Drugs and the BrainPart 5

Anti-anxiety Drugs Anti-anxiety Drugs

The BenzodiazepinesThe Benzodiazepines

Anxiety A broad label – difficult to defineA broad label – difficult to define Sometimes the terms 'fear' and 'anxiety' are Sometimes the terms 'fear' and 'anxiety' are

used interchangeablyused interchangeably Fear is the short-term response produced by Fear is the short-term response produced by

stress. stress. The  amygdala may be a control center for The  amygdala may be a control center for

fear, receiving fear-related sensory fear, receiving fear-related sensory information and transmitting fear-related information and transmitting fear-related motor instructions. motor instructions.

Anxiety has similar symptoms to fear, but Anxiety has similar symptoms to fear, but persists after the stress has ended. persists after the stress has ended. A fear response in the absence of A fear response in the absence of

appropriate stimulusappropriate stimulus

Anxiety Produces Physical Symptoms

Increased autonomic activity leads Increased autonomic activity leads to: to: increase in blood pressure increase in blood pressure increase in heart rate increase in heart rate erratic respiratory rate erratic respiratory rate decreased salivary flow leading to decreased salivary flow leading to

dry mouth & throat dry mouth & throat gastrointestinal disturbancesgastrointestinal disturbances

Sedatives

Sedating drugs were commonly Sedating drugs were commonly prescribed for anxiety in the 1prescribed for anxiety in the 1stst half of this centuryhalf of this century

Phenobarbitol & other barbiturates Phenobarbitol & other barbiturates did not specifically address anxietydid not specifically address anxiety

Are addictive, so only useful for Are addictive, so only useful for short periods of timeshort periods of time

Muscle Relaxants 1945 - A pharmacist trying to develop an 1945 - A pharmacist trying to develop an

antibacterial agent effective against antibacterial agent effective against Gram-negative bacteria (resistant to Gram-negative bacteria (resistant to penicillin) made the first discoverypenicillin) made the first discovery Tested safety of proposed drug in miceTested safety of proposed drug in mice Mice became paralyzed because of Mice became paralyzed because of

massive muscle relaxation, but massive muscle relaxation, but remained consciousremained conscious

This drug, mephenesin, became a muscle This drug, mephenesin, became a muscle relaxant used to treat spasticityrelaxant used to treat spasticity Mephenism also appeared to have a Mephenism also appeared to have a

tranquilizing effect, making patients tranquilizing effect, making patients calm but not sleepycalm but not sleepy

Miltown

Calming effects of mephenesin led to Calming effects of mephenesin led to exploration of derivatives that might exploration of derivatives that might treat anxietytreat anxiety

Meprobamate was a derivative that Meprobamate was a derivative that had both muscle relaxant and strong had both muscle relaxant and strong anti-anxiety effectanti-anxiety effect

Marketed as Miltown, this drug was Marketed as Miltown, this drug was thought to be more specific, non-thought to be more specific, non-sedating, and non-addictive.sedating, and non-addictive. None of these claims proved to be None of these claims proved to be

truetrue

The First Benzodiazipines Pharmaceutical companies sought other drugs Pharmaceutical companies sought other drugs

with properties similar to Miltownwith properties similar to Miltown Since molecular basis was unknown, random Since molecular basis was unknown, random

chemicals were screened for anti-anxiety effectschemicals were screened for anti-anxiety effects Roche Pharmaceuticals screened a class of Roche Pharmaceuticals screened a class of

compounds called quinazolinescompounds called quinazolines These were totally ineffectiveThese were totally ineffective

The last compound in this series was tested a The last compound in this series was tested a year after the project was abandoned year after the project was abandoned

An error in synthesis had produced a compound An error in synthesis had produced a compound that was not a quinazolinethat was not a quinazoline

This compound was an effective anti-anxiety This compound was an effective anti-anxiety drugdrug

This was the first benzodiazepine, LibriumThis was the first benzodiazepine, Librium

Continued Development Looked for derivative of LibriumLooked for derivative of Librium Most effective, Valium, was marketed in 1963Most effective, Valium, was marketed in 1963 These drugs relieve anxiety with some These drugs relieve anxiety with some

drowsiness, but patients adaptdrowsiness, but patients adapt Are somewhat addictive & produce toleranceAre somewhat addictive & produce tolerance

Less so than barbiturates or meprobamateLess so than barbiturates or meprobamate Comparatively safe; rarely lethalComparatively safe; rarely lethal

Led to widespread over-useLed to widespread over-use

Use & Abuse of Benzodiazepines

Widely prescribed to ease every-day Widely prescribed to ease every-day problems not associated with anxietyproblems not associated with anxiety

Mid-1970’s some estimated 1 ½ Mid-1970’s some estimated 1 ½ million Valium addicts in the USmillion Valium addicts in the US

Increases the depressive effects of Increases the depressive effects of alcohol and barbituratesalcohol and barbiturates Results can be lethalResults can be lethal

Senate hearings were conductedSenate hearings were conducted Prescriptions decreasedPrescriptions decreased

Rise & Fall of Benzodiazepine Use

The Role of Seratonin

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

anxiety by reducing this increased anxiety by reducing this increased serotonergic activity serotonergic activity

The Geller-Seifter Paradigm

A conflict test in which rats are trained to press a A conflict test in which rats are trained to press a bar to receive sweetened milk bar to receive sweetened milk

There are two schedules of reinforcementThere are two schedules of reinforcement a variable interval (VI)a variable interval (VI) schedule in which bar schedule in which bar

presses are rewarded at irregular intervals presses are rewarded at irregular intervals a continuous reinforcement (CRF)a continuous reinforcement (CRF) schedule in schedule in

which every bar press is rewarded with food which every bar press is rewarded with food and punished by electric shock to the feet. and punished by electric shock to the feet.

Conflict is introduced into this situation by Conflict is introduced into this situation by delivering electric shock to the animal's feet delivering electric shock to the animal's feet every time it bar presses during the CRF every time it bar presses during the CRF schedule. schedule.

Effect of Benzodiazepines Compared performance of rats injected with Compared performance of rats injected with

saline to rats injected with benzodiazapinessaline to rats injected with benzodiazapines The drug did not affect performance on the VI The drug did not affect performance on the VI

component component Performance on the CRF (punished) schedule was Performance on the CRF (punished) schedule was

increasedincreased There was a strong correlation between the There was a strong correlation between the

clinical potency of a benzodiazepine, and the dose clinical potency of a benzodiazepine, and the dose that reduces conflict in animals. that reduces conflict in animals.

This led to the theory that the anti-anxiety effect of This led to the theory that the anti-anxiety effect of benzodiazepine drugs involved the serotoninergic benzodiazepine drugs involved the serotoninergic system in the brain. system in the brain.

Interrelation of Anti-anxiety Drugs Barbiturates, meprobamate, & Barbiturates, meprobamate, &

benzodiazapines all induce tolerancebenzodiazapines all induce tolerance They exhibit cross-toleranceThey exhibit cross-tolerance

A person who becomes tolerant to one drug A person who becomes tolerant to one drug will also become tolerant to the other, even will also become tolerant to the other, even if the second drug has not been encounteredif the second drug has not been encountered

Cross-dependence is similarCross-dependence is similar Withdrawal symptoms caused by Withdrawal symptoms caused by

termination of one drug can be cured by termination of one drug can be cured by treatment with the othertreatment with the other

These drugs also exhibit cross-dependenceThese drugs also exhibit cross-dependence Suggested that these drugs actSuggested that these drugs act at the same or at the same or

similarsimilar recognition sitesrecognition sites

Site of Action of Sedating Drugs Barbiturates, meprobomate & alcohol Barbiturates, meprobomate & alcohol

act at the same recognition siteact at the same recognition site Benzodiazepines act at a related siteBenzodiazepines act at a related site GABA is a major inhibitory GABA is a major inhibitory

neurotransmitterneurotransmitter Inhibitory effects of GABA are Inhibitory effects of GABA are

increased by barbiturates, increased by barbiturates, meprobamate, alcohol, & meprobamate, alcohol, & benzodiazepinesbenzodiazepines

The Receptor 1977 – discovery of specific benzodiazepine 1977 – discovery of specific benzodiazepine

receptors in the brainreceptors in the brain Used techniques similar to those used to Used techniques similar to those used to

identify opiate receptorsidentify opiate receptors Radioactive Valium mixed with brain Radioactive Valium mixed with brain

membranesmembranes Examined ability of other benzodiazepines to Examined ability of other benzodiazepines to

compete with radioactive Valium for receptorcompete with radioactive Valium for receptorStrength of receptor binding correlated Strength of receptor binding correlated

directly with drug potencydirectly with drug potency Therefore receptor must be site of anti-Therefore receptor must be site of anti-

anxiety actionanxiety action

The Role of GABA What is the natural ligand for the What is the natural ligand for the

Valium receptor in the brain?Valium receptor in the brain? Still an unresolved controversyStill an unresolved controversy Learned that GABA plays an Learned that GABA plays an

important roleimportant role Does not compete for the same Does not compete for the same

receptor, lowering drug bindingreceptor, lowering drug binding Instead, stimulates drug binding to Instead, stimulates drug binding to

receptorreceptor

The GABA Receptor Found the reverse was also true: Valium Found the reverse was also true: Valium

stimulates binding of GABA to GABA receptorsstimulates binding of GABA to GABA receptors GABA & Valium bind to closely related sites that GABA & Valium bind to closely related sites that

influence each otherinfluence each other GABA & Benzodiazepine receptors are GABA & Benzodiazepine receptors are

located on the same large protein molecule located on the same large protein molecule GABA changes the shape of benzodiazepine GABA changes the shape of benzodiazepine

receptors so they bind more efficientlyreceptors so they bind more efficiently Benzodiazepines stimulate GABA receptors, Benzodiazepines stimulate GABA receptors,

increasing the inhibitory action of GABAincreasing the inhibitory action of GABA Explains calming action of benzodiazepinesExplains calming action of benzodiazepines

Distribution of Benzodiazepine Receptors

Receptors most highly concentrated Receptors most highly concentrated in the limbic systemin the limbic system

Highest concentration in the Highest concentration in the amygdalaamygdala Correlates with calming effectCorrelates with calming effect

Receptors are also present in the Receptors are also present in the cerebral cortexcerebral cortex May correlate with sedative effectMay correlate with sedative effect

The Action of Sedatives

Researchers looked for a unifying Researchers looked for a unifying mechanism of action for alcohol, mechanism of action for alcohol, meprobamate & barbituratesmeprobamate & barbiturates

Antagonism between sedative and Antagonism between sedative and convulsant drugs was knownconvulsant drugs was known

Sites affected by sedatives are related Sites affected by sedatives are related to sites affected by convulsantsto sites affected by convulsants

Barbiturates are effective anti-Barbiturates are effective anti-convulsantsconvulsants

Sedative-Convulsant Binding Site Radio-labeled convulsants Radio-labeled convulsants

monitored their receptor binding in the monitored their receptor binding in the presence of sedativespresence of sedatives

Alcohol, meprobamate, & barbiturates Alcohol, meprobamate, & barbiturates competed directly for the binding sitecompeted directly for the binding site Benzodiazepines did notBenzodiazepines did not

Called this the sedative-convulsant receptorCalled this the sedative-convulsant receptor Theorized that the sedative-convulsant, GABA, Theorized that the sedative-convulsant, GABA,

& benzodiazepine receptors were close & benzodiazepine receptors were close together on a receptor complextogether on a receptor complex

Binding of drugs to one subunit on the receptor Binding of drugs to one subunit on the receptor complex could alter the way drugs bound to a complex could alter the way drugs bound to a second receptor subunit on the complexsecond receptor subunit on the complex

How GABA Inhibits Neuronal Firing

Widens the ClWidens the Cl-- ion channels in the ion channels in the membranemembrane ClCl-- moves in, hyperpolarizing the moves in, hyperpolarizing the

neuronneuron How is GABA linked to the ion channel?How is GABA linked to the ion channel? Receptor binding studies of barbiturates Receptor binding studies of barbiturates

& benzodiazapines showed that Cl& benzodiazapines showed that Cl-- was was necessary for receptor bindingnecessary for receptor binding

Concluded that benzodiazepine-sedative-Concluded that benzodiazepine-sedative-convulsant receptor complex is a portion convulsant receptor complex is a portion of the Clof the Cl-- ion channel ion channel

Isolating the Receptor 1990’s – isolated a single protein molecule 1990’s – isolated a single protein molecule

containing binding sites for GABA, containing binding sites for GABA, benzodiazepines, barbiturates, convulsantsbenzodiazepines, barbiturates, convulsants

Sensitive to ClSensitive to Cl-- ions ions A single protein molecule contained A single protein molecule contained

recognition sites for GABA & all the drugs recognition sites for GABA & all the drugs that influence GABA transmissionthat influence GABA transmission Has distinct subunits which can interactHas distinct subunits which can interact

Explains synergistic (additive) effect of Explains synergistic (additive) effect of benzodiazepines & alcohol or barbituratesbenzodiazepines & alcohol or barbiturates

GABA Receptor Model

GABA Effects Many Systems

Recent research Recent research has returned to has returned to examining the role examining the role of 5-HT in anxiety of 5-HT in anxiety (serotonin)(serotonin)

GABA exerts GABA exerts inhibitory effects inhibitory effects on other on other neurotransmitter neurotransmitter systems which may systems which may account for the account for the effects of anti-effects of anti-anxiety drugs anxiety drugs

Unanswered Questions

What normally binds to the What normally binds to the benzodiazapine receptor site? benzodiazapine receptor site? Termed “GABA-modulins” - unknown Termed “GABA-modulins” - unknown

What is the normal function of GABA-What is the normal function of GABA-modulin - increase or decrease modulin - increase or decrease anxiety? anxiety?

Can GABA-modulins be found in the Can GABA-modulins be found in the body? body? Beta-carbolines (beta-CCM) are one Beta-carbolines (beta-CCM) are one

candidate. (produce anxiety)candidate. (produce anxiety)