History of Psychopharmacology

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History of Psychopharmacology

• In most cultures psychotropic plant drugs have
  played a role in religious practices, magic
  rituals and healing
• In Europe best known opium, hashish and
  hellebore.
• Opium is the solidified juice of the opium poppy,
  traces of poppy have been found in stone age lake
  dwellings in Italy Switzerland. In early 19th
  century isolated active morphine from opium, used
  in military as analgesic and anaesthetic
• Hashish is the resin of hemp, widely consumed in
  islamic world but not used medicinally
• Hellebore root plant of the Ranunculaceae. White
  hellebore used as emetic and back as laxative,
  demonstrated guiding principle that a mental
  illness has a physical cause that can be treated
  by removal of pathogenic substances.Used in
  mania, melancholy,mental retardation,epilepsy.Ment
  ioned in Aristophanes go drink hellebore
  youre crazy.

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History of Psychopharmacology(2)

• Start of scientific approach to mental health 6BC
  Greeks.Post mortem studies showing link between
  eyes,ears and brain, suggesting that brain seat
  of reason and the soul.
• Humoral theory of Hippocrates most influential in
  history of Psychology and Psychiatry.
• Middle ages not a high spot in history of
  Psychiatry, possession by the devil,
  demons,science could not develop further in that
  climate.

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Hippocrates - Treatments
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History of Psychopharmacology(3)

• In the age of enlightenment psychiatry developed
  in different directions in the different European
  countries depending on local political and social
  circumstances. Essential features
• a)Spatial segregation of the insane outside
  cities
• b)Gradual rediscovery of the medical model
• c)Attempts to return the insane to a normal life
  through work etc.

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History of Psychopharmacology(4)

• Earliest compendia Schneider (1824).
• Early 19C considerable advances in England and
  France. Classification of illnesses . Esquirol
  (1838) used the term maladie mentale instead of
  alienation. Marked triumph of medical model
  over spiritualistic accounts.
• German school underwent similar, Kraeplin
  (1899)created psychiatric classification still
  used today.
• Modern psychopharmacology linked to discovery of
  chlorpromazine as an antipsychotic drug.Laborit
  safer anaesthetic, drug company Rhone-Poulenc in
  Paris looking for antihistamines,psychiatrists
  interested in biology ready to try drugs.
• Delay Deniker(1952) read Laborits reports and
  asked company for samples. Beneficial effects.

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Behavioural Pharmacology

• Study of how drugs affect behaviour
• Test novel compounds as potential new treatments
• Ascertain mechanism of action of current
  treatments
• Establish biological/toxicological effects of
  drugs of abuse/food

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Drug A Drug B

• Increased activity
• Increased alertness
• insomnia
• tachycardia
• diuresis
• high doses seizures

• Increased activity
• increased alertness
• increased respiration
• insomnia
• tachycardia

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Drug C Drug D

• Relaxation
• elevation of mood
• increased appetite
• loss of inhibition
• anxiolytic
• fatal at high doses

• Increased alertness
• tachycardia
• increases respiration rate
• fatal at high doses

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Hallucinogenic Drugs

• PCP, LSD,Psilocybin,MDMA,Mescaline
• Ability to markedly alter sensory perception,
  awareness, thoughts
• With the exception of MDMA use is now low approx
  8 of population have tried at some time in their
  lives

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Hallucinogenic Drugs

• Consist of a number of different drugs with
  varying chemical structures and behavioural
  effects
• Ability to alter sensory perception, awareness,
  thoughts
• Other terms have been phantasticants,psychotomimet
  ic, Psychedelic

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Nomenclature

• Belong to several chemical classes
• 1. Phenethylamines (mescaline)
• 2. Indolealkylamines (psilocibin)
• 3. Lysergamides (LSD)
• Amphetamine derivatives (MDMA)
• Also dissociative anaesthetics produce
  hallucinogenic effects but pure hallucinogens don
  not produce anaesthesia at high doses. (PCP,
  Ketamine).

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LSD(D-Lysergic acid diethylamide) (1)

• Synthetic drug related to a number of compounds
  found in ergot fungus
• In 1940s Hofman discovered hallucinogenic
  properties
• Produced a distortion of perceived reality,
  Visual and auditory illusions and synesthesias.

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Chemical structure of hallucinogenic drugs
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Drug Discrimination procedure 1)Repeated
pairings of drug with a specific lever (training
drug) 2)If give drug with similar pharmacological
mechanism of action will respond on drug lever as
if received training drug 3)If give training drug
and antagonist will respond as if received
placebo
Drug with known action (e.g. 5HT agonist) Left
lever gives food
Saline/placebo Right lever gives food
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EFFECTS ON SEROTONIN RECEPTORS (2)
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EFFECTS ON SEROTONIN RECEPTORS (1)

• Affects serotonergic pathways in the brain
• In the locus coeruleus (LC) and the cerebral
  cortex the actions of indoleamine and
  phenethylamine hallucinogens have been shown to
  be mediated via 5HT2 receptors
• Mescaline is a partial agonist at 5HT2 (mainly
  5HT2A) receptors
• 5HT2A receptor stimulation promotes glutamate
  release

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Hallucinogenic drugs (2)

• Most hallucinogens are derived from plant
  substances and similar to biogenic amines in
  structure
• Often used in religious ceremonies and folk
  medicine
• Stone statues of psychoactive mushrooms date from
  well before 500 BC

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PCP Phencyclidine 1- phencyclo

• Early studies showed anaesthetic effect but
  patients showed a catatonic like state
  (Dissociative anaesthetics)
• Angel dust on street, produces signs of
  intoxication as shown by staggering gait, slurred
  speech catatonia at high doses

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ORIGINS

• Present in two cacti

• San Pedro
• Trichocereus pachanoi

• Peyote
• Lophophora williamsii

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SAN PEDRO CACTUS

• Mainly found in the Andes
• Used in Peru for over 3000 years
• Contains other psychoactive alkaloids
• Mescaline is highly concentrated in the skin
• The skin is peeled, dried and made into a powder
• NATIVES- Boil slices of stem, cool and drink the
  liquid

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USE IN PSYCHIATRIC RESEARCH

• Common experiences between hallucinogen-induced
  states and schizophrenia
• Hallucinogens used to model psychoses
• Due to widespread abuse of hallucinogenic drugs
  research ended
• Current revival of interest in this area of
  research
• Some studies suggest hallucinogen-induced states
  are appropriate models for acute stages of
  schizophrenia only

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MDMA (Ecstasy)3,4-methylenedioxymethamphetamine

• Although an amphetamine anlaogue classed as
  hallucinogen not as stimulant because it changes
  perceptual awareness
• Causes feelings of euphoria, tingling and a sense
  of increased sociability (love drug)
• Enhances release DA and 5-HT

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MDMA (Ecstasy)3,4-methylenedioxymethamphetamine

• Widely used a recreational drug
• (18 University students GB, c.60- all clubbers)
• Very intense positive effects on mood and
  wellbeing
• Mechanism of this positive effect?
• (Liechti Vollenweider (2001)-citalopram,
  ketanserin, haloperidol
• Psych effect- serotonin
• Stimulant effects- dopamine

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Ecstasy use?

• Changing from infrequent to Frequent
• Route is mainly oral
• Physiological effects temperature control
• Induces changes in homeostatic control of bosy
  temperature due to altered hypothalamic function.
• Malberg Seiden(1998)- rats increase in temp
  in MDMA not control
• 85-90 users report increase in body temperature

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MDMA Neurotoxicity

• Highly neurotoxic shown using biochemical and
  histological methods
• Highly selective neurotoxicity for 5-HT system,
  loss of fine axon endings that arise from the
  dorsal raphe nucleus
• Too early for longitudinal studies in
  humansMcCann (1994) showed lower CSF 5-HIAA in
  MDMA users

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5-HT(serotonin) Syndrome

• Gillman (1999) SS caused by drug induced excess
  of intrasynaptic 5-HT.
• Symptoms behavioural hyperactivity,
  agitation,mental confusion,hyperrefelxia,
  tachycardia,shivering, clonus,tremor
• Parrott (2002) clubbers show many signs of 5-HT
  syndrome part. Hyperactivity, jaw-clenching

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Mid-Week Blues

• Poor moods, anhedonia, lethargy reported.
  Parrott Lasky (1998)
• Baseline study before,during after MDMA.
• 2 days-increased depression, unpleasantness,
  unsociable,sadness in MDMA, Back to baseline by
  day 7.
• Topp et al(1999) energy loss, irritability

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Neurotoxic?

• Long term damage first shown in 1980s. Rats
  treated with successive doses of MDMA loss of
  5-HT markers 5-HT, 5-HIAA,5-HT uptake sites
  (Ricaurte, 1985, Schmidt, 1986).
• Temperature a key factor-greater neurotoxicity
  under high ambient temperatures, coller
  protective (Malberg Seiden, 1998).
• Recovery occurs over several months in lab rats,
  monkeys and primates only partial recovery even
  after extended period (Ricaurte 2000)

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Neurotoxic ? Contd

• Humans-
• PET scan (McCann, 1998) reduced density of 5-HT
  transporter sites correlated with extent of past
  ecstasy use. Semple (1999) decreased density 5-HT
  transporter sites in neuroimaging study
• McCann (1994) gender effect F greater 5-HIAA
  reduction (-46) than M (-20) compared to
  non-MDMA users.

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Neurotoxic?contd

• Renemann (2000) SPECT investigation of 5-HT2A
  receptor density and cog test.
• Increased 5-HT2A receptor density occ cortex-
  upregulation following drug induced depletion.
  Impairment in verbal learning (8.1 vs 12.3 words
  recalled) (.98 corr Verb lear/5-HT2A density)
• Fox et al (2001) heavy vs light users. Lower
  spatial working memory. Using CANTAB profile
  similar to frontal lobe neurosurgical patients

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Psychiatric Consquences?

• Numerous case studies major depression, panic
  disorder, aggressiveness, phobic anxiety,eating
  disorder,schizophrenia. Not necessarily typical.
• Schifano (1998) 150 attendees drug clinic
• Higher depression, psychotic disorder, cog
  impairment,bulimia,impulse control,panic
  disorder. Atypical group?
• Parrott (2002) polydrug vs cannabis, heavy and
  light MDMA users. Only slight diffs between
  polydrug users and MDMA users.

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Elevated plus maze test anxiety
Closed arms
Open arms
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Plus maze anxiety from Mechan, Moran et al (2002)
following MDMA
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MDMA is a prime example of how animal and human
research are often complementaryGeorge Ricaurte
(2002)
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MDMA and Dopamine

• Early studies showed increase in release of
  extracellular levels of 5-HT AND Dopamine
  (Nichols (1982), Kanaapaa (1998)
• Tissue concentration of DA decreased (Schmidt
  (1986), Green(1994)
• Extracellular DA levels deacreased microdialysis
  (Sabol Seiden,1998)

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MDMA Dopamine

• MDMA effects are different in rat and mouse. In
  both a rapid 5_HT release immediately but in mice
  much less. Mice show lowered striatal DA
  concentration (Stone et al,1987, OShea et al,
  2001).
• I.e.Long term effect of MDMA in mice is
  neurotoxic damage to dopamine but not 5-HT while
  reverse is true in rats

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MDMA Dopamine Neurotoxicity

• SOD gene knockout mice resistant to neurotoxic
  action of MDMA (Cadet 1995)
• Suggests overproduction of free radicals role in
  MDMA induced neurodegeneration
• Camarero(2002) protective effect of DA uptake
  inhibitor GBR12909 agonist on MDMA induced
  increase in lipid peroxidation in striatal
  synaptosomes

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Camarero et al (2002)

• Dopamine Concentration in striatum(ng/g tissue)
• Saline 11,455 /- 266
• MDMA 8,411 /- 585
• MDMAGBR 11,124 /- 230

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Dopamine MDMA (human study)

• Gerra et al (2002)
• Prolactin and growth hormone responses to DA
  agonist bromocriptine psychometric measures 3
  weeks after stopping MDMA.
• GH responses to Bromocriptine significantly
  reduced in MDMA users. Measurement of novely
  seeking inversely correlated to GH response.
  Demonstrates a direct pharmacological action of
  MDMA on brain DA function in humans.

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Severe Dopaminergic neurotoxicity in primates
after a common recreational dose regimen of MDMA
("ecstasy")Ricaurte GA, Yuan J, Hatzidimitriou
G, Cord BJ, McCann UDSCIENCE
297 (5590) 2260-2263 SEP 27 2002
AbstractThe prevailing view is that the
popular recreational drug (/-)3,4-methylenedioxym
ethamphetamine (MDMA, or "ecstasy") is a
selective serotonin neurotoxin in animals and
possibly in humans. Nonhuman primates exposed to
several sequential doses of MDMA, a regimen
modeled after one used by humans, developed
severe brain dopaminergic neurotoxicity, in
addition to less pronounced serotonergic
neurotoxicity. MDMA neurotoxicity was associated
with increased vulnerability to motor dysfunction
secondary to dopamine depletion. These results
have implications for mechanisms of MDMA
neurotoxicity and suggest that recreational MDMA
users may unwittingly be putting themselves at
risk, either as young adults or later in life,
for developing neuropsychiatric disorders related
to brain dopamine and/or serotonin deficiency.
WITHDRAWN
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Study focus points Refs

• Which are the hallucinogenic drugs
• What is the evidence that MDMA has behavioural
  consquences, can this be related to
  neurotoxicity?
• The field has enlarged its focus from serotonin
  to include Dopamine in 2002 why?
• Given their low abuse potential why study
  hallucinogenic drugs?

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Some useful general texts

• Rosenzweig, Breedlove Leiman Biological
  Psychology
• Leonard. Principles of Psychopharmacology
• Feldman Principles of neuropsychopharmacology
  (very detailed
• more suitable for final year but very
  comprehensive)
• 4. McKim Drugs and Behaviour
• Much of the lecture material is based on up to
  date scientific material
• In addition recent reviews quoted in individual
  lectures which are
• Available as PDFs from www.sciencedirect.com
  (log in using Athens
• Password) or web of science details on library
  home pages

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References

• Parrott, A.C. (2002) Recreational ecstasy/MDMA.
  Pharmacology,Biochemistry,Behavior, 71, 837-844.
• Kish, S.J.(2002)What is the evidence that brain
  serotonin neurons are damaged in human users of
  ecstasy , Pharmacology,Biochemistry,Behavior, 71,
  845-855.
• Drug discrimination procedure http//www.acnp.org/
  g4/GN401000072/CH072.html
• Hallucinogenic drugs RM Julien, A Primer of Drug
  action , Worth publishers , 2001. Chapter 12.
  Most text books contain a section devoted to
  hallucinogenic drugs.
• e.g. McKim Drugs and behavior