Download A PHARMACOLOGISTS VIEW OF THE BRAIN

A PHARMACOLOGISTS VIEW OF THE BRAIN
PHARMACOLOGICAL VIEW OF THE BRAIN
1. Main interest is centered upon the nerve terminal and the
synaptic cleft
2. If you can find a pharmacological means of altering the function
of the transmitter in this region, you may have a therapeutic agent
that can be used to treat a brain disorder
3. So the 1 st question becomes: In what direction do you would
want to alter transmitter functioning (e.g., increase, decrease?)
4. And the 2 nd question becomes: How can you achieve this goal
(i.e., what tools are available?)
a. and by tools, we are usually thinking of drugs
GENERAL POINTS TO CONSIDER WHEN USING
PSYCHOPHARMACOLOGICAL DRUGS
1. Does the drug get into the central nervous system (CNS)?
a. in general, because of the blood-brain barrier, to get into the brain a drug would have to have one of the
following two characteristics:
1. lipophilic
2. user of a transport system
b. Many drugs of abuse are lipophilic
1. stimulant drugs such as amphetamine
2. opiate drugs such as heroin
3. hallucinogenic drugs such as LSD and cannabinoids (found in marijuana)
c. some CNS-acting drugs can make use of transporters
1. L-DOPA, used in the treatment of Parkinson's disease, is an amino acid, and can use an amino acid
transport system to get into the brain
2. Which neurotransmitter system do you want to interact with?
a. the total number of transmitter systems in the brain is quite large, with additional transmitters
discovered every year
1. right now, we can say that there are probably over 50 different transmitters used in the brain
b. some of these transmitters are familiar from study of the peripheral nervous system
1. acetylcholine
2. norepinephrine
c. the brain transmitters can be divided into 3 main categories
d. one category is often referred to either as biogenic amines or classical neurotransmitters
1. acetylcholine
2. dopamine
3. norepinephrine
4. epinephrine
5. serotonin
6. histamine
e. a 2 nd category is represented by amino acids
1. glutamic acid (glutamate)
2. aspartic acid (aspartate)
3. GABA (gamma-aminobutyric acid)
4. glycine
f. a 3 rd category consists of peptides
1. endogenous opiate peptides, often referred to as opioids
a. enkephalins
b. endorphins
2. substance P
g. the peptides have the largest number of members, since there can be so much diversity in peptide
structure
h. however, the category that is probably used the most in the brain is the amino acid category
1. it has been estimated that at least half of all of our synaptic connections make use of an amino acid
transmitter
2. glutamate and GABA have been called the workhorses of the brain
i. for many transmitters, the effect on target tissue can be either excitatory or inhibitory
1. for amino acids, we can generalize
a. glutamate and aspartate are usually excitatory
b. GABA and glycine are usually inhibitory
2. this stems from their general effects on ion pemeability
a. the excitatory amino acid transmitters increase sodium permeability
1. this drives the neuron towards the threshold potential (about -40 mv), at which point an action
potential is generated
b. the inhibitory amino acid transmitters increase chloride permeability
1. this either hyperpolarizes the neuron, or at least tends to keep it at the resting potential, making it
harder to generate an action potential
3. How specific is the drug action?
a. drug side effects can come about in one of two general ways
1. through an action at the site you are aiming for
a. perhaps because you are achieving your goal too well!
1. if you are trying to achieve some receptor blockade, perhaps you are producing too much
2. this might be corrected simply by lowering the drug dosage
2. through an action at a site different from the one you are aiming for
a. perhaps the drug is blocking another receptor in addition to the one you are aiming at
b. or even more indirect, perhaps the drug (or one of its metabolites) is causing damage to an organ,
such as the liver
OVERVIEW OF DRUG ACTION IN THE BRAIN
1. In using psychoplarmacological agents, we want to be able to manipulate transmitter systems
2. can be useful to think of the 5 stages of the life cycle of all transmitters as providing possible targets
a. synthesis
b. storage
c. release
d. receptor interaction
e. transmiter inactivation
3. synthesis
a. for biogenic amines and amino acid transmitters, most of the synthesis occurs in the nerve terminal
1. ater the synthetic enzymes are made in the cell body and transported to the terminal
b. can target transmitter synthetic enzymes to either inhibit or activate synthesis
1. use of L-DOPA to increase dopamine formation in the brains of Parkinson's patients
a. this requires that there are sufficient numbers of pre-synaptic nerve termnals to convert the L-DOPA
into dopamine
b. this can be a problem if you are dealing with a neurodegenerative disorder where the neurons are being
destroyed
4. storage
a. most transmitters are taken up and stored in synaptic vesicles after they are synthesized
b. drugs can interfere with storage
1. amphetamine can displace catecholamines and serotonin from their synaptic vesicles
2. the buildup of transmitter in the cytoplasm of the nerve terminal can aid in producing an egress of the
transmitter into the synatpci cleft
3. in the periphery, this will cause an increased norepinephrine concentration in the synaptic cleft
a. this will mimic the effect of sympathetic nerve stimulation
b. can produce a significant increase in blood pressure
4. in the CNS, the release of catechoamines and serotonin plays a significant role in the behavioral
effects of amphetamine
a. mood elevation
b. increased sense of energy
c. decreased appetite
5. release
a. as indicated above, catecholamine and serotonin release is increased by stimulant drugs such as
amphetamine and related drugs
b. many nerve terminals possess receptors which can inhibit release of their transmitter
1. sometimes these inhibitor receptors are activated by the same transmitter that they release
a. this would be called autoinhibition and the receptors would be designated as autoreceptors
b. this would be a form of feedback inhibition
c. receptors can exist on the pre-synaptic terminals for transmitters other than the ones released from
that terminal
1. for instance, if a terminal has receptors on it for opiates, occupation of the opiate receptor will
produce an inhibition of transmitter release
a. via inhibition of calcium entry
2. this is known as pre-synaptic inhibition
6. receptor interaction
a. this is a major site for CNS drug action
b. can use drugs to activate the receptors
1. agonists
c. can use drugs to inhibit the receptors
1. antagonists
d. an example of an agonist
1. bromocriptine to activate dopamine receptors in Parkinson's patients
e. an example of an antagonist
1. haloperidol to block dopamine receptors in schizophrenic patients
7. transmitter inactivation
a. also an important site of action of CNS drugs
b. two main routes of inactivation
1. reuptake back into the nerve terminal
a. seen for catecholamines, serotonin, glutamate and GABA
b. can use drugs to block this reuptake, and thus potentiate the action of the transmitter in the synaptic
cleft
1. fluoxetine (Prozac) to block serotonin reuptake in the treatment of depression
2. note: fluoxetine is the generic name of the drug
a. Prozac is the proprietary name
3. we will focus on the generic names
a. but in dealing with patients, the proprietary names are often used because they are often easier to
remember
2. enzymatic metabolism
a. seen for acetylcholine and peptide transmitters
b. transmitter action can be potentiated via inhibition of metabolism
1. donepezil (Aricept) as an acetycholinesterase inhibitor in the treatment of Alzheimer's disease
8. Summary point to keep in mind when studying: Many of the drugs used for their CNS action can be
understood better with regard to mechanism of action and side effects, when considered with regard to their
effects on the life cycle of the neurotransmitters in the brain