Anxiety, barbiturates and benzodiazepines

1. Anxiety, barbiturates and benzodiazepines

2. 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

3. 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

4. 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

5. The GABAA receptor : a chloride-conducting channel

6. 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

7. Effects of GABA and diazepam (benzodiazepine) on membrane potentials and chloride flux (Part 1)

8. serotonin Serotonin : • Produced from the raphe nuclei in the brainstem • Modulate : • Appetite • Sleep • Mood • Libido • Cognitive functions

9. 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

10. Amygdala Receive the messages warning of danger : • Direct route from the thalamus • Slower route via the cortex

11. Amygdala Amygdala : • Information input through the lateral nucleus • Response output through the central nucleus

12. The amygdala coordinates components of emotion

13. 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

14. 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

15. Three-component model of anxiety

16. 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)

17. Generalized anxiety disorder Leading to fatigue, poor concentration, irratibility, and sleep disturbance 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

18. 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

19. 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

20. Phobias Region involved : • amygdala

21. Phobias

22. Panic attacks and panic disorder Strong arousal of the autonomic nervous system 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 Amygdala (central nucleus) and locus coeruleus (Norepinephrine) involved

23. 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

24. Agoraphobia

25. 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

26. 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

27. 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

28. PTSD Region involved : • hippocampus • Amygdala

29. 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.

30. PTSD Amygdala : • more active than in normal people when bad memories are recalled

31. 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.

32. Obsessive-compulsive disorder Characterization : • recurrent, persistent, intrusive thoughts : • contamination • violence • sex • religion Causing anxiety, guilt, shame • 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)

33. OCD • Obsessions : • undesired thoughts • Compulsions : • uncontrollable behaviors designed to calm obsessions

34. Occurrence of OCD symptoms (Part 1)

35. Occurrence of OCD symptoms (Part 2)

36. Neurobiological Model of OCD (Part 1)

37. 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%)

38. Neurobiological Model of OCD (Part 3)

39. 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

40. 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)

41. Animal models of anxiety

42. Drugs for treating anxiety 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 Name : • Anxiolytics (by opposition to Anxiogens) Category : • sedative-hypnotics (part of the CNS depressants)

43. Dose-dependent effects of CNS depressants on levels of consciousness

44. 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

45. The GABAA receptor : a chloride-conducting channel

46. Effects of GABA and diazepam (benzodiazepine) on membrane potentials and chloride flux (Part 1)

47. Effects of GABA and diazepam on membrane potentials and chloride flux (Part 2)

48. Barbiturates • the oldest sedative hypnotics • classified in three different pharmacokinetics category • Used for treatment of anxiety disorders • Replaced by benzodiazepines

49. Chemical structure of the barbiturates (Part 1) (Seconal) (Amytal) (Pentothal)

50. Chemical structure of the barbiturates (Part 2) (Nembutal) (Mebaral) (Evipal) (Luminal)