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CHEMICAL TRANSMISSION 
DRUG ACTION IN THE CNS
Ján Mojžiš
P.J. Šafárik University
Faculty of Medicine
Department of Pharmacology
Košice
Neurotransmiters
Noradrenaline
Acetylcholine
Dopamine
Serotonin
GABA
Glutamate
Aspartate
Noradrenaline
 relatively large amount of NA  hypothalamus and limbic
system
 also present in other brain region
Receptors: 1A-C, 2A-C, 1, 2, 3
 depression (deficiency of NA)
 mania (excess of NA)
Acetylcholine
 ACh - widely distributed in the brain
Receptors: N, M1-5
 some M-receptors act presynaptically   ACh release
 M-antagonists   ACh release
 little information about function of N-receptors in the brain
Acetylcholine
Dementia and Alzheimer´s disease
 senile dementia – slowly progressive loss of intellectual
ability (5 % over the age of 65, 20% over 80)
 Alzheimer´s disease – same pathology irrespective of the
age of onset
 selective loss of cholinergic neurons was found in dementia
 to facilitate cholinergic transmision  choline (precursor),
donepezil (AChE-I)
Acetylcholine
Parkinson´s disease, Huntington´s chorea
 cholinergic neurons of the corpus striatum
 ACh release from the striatum is strongly inhibited by D 
hyperactivity of cholinergic neurons (associated with a
lack of D)  hypokinesia, rigidity, tremor (Parkinson´s d.)
- M – antagonists
 hypoactivity (associated with an excess of dopamine) 
hyperkinetic movements, hypotonia (Huntington´s
chorea) - anticholinesterase
Dopamine
 large amount  corpus striatum (coordination of
movement)
 also in limbic system
 dopaminergic neurons lack dopamine -hydroxylase,
and thus do not produce NA
Receptors: D1, D5 -  of AC; D2 , D3, D4 -  of AC
Dopamine
Motor system
Deficiency of dopamine in nigrostriatal pathway
 Parkinson´s disease (degenerative disorder - lack of
dopamine)
 parkinsonism (e.g. long term use of antipsychotic drugs receptor blockade)
 rigidity
 tremor
 hypokinesia
Dopamine
Behavioral effects
 schizophrenia in man is associated with
dopaminergic hyperactivity
Anterior pituitary gland
 dopamine and dopamine receptor agonists  
of prolactin secretion
 dopamine increases growth hormone secretion

 paradoxically, dopamine agonists  the
excessive secretion responsible for acromegaly
(bromocriptine)
Dopamine
Vomiting
 D2- receptors (in chemoreceptor trigger zone) 
important role in nausea and vomiting
 drugs that  dopamine release in the brain  nausea
and vomiting
 D-antagonists (phenotiazines, metoclopramide)  antiemetic activity
Serotonin (5-HT)


distribution of 5-HT neurons is very similar to that of NA neurons
Receptors: 5-HT1A-F, 5-HT2A-C, 5-HT3, 5-HT4, 5-HT5A-B, 5-HT6,
5-HT7
Sleep, mood


depletion of 5-HT  Insomnia
5-HT, as well as NA, may be involved in the control of mood
 deficit  depression
Hallucinatory effects


many centrally acting 5-HT antagonists are hallucinogens (LSD)
5-HT neurons  inhibitory influence on cortical neurons  loss of
cortical inhibition (e.g. by LSD)  hallucinogenic efect
Serotonin
Sensory transmission
 depletion of 5-HT exagerated responses to many
forms of sensory stimuly
 5-HT exerts an inhibitory effect on pain transmission 
synergistic effect between 5-HT and opioid analgesics
 depletion of 5-HT antagonises the analgetic effect
of opioids
Serotonin
Autonomic and endocrine function
 temperature regulation
 control of BP
 control of sexual function
Clinical implications
 depression, anxiety
 migraine, emesis
GABA
 mainly in the nigrostratial system
 principal inhibitory transmitter in the brain
Receptors
 GABA-A – part of Cl- channels (BZD, barbiturates, alcohol)
 GABA-B - presynaptic, G-protein linked - inhibition of
transmitter release
Clinical implications
 Insomnia, anxiety
 alcohol withdrawal
 Spasticity, epilepsy
EXCITATORY AMINO ACIDS (EAA)
 particularly glutamate and aspartate
Receptors:
 AMPA, Kainate receptors
 rapid neurotransmission
 NMDA
 long-term potentiation
 excitotoxicity
 pathogenesis of epilepsy
Functional aspects of NMDA receptors
long-term potentiation

enhancement of synaptic transmission (days or week)
in various CNS synapses after short stimulation
(learning, memory)
excitotoxicity

entry of Ca2+ produced by NMDA receptor activation 
neuronal damage following cerebral ischemia
pathogenesis of epilepsy

??? - high concentration of glutamate in areas
surrounding an epileptic focus
Antipsychotic drugs
Features of psychosis
Delusions
Hallucinations
Grossly disorganized speech or behavior
Uses of antipsychotic drugs
Schizophrenia
Manic phase of Bipolar Disorder
Major depression with psychotic features
others
Characteristics of schizophrenia
 Chronic psychotic illness characterized by disordered
thinking and a reduced ability to comprehend reality.
 Prevalence 0.5–1.0% of population
 Onset
 Positive features in late adolescence or early adulthood
 Aspects of cognitive deficits detectable earlier in life
 Comorbidity
 Depression: ∼30–50%
 Substance abuse: ∼50%
 Suicide: ∼5–10%
Schizophrenia - symptoms
Positive Symptoms
 delusions
 hallucinations
 thouhgt disorder
Negative Symptoms
 low motivation, social involvement
 emotional abnormalities
 cognitive deficits =  attention, planning, memory
 language problems
Schizophrenia - a disease with various
aspects
Positive Symptoms
Delusions
Hallucinations
Disorganized speech
Ca
Cognitive Deficits
Attention
Memory
Executive functions
(e.g., abstraction)
Negative Symptoms
Affective flattening
Anhedonia
Social withdrawal
Social/Occupational
Dysfunction
Work
Interpersonal
relationships
Self-care
Mood Symptoms
Depression
Anxiety
Aggression
Hopelessness
Suicidality
Simplify neurocircuitry of dopamine in
schizophrenia
Mesolimbic pathway
Hyperdopaminergia
DA
D2
Mesocortical pathway
Hypodopaminergia
DA
Limbic
Positive symptoms
D1
Negative symptoms
PFCx
The cause of schizophrenia
Etiology is unknown..... but...
 combination of genetic and environmental factors
 associated with neurodevelopmental disorder
 affects several brain areas
Dopamine theory
Dopamine theory
Schizophrenia is caused by excess dopaminergic activity
Arose in 1950s - 1960s: First effective antipsychotic drugs = dopamine
antagonists
Other supporting evidence:
 Reserpine = “dopamine depleter” has some weak antipsychotic
activity
 DA enhancers (anti-Parkinson drugs, amphetamine) mimic some
positive symptoms: hallucinations, delusions
 apomorphine  bromocriptine potent D2-receptor agonists produce similar effects exacerbate the symptoms in schizophrenic
patients
Dopamine theory: contrary evidence
 D2 antagonists are not specific for schizophrenia 
reduce psychosis in other conditions, too
 Growing appreciation of other neurotransmitter
systems
 Glutamate
 5-HT
 Others: ACh, GABA
 Lot of CSF, urine, serum, postmortem, imaging,
functional studies have not yielded consistent support
for a primary DA changes in untreated patients
Dopamine, still Important
Is schizophrenia caused by DA defect ??????
But antipsychotic drugs do act via DA system
 Which receptors?
 What brain regions?
 Role in side effects?
Dopamine receptor subtypes
D1 - D5
D2 mediates much of ‘typical APD’
therapeutic action . . .
. . . and side effects
Dopamine pathways in the brain
2
3
1
4
Mesolimbic dopamine system
DA  worsens delusions, hallucinations
D2 blockade  alleviates delusions, hallucinations
Mesocortical dopamine system
DA  motivation, reward, other ‘higher functions’
D2 blockade  worsens ‘negative symptoms’
Nigrostriatal dopamine system
DA  Essential for extrapyramidal motor function
D2 blockade  produces extrapyramidal symptoms
Tuberoinfundibular dopamine system
DA  inhibits prolactin release
D2 blockade  hyperprolactinemia
Antipsychotic drugs
 Effective with regard to positive
symptoms in 20-30% of patients
 Much weaker effect on negative
symptoms than positive symptoms
 Significant parkinsonian symptoms and
anticholinergic effects (poor
compliance and potentially disabling)
 Tardive dyskinesia in a minimum of
20% of patients who receive chronic
neuroleptic treatment.
 At least as effective as typical
neuroleptics with regard to positive
symptoms
 More effective than typical agents with
regard to negative symptoms
 Much lower incidence of parkinsonian
symptoms and anticholinergic effects
than typical agents
 TD does occur but at much lower
incidence
 Elevated risk of metabolic side effects
Typical antipsychotics
Chemical classes:
Phenothiazines - chlorpromazine, fluphenazine
Thioxanthenes - thiothixine
Butyrophenones - haloperidol, droperidol
Other: loxapine (dibenzoxazepine), molindone
Diphenylbutylpiperidines: pimozide
Typical antipsychotic drug actions
D2 Dopamine antagonism
Muscarinic receptor antagonism
1 adrenergic receptor antagonism
Histamine H1 receptor antagonism
D2 receptor blockade
Therapeutic effects
Amelioration of the positive signs, symptoms of
psychosis, manic symptoms, aggressive
behaviors
Antiemetic effect
D2 receptor blockade
Adverse effects
Extrapyramidal symptom (EPS)
Acute; akathisia, acute dystonia, parkinsonism
Late; tardive dyskinesia
Endocrine effects: prolactin elevation
Weight gain due to increase feeding
Late
onset
Acute
onset
Spectrum of EPS
Acute dystonia
Tardive Dystonia vs. Tardive Dyskinesia
Tardive dystonia
• Strikes younger
• Strikes sooner in the
course of neuroleptic
treatment
• Poor prognosis
• More males
• Patients with mood
disorders may be more
susceptible
• Anticholinergics may
improve condition
Tardive dyskinesia
• Strikes older
• Strikes later in the course
of neuroleptic treatment
• Variable prognosis
• More females (?)
• Patients with mood
disorders may be more
susceptible
• Anticholinergics usually
worsen condition
Neuroleptic malignant syndrome
 NMS is an uncommon but serious and potentially fatal
complication of therapy
 It is a syndrome of EPS, hyperthermia, altered
consciousness, and autonomic changes (tachycardia,
unstable BP, incontinence)
 Management
 Discontinuation of the antipsychotic agents
 Supportive therapy
 Bromocriptine may be benificial
 The onset is sudden and recovery may take 5-10 days
after discontinuation of the agent
Spectrum-based concept of NMS
Anticholonergics
Lorazepam
Lorazepam
Lorazepam
Dantrolene
Bromocriptine
Bromocriptine
Amantadine
Amantadine
Hyperprolactinemia
Osteoporosis
J Clin Psychopharmacol 2007;27:639–661.
M receptor blockade
Possible therapeutic effect
 Anticholinergic activity also has a beneficial effect:
 Counteracts Parkinsonian side effects of antipsychotic drugs
 Adverse effects
 All typical APDs have some muscarinic receptor
antagonism





Constipation
Urinary retention
Exacerbation of narrow angle glaucoma
Sinus tachycardia
Blurred vision
 Antimuscarinic activity varies greatly among
antipsychotic drugs
1 receptor blockade
Adverse reactions
 All typical APDs have some 1 adrenergic receptor
antagonism
 Orthostatic hypotension
 Acute high doses (e.g. psychiatric emergencies) may produce
cardiovascular collapse, death
 Anti- 1 activity varies greatly among antipsychotic drugs
Histamine H1 receptor blockade
Adverse reactions
 Somnolence - can be profound
 Weight gain
 Antihistamine activity varies greatly among antipsychotic
drugs
High-potency vs. Low-potency APDs
Antipsychotic drug spectrum:
High-potency: e.g. Haloperidol
 High: EPS
 Low: antimuscarinic, hypotension, sedation
Low-potency: e.g. Chlorpromazine
 Low: EPS
 High: antimuscarinic, hypotension, sedation
Spectrum of Adverse Effects Caused by Antipsychotic Drugs
Low Potency
High Potency
Fewer extrapyramidal reactions
(especially thioridazine)
More sedation, more postural
hypotension
Greater effect on the seizure
threshold, electrocardiogram
(especially thioridazine)
More likely skin pigmentation and
photosensitivity
Occasional cases of cholestatic
jaundice
Rare cases of agranulocytosis
More frequent extrapyramidal
reactions
Less sedation, less postural
hypotension
Less effect on the seizure
threshold, less cardiovascular
toxicity
Fewer anticholinergic effects
Occasional cases of neuroleptic
malignant syndrome
Typical (old fashioned) antipsychotic drugs
‘Typical APD’s - 1950’s to present
 still used due to low cost & in special situations
 primarily treat positive symptoms
 imperfect:
 fail to help many patients’ positive symptoms
 tend to make negative symptoms worse
 have many side effects
Despite their problems, they revolutionized
treatment of this devastating illness
Atypical Antipsychotic Agents: Mechanism
 D2 receptor antagonism
 5-HT2A serotonin receptor antagonism
 May also involve other actions:
 most of the atypicals also have substantial affinity for other DA, 5HT, adrenergic receptors
Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT
5-HT2A
DA
D1
D2
Caudate/putamen
Normal function
Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT
5-HT2A
DA
Typical
D1
D2
Caudate/putamen
EPS
Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT
5-HT2A
DA
D1
Atypical
D2
Caudate/putamen
Less EPS
What defines ATYPICAL antipsychotics?
Atypical APD’s have some of the following:
 Positive sympt.: increased therapeutic efficacy
 i.e. in treatment resistant patients
 Negative sympt : some therapeutic efficacy
 motivation, social withdrawl, cognition
 Side effects: generally less than typical drugs
 Acute EPS: Parkinsonian, Dyskinesias, Akathisia
 Chronic EPS: Tardive Dyskinesia
 Endocrine: Hyperprolactinemia
Side Effects of
Typical vs. Atypical Neuroleptics
“Typical”
“Atypical”
EPS
+/++++
0/+
Akathisia
+/++++
0/+
Cognitive problems
+++
0/++
NMS
+
0/+
Tardive dyskinesia
+++
+/++
Hyperprolactinemia
+++
0/++
Side-Effects
 Extrapyramidal side effects (EPS):
 Risperidone > Olanzapine = Ziprasidone > Quetiapine >
Aripiprazole ?=? Clozapine
 Anticholinergic:
 Clozapine > Olanzapine > others
 Hypotension:
 Clozapine > > Quetiapine, Risperidone > Ziprasidone, Olanzapine,
Aripiprazole
Side-Effects
 Sedation
 Clozapine > > Olanzapine, Quetiapine > Risperidone, Ziprasidone,
Aripiprazole
 Prolactin elevation
 Risperidone > others
 Weight gain
 Clozapine = Olanzapine > Quetiapine, Risperidone > Ziprasidone,
Aripiprazole
 Agranulocytosis: Clozapine
Metabolic effects
Weight gain over 1 year (kg)
aripiprazole
1
amisulpride
1.5
quetiapine
2–3
risperidone
2–3
olanzapine
>6
clozapine
>6
Clozapine
Few EPS, no TD, no elevated prolactin
Can cause life threatening Agranulocytosis and
risk of seizures at higher doses
Is sedating and causes weight gain
Greatest efficacy, but highest side effects of
atypical antidepressants
Side Effects of Clozapine
Highly anticholinergic
Strong 1 blocker
Agranulocytosis - loss of granulocytes
 As common as 1-2%
 Usually occurs in first 6 months of therapy
 Often fatal (to 35%)
 Adds significantly to financial cost of therapy - $10k/yr
Myocarditis
 As common as 0.2%
 Occurs mostly in first month of therapy
Risperidone
 Good at low doses, but mimics conventional neuroleptics at
higher doses
 Used with elderly, children and adolescents due to low dose
needs
 Elevates prolactin
 May improve cognitive functioning in Alzheimer’s and may
improve mood in schizophrenia, manic and depressive
phases of bipolar
 Does not block histamine H1 receptors  less weight gain
Olanzapine
Usually no EPS- even at high doses
 So used with more severe cases
Improved mood in bipolar and improved cog.
functioning in schizophrenia and dementia
Weight gain, moderate sedation, low prolactin, low
TD
Expensive
Quetiapine
Virtually no EPS at any dose, no Prolactin
 Thus good for patients with Parkinson’s and Psychosis
Weight gain, may cause cataracts (animal studies)
Mood and cog func. Bipolar, Dementia,
Schizophrenia
Ziprasidone
Low EPS, low prolactin
No weight gain
Antidepressant and anxiolytic properties due to
additional inhibition of 5HT and NE reuptake
Cog. and Mood: Bipolar, schizophrenia, Dementia
Shift in Risk Perception
of Antipsychotics
Past Areas of
Concern
Current Medical Realities
Diabetes
Weight Gain
Weight
Gain
Sedation
Tardive
Dyskinesia
Insulin
Resistance
CHD
Prolactin
Hyperlipidemia
Prolactin
TD
Hyperlipidemia
Insulin
Resistance
Sedation
Coronary Heart
Disease