 19.8 Hypoglutamate hypothesis of schizophrenia  Classic neuroleptics and atypical antipsychotics None of the drugs are consistently more effective than the others; individuals may respond better to one drug than to another Classic: phenothiazines and butyrophenones Second generation: clozapine, risperidone, and aripiprazole; produce fewer side effects Third generation: few, mechanisms may be controversial Phenothiazines and butyrophenones are classic neuroleptics Chlorpromazine was the first phenothiazine; has had many modifications Molecular modifications affect ability of drug to bind to specific receptors and alter their potency and side effects  Phenothiazines and butyrophenones are classic neuroleptics Effectiveness: ‘Law of thirds’ in response to antipsychotic treatment 1/3 exhibit significant symptom reduction 1/3 exhibit symptom improvement but relapses 1/3 exhibit reduced responsiveness and may require extended psychiatric care Antipsychotic drugs are prescribed as maintenance therapy to prevent relapse Unpleasant side effects cause many patients to stop treatment Psychotherapy and group therapy are important additions Dopamine receptor antagonism is responsible for antipsychotic action There is a strong correlation between drug binding affinity and dose required to achieve clinical effectiveness Antipsychotic drugs bind to other neurotransmitter receptors, but no clear relationship to effectiveness Correlation with D2 receptor binding clearly establishes the mechanism FIGURE 19.10 Correlation between antipsychotic drug binding to neurotransmitter receptors and clinical effectiveness Dopamine receptor antagonism is responsible for antipsychotic action D2 receptors are located in the basal ganglia, NAc, amygdala, hippocampus, cerebral cortex Acute D2 autoreceptor blockade causes initial increase in DA neuron firing and increased turnover of DA Chronic D2 autoreceptor blockade causes autoreceptor up-regulation Depolarisation block may contribute to the decrease in turnover Dopamine receptor antagonism is responsible for antipsychotic action Normally, DA inhibits prolactin release from the pituitary By blocking D2 receptors in the pituitary gland, antipsychotics stimulate secretion of prolactin, leading to lactation and breast enlargement Measuring serum prolactin levels provides a measure of D2 receptor function in the CNS Side effects are directly related to neurochemical action Four DA pathways in the brain are important for understanding drug action: Mesolimbic pathway—affects positive symptoms Mesocortical pathway—cognitive and negative symptoms Nigrostriatal pathway—motor side effects Tuberohypophyseal pathway—regulates pituitary hormone secretion; neuroendocrine effects Side effects are directly related to neurochemical action Parkinsonian symptoms involve the extrapyramidal motor system (EPS) Involvement in involuntary movements, tremors, muscle rigidity Some antipsychotics have anticholinergic action, such as thioridazine Alternatively, antipsychotic drugs are combined with an anticholinergic drug such as benztropine (Cogentin) Side effects are directly related to neurochemical action Incidence of tardive dyskinesia (TD) increases with duration of treatment with D2 receptor antagonists Stereotyped involuntary movements of face and jaw, lip- smacking, ‘fly-catching’ movement of tongue VMAT2 inhibitors interfere packaging DA into vesicles, reduce DA release Valbenazine significantly decreased abnormal movements associated with TD, as measured by the Abnormal Involuntary Movement Scale (AIMS) Side effects are directly related to neurochemical action Blockade of receptors in the DA pathway that regulate pituitary function produces neuroendocrine effects: Decreased sex drive, no menstruation, increased prolactin, inhibition of growth hormone, weight gain, inability to regulate body temperature Neuroleptic malignant syndrome (NMS): life-threatening Fever, rigidity, altered consciousness, and ANS instability (including rapid heart rate and fluctuations in blood pressure).  Atypical antipsychotics are distinctive in several ways Atypical or second-generation antipsychotics reduce positive symptoms without causing significant extrapyramidal motor system effects and other side effects Selective D2 receptor antagonists DA partial receptor agonists (DA system stabilizers) Broad-spectrum antipsychotics block other receptor types in addition to D2 receptors  Atypical antipsychotics are distinctive in several ways Clozapine has weak affinities for D1 and D2 and strong affinities for serotonergic, muscarinic, histaminergic, and D4 receptors Reduces some of negative and cognitive symptoms but has many side effects because of its action on multiple receptors Newer atypical drugs bind with varying affinities for multiple receptor subtypes Side effects can be predicted on the basis of receptor affinity Controversy over mechanisms, such as partial agonism or receptor functional selectivity D2 receptor occupancy by antipsychotic drugs – [11C]raclopride binding Patients with schizophrenia Practical clinical trials help clinicians make decisions about drugs Pragmatic (practical) clinical trials focus on drug in real-world conditions, rather than testing hypotheses Do not exclude participants with confounding problems, unlike typical clinical trial A practical (pragmatic) clinical trial (CATIE) using 1500 patients (2001 – 2004): Atypical drugs were no more effective than the classical drug perphenazine in reducing positive, negative, or cognitive symptoms Occurrence of extrapyramidal motor system effects was similar for all drugs tested Potential new approaches to improving cognitive impairments Enhancing ACh with subtype-selective nicotinic agonists or positive allosteric modulators (PAMs) Patients with schizophrenia may show cholinergic deficits Selectively enhance D1 receptor signaling in PFC with D1 agonists Inhibit the enzyme (COMT) that degrades DA in the synapse Glycine agonists; glycine transporter inhibitors Anti-inflammatory agents Effects of positive allosteric modulators on novel object recognition