Drugs and the Brain Part 5 Anti-anxiety Drugs  The Benzodiazepines
Anxiety <ul><li>A broad label – difficult to define </li></ul><ul><li>Sometimes the terms 'fear' and 'anxiety' are used in...
Anxiety Produces Physical Symptoms <ul><li>Increased autonomic activity leads to:  </li></ul><ul><ul><li>increase in blood...
Sedatives <ul><li>Sedating drugs were commonly prescribed for anxiety in the 1 st  half of this century </li></ul><ul><li>...
Muscle Relaxants <ul><li>1945 - A pharmacist trying to develop an antibacterial agent  effective against Gram-negative bac...
Miltown <ul><li>Calming effects of mephenesin led to exploration of derivatives that might treat anxiety </li></ul><ul><li...
The First Benzodiazipines <ul><li>Pharmaceutical companies sought other drugs with properties similar to Miltown </li></ul...
Continued Development <ul><li>Looked for derivative of Librium </li></ul><ul><li>Most effective, Valium, was marketed in 1...
Use & Abuse of Benzodiazepines <ul><li>Widely prescribed to ease every-day problems not associated with anxiety </li></ul>...
Rise & Fall of Benzodiazepine Use
The Role of Seratonin <ul><li>Some researchers suggested that anxiety may involve increased serotonergic activity within t...
The Geller-Seifter Paradigm <ul><li>A conflict test in which rats are trained to press a bar to receive sweetened milk  </...
Effect of Benzodiazepines <ul><li>Compared performance of rats injected with saline to rats injected with benzodiazapines ...
Interrelation of Anti-anxiety Drugs <ul><li>Barbiturates, meprobamate, & benzodiazapines all induce tolerance </li></ul><u...
Site of Action of Sedating Drugs <ul><li>Barbiturates, meprobomate & alcohol act at the same recognition site </li></ul><u...
The Receptor <ul><li>1977 – discovery of specific benzodiazepine receptors in the brain </li></ul><ul><li>Used techniques ...
The Role of GABA <ul><li>What is the natural ligand for the Valium receptor in the brain? </li></ul><ul><li>Still an unres...
The GABA Receptor <ul><li>Found the reverse was also true: Valium stimulates binding of GABA to GABA receptors </li></ul><...
Distribution of Benzodiazepine Receptors <ul><li>Receptors most highly concentrated in the limbic system </li></ul><ul><li...
The Action of Sedatives <ul><li>Researchers looked for a unifying mechanism of action for alcohol, meprobamate & barbitura...
Sedative-Convulsant Binding Site <ul><li>Radio-labeled convulsants  </li></ul><ul><ul><li>monitored their receptor binding...
How GABA Inhibits Neuronal Firing <ul><li>Widens the Cl -  ion channels in the membrane </li></ul><ul><ul><li>Cl -  moves ...
Isolating the Receptor <ul><li>1990’s – isolated a single protein molecule containing binding sites for GABA, benzodiazepi...
GABA Receptor Model
GABA Effects Many Systems <ul><li>Recent research has returned to examining the role of 5-HT in anxiety (serotonin) </li><...
Unanswered Questions  <ul><li>What normally binds to the benzodiazapine receptor site?  </li></ul><ul><ul><li>Termed “GABA...
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Drugsandthe Brain Part5 Antianxiety Drugs

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Drugsandthe Brain Part5 Antianxiety Drugs

  1. 1. Drugs and the Brain Part 5 Anti-anxiety Drugs The Benzodiazepines
  2. 2. Anxiety <ul><li>A broad label – difficult to define </li></ul><ul><li>Sometimes the terms 'fear' and 'anxiety' are used interchangeably </li></ul><ul><li>Fear is the short-term response produced by stress. </li></ul><ul><ul><li>The  amygdala may be a control center for fear, receiving fear-related sensory information and transmitting fear-related motor instructions. </li></ul></ul><ul><li>Anxiety has similar symptoms to fear, but persists after the stress has ended. </li></ul><ul><ul><li>A fear response in the absence of appropriate stimulus </li></ul></ul>
  3. 3. Anxiety Produces Physical Symptoms <ul><li>Increased autonomic activity leads to: </li></ul><ul><ul><li>increase in blood pressure </li></ul></ul><ul><ul><li>increase in heart rate </li></ul></ul><ul><ul><li>erratic respiratory rate </li></ul></ul><ul><ul><li>decreased salivary flow leading to dry mouth & throat </li></ul></ul><ul><ul><li>gastrointestinal disturbances </li></ul></ul>
  4. 4. Sedatives <ul><li>Sedating drugs were commonly prescribed for anxiety in the 1 st half of this century </li></ul><ul><li>Phenobarbitol & other barbiturates did not specifically address anxiety </li></ul><ul><li>Are addictive, so only useful for short periods of time </li></ul>
  5. 5. Muscle Relaxants <ul><li>1945 - A pharmacist trying to develop an antibacterial agent effective against Gram-negative bacteria (resistant to penicillin) made the first discovery </li></ul><ul><ul><li>Tested safety of proposed drug in mice </li></ul></ul><ul><ul><li>Mice became paralyzed because of massive muscle relaxation, but remained conscious </li></ul></ul><ul><li>This drug, mephenesin, became a muscle relaxant used to treat spasticity </li></ul><ul><ul><li>Mephenism also appeared to have a tranquilizing effect, making patients calm but not sleepy </li></ul></ul>
  6. 6. Miltown <ul><li>Calming effects of mephenesin led to exploration of derivatives that might treat anxiety </li></ul><ul><li>Meprobamate was a derivative that had both muscle relaxant and strong anti-anxiety effect </li></ul><ul><li>Marketed as Miltown, this drug was thought to be more specific, non-sedating, and non-addictive. </li></ul><ul><ul><li>None of these claims proved to be true </li></ul></ul>
  7. 7. The First Benzodiazipines <ul><li>Pharmaceutical companies sought other drugs with properties similar to Miltown </li></ul><ul><li>Since molecular basis was unknown, random chemicals were screened for anti-anxiety effects </li></ul><ul><li>Roche Pharmaceuticals screened a class of compounds called quinazolines </li></ul><ul><ul><li>These were totally ineffective </li></ul></ul><ul><li>The last compound in this series was tested a year after the project was abandoned </li></ul><ul><li>An error in synthesis had produced a compound that was not a quinazoline </li></ul><ul><li>This compound was an effective anti-anxiety drug </li></ul><ul><li>This was the first benzodiazepine, Librium </li></ul>
  8. 8. Continued Development <ul><li>Looked for derivative of Librium </li></ul><ul><li>Most effective, Valium, was marketed in 1963 </li></ul><ul><li>These drugs relieve anxiety with some drowsiness, but patients adapt </li></ul><ul><li>Are somewhat addictive & produce tolerance </li></ul><ul><ul><li>Less so than barbiturates or meprobamate </li></ul></ul><ul><li>Comparatively safe; rarely lethal </li></ul><ul><ul><li>Led to widespread over-use </li></ul></ul>
  9. 9. Use & Abuse of Benzodiazepines <ul><li>Widely prescribed to ease every-day problems not associated with anxiety </li></ul><ul><li>Mid-1970’s some estimated 1 ½ million Valium addicts in the US </li></ul><ul><li>Increases the depressive effects of alcohol and barbiturates </li></ul><ul><ul><li>Results can be lethal </li></ul></ul><ul><li>Senate hearings were conducted </li></ul><ul><li>Prescriptions decreased </li></ul>
  10. 10. Rise & Fall of Benzodiazepine Use
  11. 11. The Role of Seratonin <ul><li>Some researchers suggested that anxiety may involve increased serotonergic activity within the punishment system </li></ul><ul><ul><li>benzodiazepine drugs would reduce anxiety by reducing this increased serotonergic activity </li></ul></ul>
  12. 12. The Geller-Seifter Paradigm <ul><li>A conflict test in which rats are trained to press a bar to receive sweetened milk </li></ul><ul><li>There are two schedules of reinforcement </li></ul><ul><ul><li>a variable interval (VI) schedule in which bar presses are rewarded at irregular intervals </li></ul></ul><ul><ul><li>a continuous reinforcement (CRF) schedule in which every bar press is rewarded with food </li></ul></ul><ul><ul><li>and punished by electric shock to the feet. </li></ul></ul><ul><li>Conflict is introduced into this situation by delivering electric shock to the animal's feet every time it bar presses during the CRF schedule. </li></ul>
  13. 13. Effect of Benzodiazepines <ul><li>Compared performance of rats injected with saline to rats injected with benzodiazapines </li></ul><ul><li>The drug did not affect performance on the VI component </li></ul><ul><li>Performance on the CRF (punished) schedule was increased </li></ul><ul><li>There was a strong correlation between the clinical potency of a benzodiazepine, and the dose that reduces conflict in animals. </li></ul><ul><li>This led to the theory that the anti-anxiety effect of benzodiazepine drugs involved the serotoninergic system in the brain. </li></ul>
  14. 14. Interrelation of Anti-anxiety Drugs <ul><li>Barbiturates, meprobamate, & benzodiazapines all induce tolerance </li></ul><ul><li>They exhibit cross-tolerance </li></ul><ul><ul><li>A person who becomes tolerant to one drug will also become tolerant to the other, even if the second drug has not been encountered </li></ul></ul><ul><li>Cross-dependence is similar </li></ul><ul><ul><li>Withdrawal symptoms caused by termination of one drug can be cured by treatment with the other </li></ul></ul><ul><ul><li>These drugs also exhibit cross-dependence </li></ul></ul><ul><li>Suggested that these drugs act at the same or similar recognition sites </li></ul>
  15. 15. Site of Action of Sedating Drugs <ul><li>Barbiturates, meprobomate & alcohol act at the same recognition site </li></ul><ul><li>Benzodiazepines act at a related site </li></ul><ul><li>GABA is a major inhibitory neurotransmitter </li></ul><ul><li>Inhibitory effects of GABA are increased by barbiturates, meprobamate, alcohol, & benzodiazepines </li></ul>
  16. 16. The Receptor <ul><li>1977 – discovery of specific benzodiazepine receptors in the brain </li></ul><ul><li>Used techniques similar to those used to identify opiate receptors </li></ul><ul><ul><li>Radioactive Valium mixed with brain membranes </li></ul></ul><ul><li>Examined ability of other benzodiazepines to compete with radioactive Valium for receptor </li></ul><ul><ul><ul><li>Strength of receptor binding correlated directly with drug potency </li></ul></ul></ul><ul><li>Therefore receptor must be site of anti-anxiety action </li></ul>
  17. 17. The Role of GABA <ul><li>What is the natural ligand for the Valium receptor in the brain? </li></ul><ul><li>Still an unresolved controversy </li></ul><ul><li>Learned that GABA plays an important role </li></ul><ul><li>Does not compete for the same receptor, lowering drug binding </li></ul><ul><li>Instead, stimulates drug binding to receptor </li></ul>
  18. 18. The GABA Receptor <ul><li>Found the reverse was also true: Valium stimulates binding of GABA to GABA receptors </li></ul><ul><li>GABA & Valium bind to closely related sites that influence each other </li></ul><ul><ul><li>GABA & Benzodiazepine receptors are located on the same large protein molecule </li></ul></ul><ul><li>GABA changes the shape of benzodiazepine receptors so they bind more efficiently </li></ul><ul><li>Benzodiazepines stimulate GABA receptors, increasing the inhibitory action of GABA </li></ul><ul><ul><li>Explains calming action of benzodiazepines </li></ul></ul>
  19. 19. Distribution of Benzodiazepine Receptors <ul><li>Receptors most highly concentrated in the limbic system </li></ul><ul><li>Highest concentration in the amygdala </li></ul><ul><ul><li>Correlates with calming effect </li></ul></ul><ul><li>Receptors are also present in the cerebral cortex </li></ul><ul><ul><li>May correlate with sedative effect </li></ul></ul>
  20. 20. The Action of Sedatives <ul><li>Researchers looked for a unifying mechanism of action for alcohol, meprobamate & barbiturates </li></ul><ul><li>Antagonism between sedative and convulsant drugs was known </li></ul><ul><li>Sites affected by sedatives are related to sites affected by convulsants </li></ul><ul><li>Barbiturates are effective anti-convulsants </li></ul>
  21. 21. Sedative-Convulsant Binding Site <ul><li>Radio-labeled convulsants </li></ul><ul><ul><li>monitored their receptor binding in the presence of sedatives </li></ul></ul><ul><li>Alcohol, meprobamate, & barbiturates competed directly for the binding site </li></ul><ul><ul><li>Benzodiazepines did not </li></ul></ul><ul><li>Called this the sedative-convulsant receptor </li></ul><ul><li>Theorized that the sedative-convulsant, GABA, & benzodiazepine receptors were close together on a receptor complex </li></ul><ul><li>Binding of drugs to one subunit on the receptor complex could alter the way drugs bound to a second receptor subunit on the complex </li></ul>
  22. 22. How GABA Inhibits Neuronal Firing <ul><li>Widens the Cl - ion channels in the membrane </li></ul><ul><ul><li>Cl - moves in, hyperpolarizing the neuron </li></ul></ul><ul><li>How is GABA linked to the ion channel? </li></ul><ul><li>Receptor binding studies of barbiturates & benzodiazapines showed that Cl - was necessary for receptor binding </li></ul><ul><li>Concluded that benzodiazepine-sedative-convulsant receptor complex is a portion of the Cl - ion channel </li></ul>
  23. 23. Isolating the Receptor <ul><li>1990’s – isolated a single protein molecule containing binding sites for GABA, benzodiazepines, barbiturates, convulsants </li></ul><ul><li>Sensitive to Cl - ions </li></ul><ul><li>A single protein molecule contained recognition sites for GABA & all the drugs that influence GABA transmission </li></ul><ul><ul><li>Has distinct subunits which can interact </li></ul></ul><ul><li>Explains synergistic (additive) effect of benzodiazepines & alcohol or barbiturates </li></ul>
  24. 24. GABA Receptor Model
  25. 25. GABA Effects Many Systems <ul><li>Recent research has returned to examining the role of 5-HT in anxiety (serotonin) </li></ul><ul><li>GABA exerts inhibitory effects on other neurotransmitter systems which may account for the effects of anti-anxiety drugs </li></ul>
  26. 26. Unanswered Questions <ul><li>What normally binds to the benzodiazapine receptor site? </li></ul><ul><ul><li>Termed “GABA-modulins” - unknown </li></ul></ul><ul><li>What is the normal function of GABA-modulin - increase or decrease anxiety? </li></ul><ul><li>Can GABA-modulins be found in the body? </li></ul><ul><ul><li>Beta-carbolines (beta-CCM) are one candidate. (produce anxiety) </li></ul></ul>

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