Understanding Central Nervous System Effects of Deliriant

Review Cite This: ACS Chem. Neurosci. 2019, 10, 143−154

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Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models Andrey D. Volgin,†,‡,§ Oleg A. Yakovlev,†,‡,§ Konstantin A. Demin,‡ Polina A. Alekseeva,‡ Evan J. Kyzar,∥,⊥ Christopher Collins,⊥ David E. Nichols,# and Allan V. Kalueff*,∇,○,□,@,$,%,& †

Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia Almazov National Medical Research Centre, St. Petersburg 197341, Russia § Military Medical Academy, St. Petersburg 194044, Russia ∥ College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, United States ⊥ The International Zebrafish Neuroscience Research Consortium (ZNRC), New Orleans, Louisiana 70458, United States # Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States ∇ School of Pharmacy, Southwest University, Chongqing 400716, China ○ Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk 630117, Russiai □ Ural Federal University, Ekaterinburg 620075, Russia @ ZENEREI Research Center, Slidell, Louisiana 70458, United States $ Laboratory of Biological Psychiatry, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia % Institute of Experimental Medicine, Almazov National Medical Research Centre, St. Petersburg 197341, Russia & Granov Russian Center of Radiology and Surgical Technologies, St. Petersburg 197758, Russia

ACS Chem. Neurosci. 2019.10:143-154. Downloaded from pubs.acs.org by OPEN UNIV OF HONG KONG on 01/28/19. For personal use only.

‡

ABSTRACT: Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as “deliriants”. Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field. KEYWORDS: Hallucinogens, antimuscarinic agents, deliriants, zebrafish, rodents logical conditions.10 The interest in hallucinogenic research is currently growing as their mechanisms may provide new targets for treating various brain disorders.1 Complementing a rich clinical literature,4,11−13 various animal models of hallucinogenic states have been developed that combine pharmacological and genetic modulation with sophisticated behavioral characterization.

1. INTRODUCTION Hallucinogens are chemically heterogeneous compounds that potently affect behavior, mood, thought and perception.1,2 While employed in human spiritual and medicinal practice for millennia, hallucinogen use and possession were criminalized in the 1970s3 and remain strictly regulated despite the growing evidence of their potential clinical use4,5 and low addiction potential.6,7 Over-regulation of these compounds impedes scientific research, as understanding the mechanisms of their action may not only help uncover the neural bases of hallucinations1,8,9 but also further dissect the role of various neurotransmitter systems in normal and pathological neuro© 2018 American Chemical Society

Received: August 26, 2018 Accepted: September 25, 2018 Published: September 25, 2018 143

DOI: 10.1021/acschemneuro.8b00433 ACS Chem. Neurosci. 2019, 10, 143−154

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Abbreviations: NMDA, N-methyl-D-aspartate, LSD, lysergic acid diethylamide. bEntactogenic - increasing empathy and prosocial behaviors.

Kappa-opioid agonists

a

Decreased visual aptitude, hallucinations and perceptual delusions, drifting, double vision, vibrating, after-images,136 impaired attention and sensory/stimulus discrimination, “anticholinergic” peripheral side-effects (e.g., pupil dilation and salivation),35 confusion, agitation, delirium, drowsiness and coma.137,138 Antinociception, antidepressant/anxiolytic properties, memory disturbances, dose-dependent hyper- or hypo-locomotion.139 Acetylcholine muscarinic M-receptor antagonists κ-opioid agonist Deliriants

Dissociatives

LSD, mescaline, psilocybin Phencyclidine (PCP), ketamine Atropine, scopolamine Salvinorin A Psychedelics

Serotonin (5-HT2A) receptors agonists Glutamate NMDA receptor antagonists

Typical drugs Class

Table 1. Brief Summary of Major Classes of Hallucinogenic Drugsa

2. DELIRIANT HALLUCINOGENS Delirium, from Latin de (away from) and lira (the earth thrown up between two furrows),28 is a confused mental state characterized by altered consciousness, circadian, cognitive and perceptual disturbances (hallucinations) and behavioral deficits, such as agitation, restlessness and aggression29−31 (Figure 2). The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-V) provides several main criteria for clinical delirium, as follows. (i) The presence of disturbances in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment); (ii) These disturbances develop over a short period of time (hours to days), represent a change from baseline attention and awareness, and tend to fluctuate in severity during the course of a day; (iii) The presence of cognitive disturbances (e.g., memory deficits, disorientation, language deficits, visuospatial deficits, and/or perceptual alterations); (iv) Evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition (e.g, sepsis, hypoxia, electrolyte imbalance), substance intoxication, or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple medical etiologies. Delirium-like states are common in psychosis and other mental disorders, such as depression, bipolar disorder, and substance abuse (Figure 2) but can also be evoked pharmacologically by “deliriant” hallucinogenic drugs. The best-known deliriants are atropine, scopolamine, and hyoscyamine (Figure 1), toxic alkaloids derived from Atropa belladonna (deadly nightshade).23 Atropine and scopolamine

Main action mechanism

Distinctive effects

Classical hallucinogens can be generally divided into several major classesserotonergic psychedelics,14 antiglutamatergic dissociatives,15 and anticholinergic deliriants16,17 (Table 1). Additionally, several agents, such as the multitarget drug ibogaine18 and the κ-opioid agonist salvinorin A,19 act at other brain targets to produce hallucinogenic effects. Psychedelics are the most well-studied group of hallucinogens (Figure 1), consisting of tryptamines (e.g., psilocin, the psychoactive metabolite of psilocybin derived from “magic” mushrooms and N,N-dimethyltryptamine DMT, the psychoactive compound of ayahuasca), lysergamines (e.g., lysergic acid diethylamide, LSD), and phenethylamines (e.g., mescaline, the psychoactive compound in the peyote cactus).3,14 Dissociatives are the second most well-studied group of hallucinogens and include ketamine, phencyclidine (PCP) and MK-801 (dizocilpine) all of which are classical N-methyl-D-aspartate (NMDA) receptor antagonists20 used for medical anesthesia and also recreationally for their mind-altering effects.21 Deliriants include the anticholinergic tropane alkaloids atropine, scopolamine, and hyoscyamine (Figure 1) that are present in the flowering plants of the Solanaceae family, such as Brugmansia and Datura.22−24 These alkaloids induce delirium, anterograde amnesia, and hallucinations with characteristic complex visual imagery.22 Despite their wide use in cholinergic physiology,25−27 the hallucinogenic and neurological effects of deliriant compounds are poorly understood and underrepresented in both clinical and preclinical research (Figure 1), meriting further scrutiny. Here, we summarize their effects in various model systems, discuss translational relevance to human conditions, and outline future avenues of research in this field.

Distorted sensory perception, space, time, color, sounds and shapes, dreamlike feeling,14 simple and complex hallucinations, euphoria with involuntary grinning, uncontrollable laughter, playfulness, and exuberance,131 entactogenicb mood effects,132 divergent thinking, higher creativity133 A full range of high-level hallucinatory states, scenery slicing, cubism,15 violent behavior, nystagmus, anesthesia, analgesia,134 agitation, muscle rigidity, ataxia, stupor,135 comatose states (with no response to deep pain), hyperthermia, convulsions134

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Figure 1. Place of deliriants in current knowledge base of neuropharmacology. The top diagram illustrates PubMed data on the percentage of publications on various classes of hallucinogenic drugs. Data were generated from a PubMed online search of articles published between 2000 and 2018, using selected main representative drugs of the three major classes of hallucinogens: a psychedelic lysergic acid diethylamide (LSD), a dissociative phencyclidine (PCP), and a deliriant scopolamine (chemical structures of common antimuscarinic agents with deliriant hallucinogenic properties are provided below).

Figure 2. Delirium overlaps with other clinical conditions. Note that most of the clinical signs and symptoms of delirium, expect for disordered thought and language deficits (marked with *), can be successfully modeled experimentally in various animal models.

(TTS-patch) specifically for treating motion sickness.34 The CNS effects of these drugs include attention and sensory/ stimulus discrimination, nonspecific effects on locomotion and anxiety, as well as classical anticholinergic peripheral sideeffects (e.g., pupil dilation and salivation).35 Atropine has overt memory-impairing effects36,37 and may evoke confusion, agitation, delirium, drowsiness, and coma.38 Albeit similar in structure, atropine has fewer CNS effects than scopolamine,

are nonselective muscarinic (M-) acetylcholine receptor antagonists, representing naturally occurring tertiary amines with multiple CNS actions and robust side-effects.32,33 In both humans and animals, deliriants evoke robust hyperactivity, altered affective states, and amnesia (Table 3). Anticholinergic drugs are also used clinically to treat motion sickness, postoperative nausea/vomiting, muscle spasm, and other conditions.34 In fact, scopolamine was the first drug made commercially available in a transdermal therapeutic system 145


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No data Atropine-like stimulatory effects on central and motor neurons in frogs and mammals,49,52,53 nociceptive effect in rabbits and rodents54 Hyoscyamine

No data

Trihexy-phenidyl Procyclidine

No data

Memory impairments (passive avoidance test),155 antidepressant-like effects,156 delirium (alternation of hyperactive and hypoactive state)157 Enhanced cocaine effects,158 hyperactivity,159 amnesia,160−162 increased male sexual behavior,163 wakefulness and decreased REM sleep164 Cognitive impairment (preference deficit)165

Reducing extrapyramidal symptoms of neuroleptics,153 Parkinson’s disease153,154 Reducing extrapyramidal symptoms of neuroleptics, treating Parkinson’s disease154 Reducing extrapyramidal symptoms of neuroleptics, treating Parkinson’s disease154 Reducing spasms, glandular and gastric secretion,41−47 but causes tachycardia that limits its use.48 Biperiden

Scopolamine

Impaired memory104 (reversed by physostigmine,106 quercetin, rutin107 and lithium108). Impaired acquisition and retention.151 Anxiolytic-like and shoalingdisrupting effects110 (but may be related to hallucinogenic and memory-disrupting action152). No data

CNS effects in zebrafish

Higher survival of larvae following organophosphorus intoxication.145 Biphasic effects (stimulation followed by sedation) on locomotor activity.146 Reduced shoaling behavior (AVK lab pilot observations).

CNS effects in mammals

Impaired stimulus sensitivity, sensory discrimination, vision and behavioral patterning;141 delirium-like state;142 reduced passive avoidance,116 evoked sleep-like slow wave cortical activity,143 impaired memory.144 Impaired working memory,76 radial maze learning148 and social memory;77 impaired fear conditioning;149 other cognitive deficits150

Clinical use and effects beyond delirium Drug

3. EXPERIMENTAL ANIMAL MODELS FOR DELIRIANT DRUG ACTION 3.1. Rodent Models. In rodents, various hallucinogens alter locomotion, specific motor phenotypes (e.g., head twitching or other stereotyped behaviors), startle responses, and prepulse inhibition (PPI).62 For example, although serotonergic psychedelics evoke characteristic head twitches,63 they differ from head-weaving (slow, side-to-side lateral head movement) and wet-dog shakes (repetitive shaking of the body), typically evoked in rodents by dissociatives.64 In contrast, head-twitching or weaving are not observed in rodents after scopolamine or atropine (which induce hyperlocomotion and walking stereotypes,65,66 even in akinetic rodents after catecholamine depletion67 or spinal cord injury68 ). In general, PPI reflects sensorimotor gating mechanisms, which is often deficient in schizophrenic patients.69 Deliriant drugs biperiden and scopolamine disrupt PPI in food-restricted rats,70 and these effects are blocked by atypical antipsychotics71,72 and a nootropic agent CDPcholine.73 Although scopolamine dose-dependently reduces rodent PPI, unlike the dissociative PCP, it has no effect on

Atropine

Table 2. Clinical Use of Selected Anticholinergic Drugs and Their Effects in Preclinical Animal Models (see Figure 1 for Chemical Structures)

which is possibly due to different conformational changes evoked upon binding to the M-receptor.39 Hyoscyamine (daturine) is the naturally occurring levorotatory form of racemic atropine and similarly acts as a nonselective competitive M-receptor antagonist.40 This agent is used clinically to relieve spasms, decrease glandular and gastric secretion,41−47 and as a preanesthetic drug (similarly to atropine and scopolamine),42 although the evoked tachycardia limits its clinical use48 (Table 2). Psychomotor effects of hyoscyamine resemble those of atropine and scopolamine and include cerebral excitement,49 motor paralysis,49 loss of voluntary coordination,49 spatiotemporal disorientation,50 depersonalization,50 memory impairment,50 sleep49 and hallucinations/delirium-like state.50,51 At the same time, its recreational potential is relatively weak due to low overall attractiveness of the experience.50 Little is known about hyoscyamine effects in animal models. Early studies have revealed similar (to atropine) excitatory effects on central and motor neurons of frogs and mammals, with somewhat stronger stimulation of frog reflexes52,53 and some other species.49 Hyoscyamine may also cause a nociceptive effect in rabbits and rodents.54 Anticholinergic drugs biperiden, benztropine, procyclidine and trihexyphenidyl are regularly used in clinical practice to reduce the extrapyramidal side-effects associated with neuroleptics and tremors in Parkinson’s disease (Table 3) by blocking central M1 receptors.55 However, at high and/or frequent doses, all of these agents are capable of inducing hallucinations. For example, trihexyphenidyl, a synthetic M1 antagonist,56 induces tactile and visual hallucinations,57 mental alterations, and delirium.58 Similar visual hallucinations have been observed following high doses of biperiden.59,60 Furthermore, other novel compounds with shared pharmacological and deliriant hallucinogenic properties have emerged. For instance, benzydamine, an indazole nonsteroidal antiinflammatory drug (NSAID), induces delirium-like hyperreactivity, excitation, and visual hallucinations when used/ abused recreationally at high doses.61 Further research of deliriant hallucinogens in both clinical and preclinical models is needed to fully understand the behavioral and neurological effects of these drugs.

Antidote for mushroom poisoning or overdose of cholinergic drugs, threats bradycardia, acts as a promydriatic and cycloplegic agent;140 evokes cognitive deficits Motion sickness, premedication for anesthesia,147 evokes cognitive deficits



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ACS Chemical Neuroscience startle amplitude.74 Two other M-receptor antagonists, trihexyphenidyl and benztropine, decrease PPI like scopolamine, whereas biperiden does not alter PPI but decreases startle amplitude.75 Another prominent effect of M-antagonists that is also a component of clinical delirium is memory impairment. Scopolamine leads to working memory errors76 (rescued by the cholinesterase inhibitor donepezil,77) and its administration prior to training impairs learning and memory processing.78 Similarly, acute atropine reduces passive

many brain diseases have genetic causes, hundreds of mutant zebrafish phenotypes have been identified so far, many of which bear similarity to clinical syndromes.98 Sensitivity to most psychotropic pharmacological agents make zebrafish indispensable in studying psychiatric diseases and their therapies.97,99,100 Zebrafish are highly sensitive to all major hallucinogenic drugs, including LSD, mescaline, PCP, MK-801, ketamine, ibogaine, salvinorin A, as well as atropine and scopolamine.62,101,102 Zebrafish brain shows a relatively high number of acetylcholine receptors that bind M-antagonists, such as atropine.103 The binding properties of zebrafish Mreceptors generally resemble those of mammals, suggesting zebrafish as a potentially useful model organism for evaluating cholinergic modulation of behavior and for screening deliriant drugs.103 For example, as in rodent models, the memoryimpairing effects of scopolamine have also been established in zebrafish.104,105 Similarly, these effects are reversed by physostigmine,106 quercetin, rutin,107 and lithium108 (Table 2). Studying the impact of anticholinergic drugs on zebrafish locomotion and anxiety yields conflicting results, reporting both anxiogenic-like109 and anxiolytic-like110 effects. Both scopolamine110 and atropine (AVK lab pilot data) impair group cohesion in zebrafish shoals, which may reflect social deficits and/or impaired perception. Finally, treatment with hallucinogens may induce vegetative responses in zebrafish (e.g., altered heart rate, defecation, nutrition) which can be extended to deliriants and compared with human data, thereby enriching our understanding of deliriant pharmacology in vivo.62

Table 3. Summary of Clinical Symptoms Evoked by Deliriant Drugs Effects Memory-impairing effects Drowsiness Antidepressant effect

Delusions, visual hallucinations, blurred vision, photophobia Agitation, excitement, restlessness Antiemetic Anticholinergic peripheral side-effectsa

Implicated mechanism of action

References

Inhibited cholinergic control of attention

166

Lowered stimulus sensitivity and cholinergic arousal systems of the brain Reduced depression (characterized by lower central cholinergic activity relative to noradrenergic tone) Hyperactivation of substantia nigra dopaminergic cells by disinhibition of the tegmental cholinergic cells CNS stimulation (due to dysregulated serotonergic and γ-aminobutyric (GABA)-ergic tone) Competitive antagonism at the serotonergic 5-HT3 receptors Inhibited cholinergic transmission at Mreceptors affecting peripheral receptors

167, 168 25

169

170

171 172

a

Tachycardia, hyperthermia, dry skin, mydriasis, decreased bowel activity, and urinary retention (deliriants can also cause death due to tachycardia and hyperthermia173).

4. DISCUSSION Neurotransmitter system dysfunctions are a well-known cause of a wide spectrum of CNS disorders including schizophrenia, anxiety, and depression. Typical deliriant hallucinogens impair M-cholinergic innervation and lead to an imbalance of dopaminergic stimulation of the central mesolimbic system111 underlying the classical “core” symptoms of delirium (disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, and hallucinations).112 As M-receptors are particularly widespread in the brain, their role in deliriumlike states seems to be complex and subtype-specific. The M1, M3, and M5 receptors, preferentially coupling to the Gq/11 family of G-proteins, activate phospholipase C leading to hydrolysis of inositol phosphates and mobilization of intracellular Ca2+.113 The M2 and M4 subtypes preferentially couple to the pertussis toxin-sensitive Gi/o family of G-proteins, inhibiting adenylyl cyclase cAMP formation.113 Various M-receptors modulate striatal dopamine release,114 suggesting that M-antagonism has a general excitatory effect on the striatal dopaminergic system.115 Although elevated dopamine in the mesolimbic circuits is a key endophenotype of schizophrenia116 which shares clinical features with some forms of delirium, M- and dopamine receptors often colocalize, likely modulating the effects of M- and dopaminergic drugs on basal ganglia physiology.117 For instance, M1, M2, M4, and dopamine (D2) receptor mRNA are detected in the striatum, while M5 and D2 receptors are expressed in the substantia nigra pars compacta.117 However, not all M-receptors evoke similar effects on dopamine levels, because activation of M2 and M4 receptors reduces dopaminergic transmission in the nucleus accumbens, while activation of M5 receptors exerts the opposite effect.118 Moreover, the M5 receptor is the only subtype found in rodent midbrain dopaminergic neurons.119

avoidance and evokes sleep-like slow wave activity in the rat neocortex, hippocampus, and reticular formation.79 Scopolamine and atropine cause similar effects in rats of various ages.80 Atropine-induced learning deficits are short- to medium-term, typically lasting only for several hours.81 The amnestic effects of biperiden and trihexyphenidyl generally resemble those produced by scopolamine,82 although some selective M-antagonists may be less potent in terms of memory-impairing abilities when compared to nonselective deliriants.83 Mounting evidence suggests that scopolamine stimulates rodent locomotor activity,84−87 likely acting via mesopontine cholinergic neurons that activate dopaminergic circuits controlling reward and locomotion.88 Mutant mice lacking the M5 receptor gene display increased scopolamine-induced hyperlocomotion,88 whereas atropine in combination with the α-adrenergic agonist clonidine produces pronounced hyperactivity in monoamine-depleted mice.89 Finally, M-antagonists also modulate emotional behavior, as scopolamine inhibits rodent aggression without causing motor deficits,90 increases defecation and grooming (two anxiety-related indices),91 and reduces social behaviors.92,93 3.2. Aquatic Models. Aquatic species are rapidly becoming popular in neuroscientific research, mainly due to low cost of handling and experimental manipulations.94 In particular, zebrafish (Danio rerio) are an important model organism for CNS research and drug discovery95−97 due to their high genetic and physiological homology with mammals and well-developed monoaminergic, glutamatergic, opioidergic, cholinergic, and other neurotransmitter systems.62 As 147


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ACS Chemical Neuroscience Thus, M5 receptors may be an appropriate novel pharmacological target for disorders with imbalanced mesopontine cholinergic and ventral midbrain dopaminergic systems,114 such as delirium. Therefore, further preclinical research of deliriant drugs may lead to the development of novel M-active modulators of dopaminergic signaling118 in schizophrenia, addiction, and other CNS disorders. However, the role of other neurotransmitter systems, especially other monoamines, γaminobutyric acid (GABA), and glutamate, in shaping neural and behavioral responses to deliriants is highly likely, necessitating further studies (Table 4). Due to the relative dearth of research into the effects of deliriants, there is limited data on the ability of these drugs to modulate the effects of other hallucinogenic agents. This problem becomes important because polydrug use is relatively common among regular users of hallucinogens.120,121 Similarly to the effects of deliriants on dopaminergic signaling, it is possible that they may also alter other neurotransmitter systems targeted by other classes of hallucinogens. For example, deliriants may hypothetically potentiate the actions of serotonergic psychedelic drugs, such as LSD, intensifying and/or prolonging subjective experiences associated with these compounds, or vice versa. A similar putative synergistic effect may be present with regard to the interaction between opioid drugs and/or dissociatives, when administered in combination with deliriant compounds. However, it is also possible that negative interactions may also exist between deliriants and some other hallucinogens (e.g., ibogaine or salvinorin A, both exerting opioidergic activity). This hypothetical situation, if confirmed in animal studies and corroborated clinically, may lead to several promising therapeutic applications. Future research should investigate the potential neural interactions of deliriant compounds with other classes of hallucinogens, as this may yield important insights in the underlying biology of delirium-like states in the clinical population.

Table 4. Selected Open Questions in Experimental Models of Deliriant CNS Action Conceptual • What are the molecular and cellular mechanisms underlying the broad behavioral changes caused by deliriants? • Are neural networks altered by deliriants, similar to the “brain rewiring” effects of psychedelic hallucinogens? • Do interneurons, astrocytes and glia play a role in hallucinogenic states induced by deliriants? • Can the hallucinatory experience of different hallucinogens reflect, at least partially, shared pathways and/or mechanisms? • How similar are the brain mechanisms responsible for hallucinations in psychotic disorders to those responsible for the hallucinations following deliriant administration? • Can the mechanism of hallucinations and cognitive impairments seen after deliriant administration be linked to pathogenesis of schizophrenia and neurodegenerative disorders (e.g., Alzheimer’s)? • Can deliriants contribute to the treatment of psychiatric pathology? • Are there any links between deliriant consumption and genetic predisposition to psychiatric diseases? • How do molecular alterations induced by deliriants alter responses to other CNS agents? • Can deliriants produce a significant effect on development of genetically determined brain disorders? • What are the epigenetic effects caused by deliriant exposure? • What are the specific genetic vulnerabilities associated with deliriant-evoked states? • What are the potential developmental effects of “early” exposure to deliriant drugs? • What are other neurotransmitter systems (beyond dopamine) that contribute to complex delirium-like hallucinations? • What are the physiological (e.g., endocrine, cytokine) molecular biomarkers of deliriant-evoked states? • What are specific gene expression profiles shared following exposure to various deliriants? • Do deliriants affect neuroprotective and neuroimmune mechanisms in the brain? • Do deliriants induce a full spectrum of clinical signs of delirium, including both hyper- and hypo-active delirium? • Do deliriants interact with other classes of hallucinogenic drugs (e.g., psychedelics or dissociatives)? Can they potentiate (or, alternatively, attenuate) hallucinogenic effects of each other? Translational • Are there clear-cut effects of deliriants on anxiety and depression across taxa? • Are there species differences (e.g., rodents vs fish vs humans) in responsivity to deliriant hallucinogens? • Are there individual differences (in both humans and animals) in responses to deliriants? • Is deliriant abuse potential similar across various model species and humans? • Are there any negative consequences of deliriants on neurons and neural networks? • To what extent are animal models of hallucinations relevant to humans? • Are there sex differences in human and animal responses to deliriants? Topic-specific • Do different strains of rodents and zebrafish respond differently to deliriant drugs? • Can animals be a good model to study hyperactive vs hypoactive delirium reported clinically? • Is there a deliriant withdrawal syndrome? • How are animal welfare parameters are influenced by long-term exposure to deliriants? • Can computer-based technologies be used in a high-throughput manner to extract phenotypic information about specific delirium-like behavioral states in animal models?

5. FUTURE DIRECTIONS AND CONCLUDING REMARKS Genetic and genomic factors can also contribute to deliriant effects (Table 4). For example, alterations in gene expression in various brain areas following long-term administration of Mantagonists (e.g., scopolamine122) may complement behavioral assays to reveal how specific transcripts correlate with the known behavioral effects of deliriants. Indeed, lower hippocampal gene expression of calcium binding proteins (CBPs) in mice by chronic scopolamine123 raises the possibility that the expression of other candidate memory-related genes can be affected by deliriant drugs. Other brain functions, such as sensory information acquisition and reception, locomotor regulation, aggression, and anxiety should be analyzed following deliriant administration, both acutely and chronically, and coupled with genetic manipulation of target genes. For example, knockout of individual M-receptors may help dissect their precise function in cholinergic modulation of delirium-like states, as well as their interplay with other mediators, such as dopamine induced by M-receptor antagonists.118 Although many hallucinogens do not often lead to addiction, the abuse potential of deliriants, especially the newest synthetic drugs, should be investigated in detail in cross-species studies. Assessing the expression of genes already implicated in the pathogenesis of psychiatric disorders (e.g., http://webqtl. org)124 following deliriant administration may help identify

shared overlap between drug-evoked and pathogenic brain states. Identification of such candidate genes can be empowered by complementary model organisms, such as zebrafish, which share high genetic homology with mammals 148


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critical review and further revision of the manuscript. All authors contributed to critical discussions and finalizing the manuscript before submission and have approved its final form.

and can be easily manipulated genetically. The small body size of zebrafish, external development, and optical transparency of larvae provide a powerful tool kit for large-scale mutagenesis, gene mapping, transgenesis, overexpression, knockdown, and chemical screens.95,125−127 Moreover, due to advanced videoanalysis software, detailed zebrafish ethograms are now available to rapidly obtain reliable behavioral data, supplemented with video capture and video tracking, and followed by a multistep assays of physiological biomarkers. Thus, animal models are indispensable tools to explore neurobiological mechanisms underlying different hallucinations-like states.64,128 This knowledge is particularly crucial for the development of novel drugs with improved therapeutic efficacy. However, because hallucinations in humans depend on subjective reports (rather than directly measurable behaviors),129 modeling deliriant-like states in animals is a difficult task despite mounting data already generated in animal models of hallucination-related states. For example, animal models often cannot recapitulate an entire disorder or disease but only one or a few symptoms that do not always reflect the main symptoms or the exact molecular mechanisms of the disease, especially such complex conditions as deliriant hallucinations. Furthermore, as the study of deliriant drugs is currently lagging behind other classes of hallucinogens, many questions (Table 4) remain open. For example, despite the availability of novel research tools, the pharmacogenetic responses to deliriants remain poorly understood. As some hallucinogenic drugs may have clinical applications, the information about genes that are activated during drug therapy may alter our understanding of drug-evoked and pathological psychiatric states. It also will help to inform a future foundation of personalized psychiatry, in which drugs and drug combinations are optimized for narrow subsets of patients or even for each individual’s unique genetic makeup.130 An important outcome of deliriant hallucinogenic research is the potential development of novel M-related compounds with therapeutic effects. Likewise, neurotransmitter systems associated with M-receptors (especially dopamine), key elements of their signaling (e.g., G-proteins), and altered gene expression patterns induced by deliriant hallucinogens necessitate further study in both clinical and preclinical models (Table 4). Finally, hallucinations as neural phenomena in general, and delirium-like states in particular, remain poorly explored at neurological and molecular levels. Thus, further translational research into CNS states evoked by deliriant agents will improve our understanding of physiological and pathological neural function.

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Funding

The research was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to A.V.K. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.V.K. is the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC) and current President of the International Stress and Behavior Society (ISBS, www.stressand-behavior.com).

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ABBREVIATIONS CBP, calcium binding protein; CNS, central nervous system; DMT, N,N-dimethyltryptamine; DSM-V, Diagnostic and Statistical Manual of the American Psychiatric Association; GABA, γ-aminobutyric acid; LSD, lysergic acid diethylamide; M, muscarinic (receptor); NMDA, N-methyl-D-aspartate; NSAID, nonsteroidal anti-inflammatory drug; PCP, phencyclidine; PPI, prepulse inhibition; TTS, transdermal therapeutic system

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*(Dr. Allan V. Kalueff) Ph.D. School of Pharmacy, Southwest University, Beibei, Chongqing, China. E-mail: avkalueff@ gmail.com. Tel/fax: 1-240-8999571. ORCID

Allan V. Kalueff: 0000-0002-7525-1950 Author Contributions

All authors have extensively contributed to this manuscript. A.V.K. conceived and coordinated the project, with conceptual input from D.E.N., E.J.K., and P.A.A. A.D.V., O.A.Ya, K.A.D., P.A.A., E.J.K., and C.C. participated in data collection, analysis, and interpretation. A.D.V., K.A.D., C.C., and P.A.A. drafted the manuscript. A.V.K., P.A.A., E.J.K., and D.E.N. participated in 149


Review

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