drugsandthe brain part5 antianxiety drugs

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  • 1.Drugs and the Brain Part 5 Anti-anxiety DrugsThe Benzodiazepines

2. Anxiety

  • A broad label difficult to define
  • Sometimes the terms 'fear' and 'anxiety' are used interchangeably
  • Fear is the short-term response produced by stress.
    • The amygdala may be a control center for fear, receiving fear-related sensory information and transmitting fear-related motor instructions.
  • Anxiety has similar symptoms to fear, but persists after the stress has ended.
    • A fear response in the absence of appropriate stimulus

3. Anxiety Produces Physical Symptoms

  • Increased autonomic activity leads to:
    • increase in blood pressure
    • increase in heart rate
    • erratic respiratory rate
    • decreased salivary flow leading to dry mouth & throat
    • gastrointestinal disturbances

4. Sedatives

  • Sedating drugs were commonly prescribed for anxiety in the 1 sthalf of this century
  • Phenobarbitol & other barbiturates did not specifically address anxiety
  • Are addictive, so only useful for short periods of time

5. Muscle Relaxants

  • 1945 - A pharmacist trying to develop an antibacterial agenteffective against Gram-negative bacteria (resistant to penicillin) made the first discovery
    • Tested safety of proposed drug in mice
    • Mice became paralyzed because of massive muscle relaxation, but remained conscious
  • This drug, mephenesin, became a muscle relaxant used to treat spasticity
    • Mephenism also appeared to have a tranquilizing effect, making patients calm but not sleepy

6. Miltown

  • Calming effects of mephenesin led to exploration of derivatives that might treat anxiety
  • Meprobamate was a derivative that had both muscle relaxant and strong anti-anxiety effect
  • Marketed as Miltown, this drug was thought to be more specific, non-sedating, and non-addictive.
    • None of these claims proved to be true

7. The First Benzodiazipines

  • Pharmaceutical companies sought other drugs with properties similar to Miltown
  • Since molecular basis was unknown, random chemicals were screened for anti-anxiety effects
  • Roche Pharmaceuticals screened a class of compounds called quinazolines
    • These were totally ineffective
  • The last compound in this series was tested a year after the project was abandoned
  • An error in synthesis had produced a compound that was not a quinazoline
  • This compound was an effective anti-anxiety drug
  • This was the first benzodiazepine, Librium

8. Continued Development

  • Looked for derivative of Librium
  • Most effective, Valium, was marketed in 1963
  • These drugs relieve anxiety with some drowsiness, but patients adapt
  • Are somewhat addictive & produce tolerance
    • Less so than barbiturates or meprobamate
  • Comparatively safe; rarely lethal
    • Led to widespread over-use

9. Use & Abuse of Benzodiazepines

  • Widely prescribed to ease every-day problems not associated with anxiety
  • Mid-1970s some estimated 1 million Valium addicts in the US
  • Increases the depressive effects of alcohol and barbiturates
    • Results can be lethal
  • Senate hearings were conducted
  • Prescriptions decreased

10. Rise & Fall of Benzodiazepine Use 11. The Role of Seratonin

  • Some researchers suggested that anxiety may involve increased serotonergic activity within the punishment system
    • benzodiazepine drugs would reduce anxiety by reducing this increased serotonergic activity

12. The Geller-Seifter Paradigm

  • A conflict test in which rats are trained to press a bar to receive sweetened milk
  • There are two schedules of reinforcement
    • a variable interval (VI) schedule in which bar presses are rewarded at irregular intervals
    • a continuous reinforcement (CRF) schedule in which every bar press is rewarded with food
    • and punished by electric shock to the feet.
  • Conflict is introduced into this situation by delivering electric shock to the animal's feet every time it bar presses during the CRF schedule.

13. Effect of Benzodiazepines

  • Compared performance of rats injected with saline to rats injected with benzodiazapines
  • The drug did not affect performance on the VI component
  • Performance on the CRF (punished) schedule was increased
  • There was a strong correlation between the clinical potency of a benzodiazepine, and the dose that reduces conflict in animals.
  • This led to the theory that the anti-anxiety effect of benzodiazepine drugs involved the serotoninergic system in the brain.

14. Interrelation of Anti-anxiety Drugs

  • Barbiturates, meprobamate, & benzodiazapines all induce tolerance
  • They exhibit cross-tolerance
    • A person who becomes tolerant to one drug will also become tolerant to the other, even if the second drug has not been encountered
  • Cross-dependence is similar
    • Withdrawal symptoms caused by termination of one drug can be cured by treatment with the other
    • These drugs also exhibit cross-dependence
  • Suggested that these drugs act at the same or similar recognition sites

15. Site of Action of Sedating Drugs

  • Barbiturates, meprobomate & alcohol act at the same recognition site
  • Benzodiazepines act at a related site
  • GABA is a major inhibitory neurotransmitter
  • Inhibitory effects of GABA are increased by barbiturates, meprobamate, alcohol, & benzodiazepines

16. The Receptor

  • 1977 discovery of specific benzodiazepine receptors in the brain
  • Used techniques similar to those used to identify opiate receptors
    • Radioactive Valium mixed with brain membranes
  • Examined ability of other benzodiazepines to compete with radioactive Valium for receptor
      • Strength of receptor binding correlated directly with drug potency
  • Therefore receptor must be site of anti-anxiety action

17. The Role of GABA

  • What is the natural ligand for the Valium receptor in the brain?
  • Still an unresolved controversy
  • Learned that GABA plays an important role
  • Does not compete for the same receptor, lowering drug binding
  • Instead, stimulates drug binding to receptor

18. The GABA Receptor

  • Found the reverse was also true: Valium stimulates binding of GABA to GABA receptors
  • GABA & Valium bind to closely related sites that influence each other
    • GABA & Benzodiazepine receptors are located on the same large protein molecule
  • GABA changes the shape of benzodiazepine receptors so they bind more efficiently
  • Benzodiazepines stimulate GABA receptors, increasing the inhibitory action of GABA
    • Explains calming action of benzodiazepines

19. Distribution of Benzodiazepine Receptors

  • Receptors most highly concentrated in the limbic system
  • Highest concentration in the amygdala
    • Correlates with calming effect
  • Receptors are also present in the cerebral cortex
    • May correlate with sedative effect

20. The Action of Sedatives

  • Researchers looked for a unifying mechanism of action for alcohol, meprobamate & barbiturates
  • Antagonism between sedative and convulsant drugs was known
  • Sites affected by sedatives are related to sites affected by convulsants
  • Barbiturates are effective anti-convulsants

21. Sedative-Convulsant Binding Site

  • Radio-labeled convulsants
    • monitored their receptor binding in the presence of sedatives
  • Alcohol, meprobamate, & barbiturates competed directly for the binding site
    • Benzodiazepines did not
  • Called this the sedative-convulsant receptor
  • Theorized that the sedative-convulsant, GABA, & benzodiazepine receptors were close together on a receptor complex
  • Binding of drugs to one subunit on the receptor complex could alter the way drugs bound to a second receptor subunit on the comp