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Anxiety, barbiturates and benzodiazepines
Characteristic of anxiety disorders
Anxiety :
 suffering
 low productivity
 poor quality of life
Occurrence :

10 to 30%
Expression :
 panic
 phobia
 compusilve behaviour
 negativing thinking patterns
Anxiety and depression : 58 % of depressions show
anxiety disorders
GABAergic system
GABA receptors : control fear and anxiety due to over-excitation
of neurons
Major inhibitory neurotransmission in the brain (specially
cortex, hippocampus)
GABA is estimated to be present in 40% of all synapses
in the human brain

 It is an Inhibitory neurotransmitter : as opposed to
excitatory neurotransmitters such as glutamate.
 It is thus reducing the excitability of the post synaptic
side of the synapse
 2 types : ionotropic (proeminent target for drugs) and
metabotropic
GABAergic system
Structure and function of the GABAa receptor :
 It is an Chloride (Cl-) ion channel. Slightly change shape to
allow passage.
 cause an hyper polarization of the membrane of the
postsynaptic cell
 Sensitive to CNS-depressants drugs as barbiturates and
benzodiazepines (and also alcohol)
 BB and BDZ potentiate the effect of GABA on the GABAa
receptor
The GABAA receptor : a chloride-conducting channel
GABA
 BB and BDZ increase the potency of GABA to open the
receptor channel (increase the number of time the
channels open, not the duration of the opening)
 do not induce the opening if the receptor channel without
GABA
 anti-convulsants, anxiolytics effects
Effects of GABA and diazepam (benzodiazepine) on membrane potentials and chloride flux (Part 1)
serotonin
Serotonin :
 Produced from the raphe nuclei in the brainstem
 Modulate :
 Appetite
 Sleep
 Mood
 Libido
 Cognitive functions
Amygdala
Amygdala : greek for almond (due to its shape)
 Play a key role in fear reactions
 Essential to feel certain emotions and to perceive
them in other people.
 Receive the messages warning of danger :
 Direct route from the thalamus
 Slower route via the cortex
Amygdala
Receive the messages warning of danger :
 Direct route from the thalamus
 Slower route via the cortex
Amygdala
Amygdala :
 Information input through the lateral nucleus
 Response output through the central nucleus
The amygdala coordinates components of emotion
amygdala
Amygdala :
 Under the control of other structures that can
influence the emotions :
 Hippocampus (emotion memory-induced)
 Frontal cortex (mature only in early aldulthood)
 Hypothalamus
Lesions of amygdala :
 interfere with manifestations of fear :
 behavioral inhibition
 autonomic response
 suppression of pain
 release of stress hormones
 potentiation of reflexes
What is anxiety?
Expressions of worries and concerns :

worried facial expression

muscle tension

restlessness

impaired concentration

sleep disturbance

irritability
 autonomic system activation (HR, sweating, shortness
of breath)
Use? :

fight or flight response : crucial for survival

necessary stimulus for optimal performance
Anxiogenic vs Anxiolytic :

anxiogenic : that create anxiety

anxiolytic : that reduce anxiety
Three-component model of anxiety
Anxiety disorders
Anxiety disorders are not everyday worries (acute anxiety)
5 principal categories :

generalized anxiety disorders (GAD)

panic disorder

phobias

post-traumatic stress disorders

obsessive-compulsive disorder (OCD)
Generalized anxiety disorder
Definition : to be worry constantly without objective reason to be
concerned
5% of the population between 15 and 45
Develop in teens and early adulthood
Characterization :

no real focus

present all day long

duration for month or years

constant worry

prediction of dreadful events
 lost of interest and pleasure from task
Symptoms :

muscle tension

agitation
Leading to fatigue, poor concentration,
irratibility, and sleep disturbance
Phobias
Characterization :
 specific fear of objects or situations
 triggered by a specific stimulus
 completely irrational and disproportionate to the
actual risk
 can turn into a panic attack if very intense
 link to traumatic personal experience
 possibility of biological predisposition
 fear in children is part of their normal development
phobias
High places, close-in spaces, water, mice, snake, spiders or speaking
in public.
Can be lowered by avoiding the situation.
But for some of them, it is more difficult to avoid the situation
(claustrophobia….) and can lead to a poor quality of life.
Symptoms as panic (arousal of the ANS , heart, respiration, sweating
etc…)
Treated by behavioral therapy : presenting the fear-inducing stimulus,
while keeping a relaxing state during presentation of the stimulus
(behavioral desensitization)
Rarely need medication
For the social phobias (fear to be embarrassed in public), cognitive
therapy to modify negative thoughts (looking foolish) and social skill
training are beneficial
Phobias
Region involved :

amygdala
Phobias
Panic attacks and panic disorder
Characterization :
 “unjustified” fear (anticipated fear without reason)
 can occur WITHOUT particular stimuli :
 Without warning
 Place related
Symptoms :

heart pounding or chest pain

sweating

shortness of breath

faintness

choking

fear of losing control or dying
Strong arousal of the
autonomic nervous
system
Amygdala (central nucleus) and locus coeruleus (Norepinephrine) involved
Panic disorder
 twice as many women than men
 33% of the population will suffer an attack/year, but
disorders is only 1% of the population.
 Last only a few minutes, but can go up to 10minutes
 Can occur at any age, most likely in early adulthood
 predisposition :
 anxiety in childhood
 overprotective parents
 substance abuse
Agoraphobia
Post-traumatic stress disorder
Occurs after :
 traumatic events (rape, abuse, war, natural disaster…)
Symptoms :

nightmares

flashbacks

increased physiological reactivity to the traumatic events

sleep disturbances

avoidance of stimuli linked to the trauma

can induce sudden irritability

detachment from others

diminished interest in life activities
PTSD
Intrusion symptoms :
 experienced memories of the traumatic events is haunting patients
Avoidance symptoms :
 stay away from situations that trigger the situation
 avoid speaking about the event
 dulling of emotions : lost of interest in things
Overstimulation symptoms :
 hypervigilance : hard to concentrate
 insomnia and nervousness
 easily frightened
 sense of imminent danger
 highly irritable
 violent behavior
PTSD
Individuals suffering PTSD have a greater incidence of suicide, as
fro substance abuse, marital problems, depression, feeling of guilt
and anger….
Prevalence varied with the trauma :
3% in personal attacks, 4-16% in natural disasters, 30% of
war veterans, 50% of person raped, 50 to 75 % of tortured
prisoners of war
If prevalence depend of the trauma, it is also variable between
individuals…
Familial studies showed that 74% of people having PTSD
disorders had a family history of psychopathology (PTSD, anxiety,
depression..)
The perception of the trauma could be different between
individual and explain the difference in occurrence
PTSD
Region involved :

hippocampus
 Amygdala
PTSD
Hippocampus :
 Where memory are processed and stored
 Stress of the traumatic event might induce a reduction
in the hippocampus size  explicit memory disturbances,
flashbacks, fragmentary memory of the event.
 Changes in activity could also be responsible.
PTSD
Amygdala :
 more active than in normal people when bad memories
are recalled
PTSD
After traumatic events :
 repercussion for the first few weeks
 Will normally disappear within a month
 50-65% will recover within the first year
10-20% will be incapacitated for several year
 among combat veterans, up to 50%.
 sometimes, symptoms takes years to appear.
Obsessive-compulsive disorder
Characterization :

recurrent, persistent, intrusive thoughts :
 contamination
 violence
Causing anxiety, guilt, shame
 sex
 religion
 compulsions : rituals to relieve anxiety related or
not to the source of anxiety
 do not get any pleasure from it (vs bulimics or
compulsive gamblers).
 Know the irrationality of their behavior
 Keep it secret, reinforcing the stress.
 2% of the population (appear in childhood)
OCD

Obsessions :
 undesired thoughts
 Compulsions :
 uncontrollable behaviors designed to calm
obsessions
Occurrence of OCD symptoms (Part 1)
Occurrence of OCD symptoms (Part 2)
Neurobiological Model of OCD (Part 1)
Neurobiological Model of OCD (Part 2)
 abnormal activity in caudate and frontal lobe
 SSRI (selective serotonin reuptake inhibitors) reduce
hyperactivity of those regions (up to 25%)
Neurobiological Model of OCD (Part 3)
Treatment of anxiety
 anxiety is related to overactivation of area of the brain
(amygdala)
 tranquilizers are used to reduce the excessive brain activity,
reducing anxiety to an acceptable level
Treatment of anxiety
Tranquilizers will accomplish two things :
 let people get on with their daily life
 enables them to undertake some psychotherapy which is
crucial to a long-term cure.
Two major families of drugs are used as tranquilizers :
 anxiolytics : produce feeling of relaxation and reduce
symptoms of anxiety
 sedatives (or hypnotics): induce and/or maintain sleep
(reducing alertness if taken during the day)
 Benzodiazepine can be both (and proportion of those two
effects depends on the molecule used)
Animal models of anxiety
Drugs for treating anxiety
Name :

Anxiolytics (by opposition to Anxiogens)
Category :

sedative-hypnotics (part of the CNS depressants)
Drugs :

alcohol

barbiturates

benzodiazepines
Reduce neuron excitability by enhancing
the inhibitory effects of GABA
Effects expected :

relieving signs of tension and worries

relieving signs of stress
 inducing a relaxing state (but often link to
drowsiness, mental clouding, incoordination and
prolonged reaction time)

Higher doses induce sleep
Sedative effect
Hypnotic effect
Dose-dependent effects of CNS depressants on levels of consciousness
GABAergic system
Major inhibitory neurotransmission in the brain (specially
cortex, hippocampus)
Structure and function of the GABAa receptor :

It is an Chloride (Cl-) ion channel
 cause an hyper polarization of the membrane of
the postsynaptic cell
 Sensitive to CNS-depressants drugs as
barbiturates and benzodiazepines (and also alcohol)
 BB and BDZ potentiate the effect of GABA on
the GABAa receptor
The GABAA receptor : a chloride-conducting channel
Effects of GABA and diazepam (benzodiazepine) on membrane potentials and chloride flux (Part 1)
Effects of GABA and diazepam on membrane potentials and chloride flux (Part 2)
Barbiturates
- the oldest sedative hypnotics
- classified in three different pharmacokinetics category
- Used for treatment of anxiety disorders
- Replaced by benzodiazepines
Chemical structure of the barbiturates (Part 1)
(Seconal)
(Pentothal)
(Amytal)
Chemical structure of the barbiturates (Part 2)
(Nembutal)
(Luminal)
(Mebaral)
(Evipal)
Duration of action
Inactivate by deposing in
muscle and fat
Inactivate by liver
Side effects
Induce sleep, but :

alter sleep architecture (reduce REM sleep)

Cause a rebound in REM sleep after withdrawal
Reduce anxiety, but :

cognitive side effets :
 mental clouding
 loss of judgment
 slowed reflexes
 impaired driving

high doses :
 coma and death by respiratory depression
Side effects
VERY BAD COMBINATION WITH ALCOHOL!!!
Side effects
Increase liver enzymes :

increased metabolism of drugs leading to tolerance :
 Tolerance to mood changes and sedation effects
 NO tolerance in respiratory depressant effects
Side effects
Produce a significant physical dependence and potential use
for abuse :

extended treatment:
 Rebound:
 tremor
 intense anxiety
 High blood pressure and heart rate
 excessive sweating
 rapid breathing
 nausea
 vomiting
Withdrawal avoided by lowering doses slowly
Illicit use
Short/intermediate used as recreational drug :
- high reinforcement effect
Self administration in rats and monkeys showed the high
reinforcement potential of the barbiturates.
Street use could be oral ingestion of high doses as a substitute for
alcohol, or even worse, with alcohol to enhance the effects.
IV injection seems to give a sensation close to the heroin “high” (used
if heroin is not available, or even in combination with heroin)
No cross dependance between opiates and barbiturates, so
barbiturates are not reducing the withdrawal effects of heroin.
Barbiturates are also used in combination on CNS stimulant like
amphetamines to “smooth” the effect of the stimulant
Benzodiazepines
- highly effective for anxiety reduction
- low incidence on tolerance
- less severe withdrawal syndrome than barbiturates
- safe therapeutic index
- some can be used as anti-convulsants (epilepsy) (clonazepam
(rivotril) or diazepam (valium))
- not efficient in OCD and rarely prescribed in panic disorders
Molecular structure of several benzodiazepines
(Valium)
(Librium)
(Halcion)
(Serax)
Benzodiazepine metabolism
Long lasting can be a problem in elderly people (excretion slowed by
age, reduced metabolic capacity)
Therapeutic effects
Generally not used for deep anesthesia (as the barbiturates)
Useful for pre anesthesia : relaxing without loss of consciousness
(dental work or stressful diagnostic procedure)
Anxiety relieving

psychological : worries and fearfulness

physical : relaxation
Sedatives effects even disappear after a week (with nearly no tolerance
for the anxiolytic effects)
Long lasting BDZ can be used as hypnotics
 Shorten the time to fall asleep
 Increase sleep time
 reduce nighttime awakenings
Can be used as muscle relaxant or anti-convulsant
Used in the prevention of alcohol and barbiturates withdrawal
symptoms
Advantages over barbiturates
Very high therapeutic index :
 nearly no effect on the respiratory center
Very high doses can induce disorientation, cognitive impairments,
amnesia, agressivity, irritability, and anxiety…
But no effect on respiration, so lethal overdose is extremely rare
(expect when taken in combination with others CNS depressant as
alcohol, opiates …)
Flumazenil is a competitive antagonist for the BDZ receptor (help
unconscious people after BDZ ingestion)
Very high doses abuses can lead to more severe symptoms… panic
delirium or seizure
No liver enzyme increase (so nearly no tolerance)
BZD
Lower probability of physical dependence and abuse
But chronic use can induce a physical dependence
 abstinence syndrome milder than barbiturates
 not life threatening
 need several weeks to take place (specially with long
lasting BDZ)
 Symptoms :
 Insomnia
 Restlessness
 Headache
 Anxiety
 Mild depression
 Muscle pain
Endogenous molecules and the BDZ receptor
Inverse agonists of the BDZ receptor :
 β-carbolines :
 produce extreme anxiety and panic
Agonists of the BDZ receptor :
 Endozepines :
 Might be naturally increase
 Reflecting the use to cope with stress and
anxiety
Second generation anxiolytics
Developed to avoid side effects of the benzodiazepines :
 example of the Buspirone :
 different structure
 different mechanism of action
 reduce the cognitive aspects of anxiety
 but less effective for the physical symptoms
 can also treat the depression associate to anxiety
 can induce sedation confusion and mental clouding
 does not affect CNS depressant effect of alcohol or
other CNS depressant
 little or no potential for recreation use or dependence
 no rebound withdrawal syndromes
 need several weeks o daily use to obtain significant
anxiolytics effects
 no cross tolerance with BDZ, barbiturates or alcohol
 no hypnotic effect : no use in insomnia
Abstinence effect after chronic diazepam but not buspirone
Antidepressants
Alternative to treat anxiety : some drugs (SSRI) are effective
to treat anxiety and the depression syndrom associate to
the anxiety disorders
Mean rating of symptoms in patients with OCD treated with desipramine (NE) or clomipramine (5HT)
Treating Insomnia (Part 1)
Stage 1 et 2 : slow light sleep (50%) of the total sleep.
Stage 3 et 4 slow deep sleep (20 to 30% in a normal sleep, but is always “constant” around 100
minutes whatever duration of sleep : deep, physical recovery essentially
REM or paradoxal sleep (20%) : linked to dreams, and to the memorization process. Mental
recovery…
Cycle last around 90 minutes (awakening can happen at the end of each cycles but not
necessarily felt by the individual
REM sleep increase with the duration of sleep (and the deep sleep phases fades
Time latency to fall asleep can vary as duration of sleep need (from 5 to 10 hours)
Insomnia is a failure to fall asleep, to maintain sleep or dissatisfaction to fall asleep
Treating Insomnia (Part 2)
Treating Insomnia (Part 3)
Long term… awakening, nearly no REM etc….
When stopped, REM rebound with dreams might be more intense, nightmares…
BDZ : rapid onset and short action induce rapid sleep and are eliminated from the body during the
normal sleep
You can use longer lasting one for people not having trouble to find sleep but have early awakenings
(but can reduce alertness during the day too..)
The BDZ still induce an increase of the stage 2 sleep over the stage 4
Chronic use can also induce rebound.
A psychological dependance can occur too (afraid not to fall asleep if no pills taken)
Corticotropin Releasing Ractor and anxiety
Norepinephrine and anxiety