Drugs and the BrainPart 4The Neuroleptics or Tricyclics

(Anti-schizophrenics)

History of Neuroleptics• Started as a tool for anesthesia• Henri Laborit, a French neurosurgeon looking for a

drug to calm patients before administering general anesthesia for surgery, made first discovery in 1950– He thought histamine released during anesthesia

accounted for some patient deaths

• Decided to try an antihistamine as a calming agent– First used promethazine

• This was so successful that he asked the manufacturer for related compounds– He was given chlorpromazine, a drug the manufacturer

had deemed to sedating to market.

Psychiatric Use of Chlorpromazine

• Laborit was so impressed by the calming effect of chlorpromazine that he recommended it to his psychiatrist colleagues as possible treatment for agitated patients

• First trials were unsuccessful• 1951 – 2 French psychiatrists tried giving

chlorpromazine in progressively increasing doses and reaching much higher levels– This was very successful– Difficult patients became more manageable

Chlorpromazine & Schizophrenia

• Chlorpromazine influenced schizophrenic patients in a unique way– Concluded that chlorpromazine was a true

anti-schizophrenic, not merely a sedative

• This suggested that the drug acted on a specific location in the brain

• Improvement in schizophrenic symptoms with chlorpromazine was accompanied by developing Parkinson’s-like side effects

Schizophrenia• A neurological disorder characterized

by altered thought patterns and social withdrawal.

• Etiology is unknown.– There may be a genetic component.

• Two main categories of symptoms. – Positive symptoms: delusions,

hallucinations, disordered thought and disorganized speech.

– Negative symptoms: flat affect, social withdrawal, emotional detachment, cognitive deficits and poverty of speech.

Resperine & Schizophrenia• Extracted from Indian snake-root plant,

Rauwolfia serpentina• Used to treat high blood pressure• A trial of resperine on schizophrenics produced

results similar to those with chlorpromazine– Patients improved but developed Parkinsonian

symptoms

• The 2 drugs are chemically unrelated• Antischizophrenic action and the Parkinsonian

side effects must be caused by a the same biochemical event– This event must be caused by both drugs

Dopamine• By the 1960’s several studies linked

Parkinsonian symptoms to loss of dopamine• Swedish pharmacologist, Arvid Carlsson

administered a series of neuroleptics to rats– Found changes in the levels of metabolites for

norepinephrine and dopamine– Levels of transmitters themselves were unchanged

• Higher levels of norepinephrine metabolites had no relation to the clinical actions of neuroleptics

• Relative increases in dopamine metabolite levels by neuroleptics paralleled the clinical potency of the drugs– The more a drug accelerated the firing of dopamine

neurons, the more potent as an antischizophrenic

Contradictions

• Increase in firing rate of dopamine neurons would mean more dopamine released and metabolized.

• But resperine causes dopamine to almost vanish from the brain.

• Chlorpromazine does not effect dopamine levels, but increases dopamine metabolites

• So how can both drugs produce the same action?

A Hypothesis• Carlsson suggested that neuroleptics block

receptors for dopamine.• Neuroleptics are dopamine antagonists.• Reduce overall dopamine-like activity in the

brain.• Feedback between neurons with dopamine

receptors and neurons that produce dopamine would result in turning on dopamine neurons, causing them to fire more rapidly & produce more dopamine.

A Biochemical Test• A biochemical method to demonstrate

chlorpromazine action on dopamine receptors• Dopamine increases cyclicAMP in the corpus

striatum– Cyclic AMP is a 2nd messenger– Mixing homogenate of corpus striatum with low

concentrations of dopamine stimulates formation of cyclicAMP

• Chlorpromazine blocks ability of dopamine to stimulate formation of cyclicAMP

• Therefore, chlorpromazine binds and blocks the dopamine receptor, without causing the subsequent 2nd messenger actions = antagonist

Identifying Dopamine Receptors

• 1975 – direct binding of radiolabeled dopamine allowed identification of dopamine receptors

• Chlorpromazine blocked binding to these receptors

• Haloperidol is a neuroleptic that does not block dopamine stimulation of cyclic AMP

• Binding of radiolabeled haloperidol was different– Bound sites that competed for dopamine– But not the same sites bound by radiolabeled

dopamine in previous experiment

• Neurotransmitters will bind to more than one type of receptor– Multiple dopamine receptors may be involved

Dopamine Receptors

• Two types of receptors: D1 & D2• Radiolabeled dopamine bound D1• Increase in cAMP resulted only from binding

D1• Radiolabeled haloperidol bound only D2• Therefore dopamine & chlorpromazine must

bind both D1 & D2 receptors• Antischizophrenic properties of neuroleptics

must be due to blocking D2 receptors

Different Dopamine Pathways• Chemical staining techniques were used to

reveal dopamine containing neuronal pathways• Major dopamine pathway has cell bodies in the

substantia nigra of the brain stem– These neurons terminate in the corpus striatum– This is the pathway involved in Parkinson’s

• 2nd pathway has cell bodies in the tegumentum– These neurons project to the limbic system, an area

dealing with emotion– Blocking dopamine receptors in these areas accounts

for the anti-schizophrenic actions of these drugs

• Another dopamine pathway has cell bodies in the hypothalamus projecting to the pituitary– Accounts for sexual side effects

Variety of Neuroleptics• A variety of neuroleptic drugs are in use• All are tricyclic compounds• All are dopamine antagonists

– Generally D2 antagonists. – There is a strong positive correlation between

the therapeutic dose of neuroleptics and their affinity for D2 receptors.

• Include the thioxanthines like flupenthixol and the phenothiazines such as fluphenazine.– Thioxanthines lack the ring nitrogen of

phenothiazines and the carbon chain begins with a double bond.

Structure of Chlorpromazine

• A typical neuroleptic (tricyclic)

• Includes three rings

• An electronegative group on the ring determines the electron density around the ring system

• The amino side chain must be on the same side of the molecule as the electronegative group approximating the conformation of dopamine

• The number of carbons between the ring carbon or nitrogen and the side-chain amine must be three for maximal activity.

Thioxanthines & Phenothiazines

Atypical Neuroleptics• Several new compounds have been developed

with unique properties • Atypical neuroleptics generally effective in

treating both the positive & negative symptoms of schizophrenia.

• Clozapine was the first dopamine antagonist with a relatively low incidence of extrapyramidal side effects. – may be due in part to its potent anticholinergic

effects– also to a high affinity for 5-HT2 (serotonin) receptors.

• Atypical neuroleptics generally have high affinity for 5-HT2, D2, M1, and H1 receptors.

Problems• Drugs relieve schizophrenic symptoms, but

they do not cure it– Patients must continue to take drugs or symptoms

return

• Not all symptoms associated with schizophrenia respond to these drugs

• Parkinsonian side effects• Prolonged use results in uncontroled

movement of tongue & limbs: tardive dyskinesia

• Clozapine, perhaps the most effective drug in this group, produces a decrease in white blood cell production– Action is on both dopamine & seratonin