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Neuropharmacology Presentation by Crystal Horse

Mary Gay Josephine Cruz

on 25 April 2011

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Transcript of Hallucinogens

Hallucinogens I suddenly became strangely inebriated. The external world became changed as in a dream. Objects appeared to gain inrelief;they assumed unusual dimensions; and colors became more glowing. Even self-perception and the sense of time were changed. When the eyes were closed, colored pictures flashed past in a quickly changing kaleidoscope. After a few hours, the not unpleasant inebriation,which had been experienced whilst I was fully conscious, disappeared. What had caused this condition?
-Laboratory Notes 1943 Albert Hofmann objectives 1 2 3 Understanding the mechanisms:
Receptors, pathways, neurotransmitters, and brain regions Apply that knowledge to understanding the subjective and somatic effects Determine the safety and raise awareness about the scientific and therapeutic uses Case what do we know/need to know? brain regions
neurotransmitters Classes of hallucinogens Encompasses all drugs that alter psyche and promote altered states of consciousness
“Classic psychedelics” are serotonergic hallucinogens
Ergolines (LSD) Lysergic acid diethylamide
(LSD) Serotonin
Model Pharmacology Animal Models Dosage and Metabolism Pharmacological Facts Physical effects Drug Discrimination Introduction Animal trained to emit a response initiated by administration of training drug
-Appetitive reinforcement or shock
Animals trained to recognize stimulus effects of training drug vs. control/saline
Different doses of training drug or drug with similar mechanisms can help to develop dose/response curve
Drug elicited head
twitch response (HTR) Rapid, rational jerking of the head which is different than grooming or scratching behaviors
Selective behavioral model for 5-HT2a receptor agonist activity in rodents
-Can develop dose-effect curve
Direct and indirect 5-HT agonists induce this effect
Antagonists block this effect Self-administration Animal trained to perform a task when it wants the drug
Oral, subcutaneous, intravenous catheter
Used to study reinforcing effects
DOM(mescaline analog) was not able to maintain self-administration in rhesus monkeys
MDMA (ecstasy) is a phenethylamine that was able to maintain self-administration in baboons and mice LSD Minimal recognizable = 25-75 uμg p.o.
Moderate dose = (75–-100 μug p.o.)
“Optimum” dose = 100–-200 uμg
Clinical dose = 100 μug
Common recreational dosage rarely cause frank hallucination
Acute psychological effects last b/w 6 to 10 hours
Half life in humans is 175 minutes Phenethylamines low nanomolar affinities for 5-HT2a receptors and 1000-fold higher affinity for 1a receptors
10 fold increase in affinity for 2a over 2c
All types of hallucinogens are partial agonists at 2c receptor
Increased receptor density leads to increased HTR
Rapid development of tolerance with repeated administration
Downregulation of 2a receptors
Behaviors mediated by 2c receptors are unaltered with increased administration; 2c receptor density also did not change
Affinity for 2a receptor comparable to that of LSD
Order of potency = 5-HT2A > 5-HT2B > 5-HT2C

Tryptamines Lower affinity for 2a receptors than phenethylamines and ergolines
Suppress firing of dorsal raphe neurons
mediated by pre-synaptic autoinhibitory feedback initiated by stimulation of somatodendritic 5-HT1A receptors
Order of potency: 5-HT2B > 5-HT2C > 5-HT2A
No known agonists of 1a receptor alone that function as hallucinogen in humans Psychological
Stimulation of affect (euphoria)
Enhanced capacity for introspection
Perceptual changes
-Alterations of time experience
Traumatic experiences (bad trips)
-Long-lasting effects of mood
swings and flashbacks
-Generally take place in
uncontrolled conditions
Controlled and supervised conditions can have lasting positive effects on attitude and personality Neurocognitive Psychomotor functions (coordination and reaction time) impaired after LSD
Decreased attention and concentration
Impaired recognition and recall of various stimuli
Higher doses impair arithmetic ability
Impairment of visual memory
Regression of intellectual functions to an ontogenetically younger state of development NO CHRONIC NEUROCOGNITIVE EFFECTS!!! Somatic Sympathetic stimulation
Pupilatory dilation
Slight increases in HR and BP Parasympathetic
Flushing of the face Receptors Serotonin review Produced by several hundred thousand neurons in Raphe Nucleus
Widespread projections
Influences: sleep, arousal, attention, processing of sensory information, and emotion and mood regulation
Serotonin Projections LSD Receptors Smaller Ki corresponds to higher binding affinity

Current hypothesis is that 5-HT2A is primary site of action because antagonists of this receptor block effects of LSD LSD also activates dopamine receptors directly

There is evidence that serotonergic hallucinogens increase DA levels indirectly through serotonergic projections from the raphe nucleus to the VTA

Dopamine likely plays a role, but the mechanism is not well known Pathways Agonist specific signaling Role of glutamate 5-HT 1A pathway Hypothesized Mechanism:
Sensory Overload Different agonists for the same receptor on the same cell can selectively cause different effects
5-HT2A phospholipase C Ca2+ and PKC
5-HT2A phospholipase A2 arachidonic acid (AA) LSD preferentially activates the PLA2 pathway
Another Pathway: PLD LSD causes an increase in glutamate and synaptic activity in the PFC
Direct excitation of pyramidal neurons in deeper layers
Retrograde messenger (AA?) triggers glutamate release by blocking K+ channels in presynaptic terminal
Excitation of thalamic afferent neurons LSD binds preferentially to 5-HT1A receptors in dorsal raphe neurons
Causes presynaptic auto-inhibitory feedback
-Normal inhibitory action of cortical
5-HT1A is removed
No subjective effects have been shown through this pathway alone
Needs further study – administering LSD in the presence/absence of specific 5-HT1A antagonists Hallucinogens directly enhance both the sensitivity and excitability of cortical processing

Concurrently they cause release of glutamate from thalamic afferent neurons
Normally signal incoming sensory information that needs to be processed

This creates a low signal to noise ratio of incoming sensory inputs to cortex from thalamus
Bypasses the normal thalamic gating system of thalamus and causes sensory overload Clinical Treatments and
Potential Therapeutic uses “Psycotomimetic” What are “psycotomimetics” Induce temporary psychosis
Mescaline produces identical symptoms
Decrease in cortical 5-HT2A receptors in dlPFC

Difficulty in habituation and prepulse inhibition (PPI)
5-HT2A agonists  PPI deficit
Similar in rats, different in humans Schizophrenia Medical treatments Pain Analgesic effects
indistinguishable model for rats: Cyclazocine and LSD

Cancer and Terminally Ill patients
LSD: analgesic effect outlasted psychological effects in 65% of patients
Psilocybin: had better mood and significantly less anxiety
Improvements: more responsive to families, environment, changed attitudes toward death Drugs of Abuse Two hypotheses:
Negative symptoms: Effects of LSD are similar to delirium tremens
Positive symptoms: Euphoria/Transcendental-type experience/mood changes

3 month follow up:
67% improvement
36% abstained

Used as a form of treatment by many Native American tribes Alcohol Two subjective cases of success
Heroine (perhaps working through similar pathway of cyclazocine)
Sedative hypnotics Opiates OCD Why?
Irregular levels of serotonin in OCD patients
Patient (1): depression and violent obsessive sexual thoughts
given 2 doses of LSD; permanent improvement
Patient (2): fear of contamination
LSD weekly for 15 months
3 years after treatment  symptom free
Patient (3) with mescaline and psilocybin:
Hour 1: obsessive thought worsened
Hours 2-5: complete remission of obsessions Crazy Success Stories Depression Low serotonin levels are associated with depression
Antidepressant treatments target system to raise levels (i.e. SSRI’s)
Others work on are structurally similar to 5-HT
LSD and similar hallucinogens are 5-HT agonists. Therefore, may be used as anti-depressants Psilocybin in fMRI
Lower blood flow in thalamus, posterior cingulate, and medial prefrontal cortex
Decreases connections between hippocampus and posterior cingulate and PFC
Posterior cingulate associated with changes in consciousness
These brain regions are overactive in people with depression, making psilocybin potential treatments
With all of these potnetial treatments,
more research and clinical studies should be done... or should they? Legality? In the US, nearly all known hallucinogens are Schedule I
Criteria: high risk of addiction or no medical use Members of the Church of Santo Daime in Brazil allowed to use DMT as part of their religious practice
UDV church (Santo Daime branch) in US is allowed to use it as well What do you think? Aghajanian, GK and Marek, GJ. Serotonin and hallucinogens. Neuropsychopharmacology. 1999; 21(2): 16-23
Archer S, Glick SD, Bidlack JM. Cyclazocine revisited. Neurochem Res. 1996: 1369-73.
DITMAN. K. S. Review and Evaluation of Current Drug Therapies in AlcoholismPsychosom . Med 1966: 28: 667 - 677.
Fantegrossi WE, Murnane AC, Reissig CJ. The behavioral pharmacology of hallucinogens. Biochemical Pharmacology. 2008; 75(1): 17-33
Hirshhorn I. D., Rosecrans, A. J. Generalization of Morphine and Lysergic Acid Diethylamide (LSD) Stimulus Properties to Narcotic Analgesics. Psycopharmacology. 1976; 47: 65-69.
Nichols, DE. Hallucinogens. Pharmacology &Therapeutics. 2004; 101(2): 131-181
Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: a review. CNS Neuroscience & Therapeutics. 2008; 17(4): 295-314 Brain Regions Dorsal Raphe Locus Coeruleus PFC Thalamus Input
Pre-synaptic autoinhibitory feedback
5-HT1A receptors
Thalamus & cortex (PFC) Input
Dorsal raphe & sensory systems
“novelty detector”
5-HT2A receptors & GABA
Thalamus & cortex (PFC) Input
5-HT2A receptors
α1-adrenergic receptors
Similar to 5-HT2A pathway
Cortico-cortico activity Input
5-HT2A receptors
Raphe & locus coeruleus & sensory systems
Cortico-striato-thalamo-cortical loops (CSTC)
Full transcript