Lecture 6 – amino acid NTs GABA Glutamate

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Lecture 6 amino acid NTsGABA
Glutamate
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Amino acid NTs

• GABA (gamma-aminobutyric acid) the principal
  inhibitory NT, found throughout the brain and
  spinal cord
• glutamate (also called glutamic acid) the
  principal excitatory NT, found throughout the
  brain

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Glutamate

• the principal excitatory NT in the brain -
• used in about 20 of synaptic connections between
  neurons
• MSG monosodium glutamate
• some people experience mild neurological symptoms
  (dizziness, numbness) after eating food
  containing high levels of MSG

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Glutamate

• there are different sub-types of glutamate
  receptor, but the most studied is the NMDA
  (N-methyl-D-aspartate) receptor -
• important role in learning memory responsible
  for initiating long-term changes in the brain
  associated with memory formation,
• also implicated in drug addiction (especially
  alcoholism),
• and in schizophrenia

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• NMDA receptor antagonists inhibit excitatory
  effects of glutamate
• ketamine phencyclidine (PCP) -
• have sedative anaesthetic effects at high doses
• hallucinogenic dissociative effects at lower
  doses
• low dose effects replicate both positive and
  negative symptoms of schizophrenia
• alcohol also acts as an NDMA antagonist

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Ketamine PCP

• early studies with PCP showed it could produce an
  extended psychotic breakdown in some individuals,
  and this drug is no longer used in human research
• ketamine is used in research with human subjects
  although its acute effects are similar, they
  are less intense and have a shorter duration
  adverse reactions are rare and follow-up of
  participants show no long-term effects (Perry et
  al, 2007)

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Acute effects of ketamine

• feeling drunk- euphoria, dizziness, nausea
• disordered thought and speech
• memory impairment
• perceptual distortions and dissociation-objects
  and surroundings seem unreal
• delusional thinking - often of a paranoid nature

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Brief Psychiatric Rating Scale (BPRS)

1 Somatic concern NA 1 2 3 4 5 6 7 2 Anxiety
NA 1 2 3 4 5 6 7 3 Depression NA 1 2 3 4 5 6 7
4 Guilt NA 1 2 3 4 5 6 7 5 Hostility NA 1 2 3
4 5 6 7 6 Suspiciousness NA 1 2 3 4 5 6 7 7
Unusual thought content NA 1 2 3 4 5 6 7 8
Grandiosity NA 1 2 3 4 5 6 7 9 Hallucinations
NA 1 2 3 4 5 6 7 10 Disorientation NA 1 2 3 4 5 6
7 11 Conceptual disorganisation NA 1 2 3 4 5 6
7 12 Excitement NA 1 2 3 4 5 6 7 13 Motor
retardation NA 1 2 3 4 5 6 7 14 Blunted affect NA
1 2 3 4 5 6 7 15 Tension NA 1 2 3 4 5 6 7 16
Mannerisms and posturing NA 1 2 3 4 5 6 7 17
Uncooperativeness NA 1 2 3 4 5 6 7 18 Emotional
withdrawal NA 1 2 3 4 5 6 7

• Instructions
• Circle the number that best describes the
  patients present condition. If a specific
  symptom is not being assessed, circle NA.
• 1 not present
• 2 very mild
• 3 mild
• 4 moderate
• 5 moderately severe
• 6 severe
• 7 extremely severe

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BPRS scores during double-blind
placebo-controlled intravenous ketamine infusion
(Newcomer et al, 1999)
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Ketamine memory

• studies consistently show impairment of episodic
  memory following sub-anaesthetic doses of
  ketamine, across a wide variety of tasks
• recognition memory, recall of spoken prose,
  recall of word lists, spatial learning, source
  memory tasks

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GABA

• the principal inhibitory NT in the brain -
• used in about 40 of synaptic connections between
  neurons
• GABA receptors are complex -
• binding sites for different chemicals on the same
  receptor

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GABA agonists

• benzodiazepines, barbiturates alcohol all
  enhance the inhibitory effects of GABA
• these drugs all have anxiolytic, sedative
  hypnotic effects
• i.e. they reduce anxiety, produce physical
  relaxation promote sleep

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GABA antagonists

• picrotoxin a poisonous plant alkaloid with
  stimulant properties
• flumazenil benzodiazepine antidote
• blocks benzodiazepine site binds but does not
  activate
• used to treat overdose, and to reverse the
  sedative effects of benzodiazepines in
  post-operative patients

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Anxiolytics

• anxiolytic drug used to reduce anxiety
• barbiturates are direct GABA receptor agonists
  bind to and activate GABA receptors
• benzodiazepines do not directly activate GABA
  receptors they enhance the effects of
  endogenous GABA, but GABA must also bind to
  receptor for drug to have effect

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Barbiturates

• amobarbital, pentobarbital, secobarbital,
  phenobarbital, etc.
• first available in 1903 (Barbital)
• euphoric effects of these drugs mean they have
  high potential for abuse, dependence addiction
• increasing dose leads to increased central
  nervous system depression
• sedation ? sleep ? coma ? death
• pronounced respiratory depression (especially
  when mixed with alcohol) means high risk of fatal
  overdose

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Benzodiazepines

• first available in 1960 (Librium)
• have replaced barbiturates in treatment of
  anxiety disorders and insomnia -
• produce less respiratory depression
• have pronounced sedative effect, but less
  euphoric
• lower incidence of dependence (but may still
  occur in 10-30 of long-term users)

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Benzodiazepines

• many different benzodiazepines (BDZs) are now
  available -
• diazepam (Valium), temazepam (Restoril),
  lorazepam (Ativan, Temesta), alprazolam (Xanax),
  midazolam (Dormicum), etc.
• these differ in potency, primary effect
  (anxiolytic, hypnotic, muscle relaxant), time to
  produce effect, and duration of effect

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Benzodiazepines

• the most commonly prescribed psychotropic drugs
  in the world
• estimated 20-30 of adult population are
  prescribed BDZ at some time
• up to 5 of adult population on long-term (one
  year or more) prescriptions
• used in treatment of anxiety disorders, insomnia,
  drug alcohol withdrawal
• also used as pre-anaesthetics muscle-relaxants
  in surgical operations

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Benzodiazepines

• side-effects
• drowsiness (e.g. following day when BDZ is used
  for insomnia)
• impaired motor co-ordination balance
• slowed reaction times
• impaired vigilance task performance
• impaired memory performance

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Benzodiazepines memory

• effects are found mainly for long-term episodic
  memory short-term memory is less affected
  semantic memory is generally intact (see Curran,
  1999)
• studies consistently show anterograde amnesia
  i.e. memory impairment for information presented
  after the drug has been administered
• but not retrograde amnesia i.e. no impairment
  for information learned before drug
  administration
• suggests impairment of encoding processes rather
  than retrieval

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Measuring drug effects in on-the-road driving
(Verster et al 2005, Current Psychiatry Reviews
1, 215-225)
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Alprazolam (Xanax) driving - Verster et al
(2002)

• (A) Weaving (SDLP)
  (B) Speed variability

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Alcohol
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• alcohol any drink containing ethanol (ethyl
  alcohol)
• produced by fermentation (conversion of sugar to
  alcohol by yeast)
• probably the oldest recreational drug -
  archaeological evidence for beer wine since
  about 10,000 years
• acute subjective effects of alcohol are biphasic
  -
• low doses are mildly stimulating
• high doses have the opposite effect i.e. are
  sedating or depressant

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Biphasic effect of alcohol

• BAL (U.S.) measured in grams of alcohol per 100ml
  of blood
• BAC measured in grams per litre, or mg per 100ml
  (U.K.)
• U.K. legal driving limit .08g/100ml (BAL)
  0.8g/l 80mg/100ml

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Alcohol neurotransmitters

• alcohol is a pharmacologically messy drug
• acute effects on NT systems are wide-ranging and
  complex -
• increases inhibitory NT activity (GABA)
• decreases excitatory NT activity (glutamate)
• this causes knock-on effects on other NT systems
  throughout the entire brain

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Alcohol abuse dependence

• chronic alcohol abuse leads to adaptations in
  physiological processes that act in opposition to
  drug effects in order to maintain homeostasis
• sudden withdrawal of alcohol leads to rebound
  effects, which are opposite to the effects of
  drug
• these are experienced as an unpleasant withdrawal
  syndrome, which can only be alleviated by
  reinstating alcohol use
• so individual becomes dependent on alcohol for
  normal functioning

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Opponent processes in alcohol abuse(see
Valenzuela, 1997)
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• acute withdrawal effects in long-term alcoholics
  
• anxiety, delirium, hallucinations potentially
  fatal seizures
• these reflect state of excessive neural
  excitation
• alcohol withdrawal symptoms are reduced by
  administering benzodiazepines (to enhance
  inhibitory GABA-ergic activity)

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Alcohol task performance

• although acute subjective responses to alcohol
  are biphasic, effects on psychomotor performance
  appear to be linear
• i.e. even low-to-moderate doses (which may be
  subjectively stimulating) can impair task
  performance
• impairment in psychomotor tasks (simple choice
  reaction time, vigilance) is evident before
  subject is drunk and at BAC levels that are
  below the legal driving limit
• impairment increases with increasing dose -

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Effects at different blood alcohol concentrations
(BAC in grams of alcohol per litre of blood)
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Alcohol task performance

• performance is most affected on more complex
  tasks (see Kerr Hindmarch, 1998)
• so a low dose that doesnt impair performance on
  simple psychomotor tasks may still have a
  negative effect on more complex tasks (e.g.
  driving)
• alcohol also produces anterograde amnesia in
  memory tasks

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Effects of 0.8g/kg alcohol on Tower of London
task ITT log. initial thinking time, STT
log. subsequent thinking time (from Weissenborn
Duka 2003, Psychopharmacology 165, 306-312)
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Alcohol TOL task - Weissenborn Duka (2003)

• all differences are plt.05
• time to first move (ITT) is shorter in subjects
  given alcohol
• but subsequent thinking times (STT) are longer
• and fewer perfect solutions are achieved
• shorter ITT may reflect increased impulsivity
• mean BAC in alcohol group at time of testing was
  lt 0.6 g/l
• legal driving limit is 0.8 g/l

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Glutamate GABA - summary

• glutamate - the principal excitatory NT in the
  brain
• NMDA glutamate receptors have an important role
  in learning memory, schizophrenia addiction
• ketamine NMDA receptor antagonist that produces
  acute dissociation schizophrenic-like symptoms
• GABA - the principal inhibitory NT in the brain
• GABA agonists (benzodiazepines, barbiturates,
  alcohol) have anxiolytic, sedative hypnotic
  effects
• benzodiazepines are the most widely prescribed
  psychoactive drugs in the world used to treat
  anxiety insomnia, side-effects include impaired
  reaction time, attention memory
• alcohol is both a GABA agonist a glutamate
  antagonist
• long-term alcohol abuse alters balance of
  inhibitory/excitatory neurotransmission, which
  can lead to alcohol dependence withdrawal
  syndromes
• acute subjective effects of alcohol are biphasic
  (low doses feel stimulating, high doses
  sedating), but even low doses can impair
  cognitive performance especially on complex
  tasks (problem solving, driving)

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Learning outcomes

• Be able to describe the acute effects of ketamine
  intoxication, and how these are related to the
  positive and negative symptoms of
  schizophrenia.
• Know the main conditions for which benzodiazepine
  drugs are prescribed, and understand the
  neuro-chemical basis of the therapeutic effects
  and side-effects of these drugs.
• Understand the psychopharmacological basis for
  the acute effects of alcohol, and the mechanisms
  underlying alcohol dependence and withdrawal
  syndromes.

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Recommended reading

• GLUTAMATE KETAMINE
• JW Newcomer et al (1999) Ketamine-induced NMDA
  receptor hypofunction as a model of memory
  impairment and psychosis. Neuropsychopharmacology
  20, 106-118
• EB Perry et al (2007) Psychiatric safety of
  ketamine in psycho-pharmacology research.
  Psychopharmacology 192, 253-260
• GABA ANXIOLYTICS
• HV Curran (1999) Effects of anxiolytics on
  memory. Human Psychopharmacology 14, S72-S79
• JC Verster et al (2002) Effects of alprazolam on
  driving ability, memory functioning and
  psychomotor performance. Neuropsychopharmacology
  27, 260-269

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• ALCOHOL
• JS Kerr I Hindmarch (1998) The effects of
  alcohol alone or in combination with other drugs
  on information processing, task performance and
  subjective responses. Human Psychopharmacology
  13, 1-9
• CF Valenzuela (1997) Alcohol and neurotransmitter
  interactions. Alcohol Health Research World 21,
  144-148