Biological Bases of Behaviour.
Lecture 5: Pharmacology of Synapses.
Normal
monkey
Monkey exposed
to ecstasy
Kalat (2001) p 73
Learning Outcomes.
 By the end of this lecture you should be able to:
 1. Describe the formation and the functions of the key
neurotransmitters.
 2. Explain (using examples) how drugs affect synapses.
 3. Describe how drugs of abuse affect synaptic events.
Transmitter Substances.
Recall that neurotransmitters can have two types of effect:
1. Depolarization (EPSP)
2. Hyperpolarization (IPSP)
One would perhaps expect that two types of
neurotransmitter would exist - excitatory and inhibitory.
 However, while some neurotransmitters are exclusively
excitatory or inhibitory, others can produce either effect
depending upon the nature of the postsynaptic receptors.
 The commonest neurotransmitters are as follows:




1. Acetylcholine (ACh).
 ACh consists of choline and
acetate.
 Normally these two
substances cannot join
together as the acetate is
connected to molecules of
Acetyl coenzyme A (Acetyl
CoA).
 However in the presence of
the enzyme choline
acetyltransferase (CAT), the
acetate ion is transferred to
the choline molecule
producing a molecule of ACh
and a molecule of CoA.
Carlson, (1994), p 61
Acetylcholine (continued).
 Acetylcholine is released at acetylcholinergic synapses on
skeletal muscles where it is excitatory.
 In the CNS it plays a role in learning, memory, and in sleep
regulation.
 In the PNS acetylcholinergic synapses are inhibitory.
 There are two kinds of ACh receptors:
 1. Nicotinic: Ionotropic, and stimulated by the poison
nicotine. They produce very rapid but short-lived potentials
and are found principally in muscle fibres and in the CNS.
 2. Muscarinic: Metabotropic, and stimulated by the poison
muscarine (in mushrooms), they produce slower but
longer-lived potentials and are found principally in the CNS.
Reuptake of Acetylcholine.
Recycled choline
 ACh is split into its
consituent parts by
the enzyme
acetylcholinesterase
(AChE).
 The choline returns to
the presynaptic
terminal by means of
reuptake.
Choline
transporter
Presynaptic
membrane
Acetate ion
ACh molecule
Carlson, (1994), p 62
choline
AChE
Actions of AChE
breaks down
ACh molecule
2. The Monoamines.
 There are four neurotransmitters in this class all distributed
widely throughout the brain:
 Dopamine
 Epinephrine
 Norepinephrine
 Serotonin
 They act as modulators - decreasing or increasing various
brain activities.
 As they are all chemically very similar many drugs can
affect their activity.
 There are two subclasses of monoamines: catecholamines
and indoleamines.
The Catecholamines.
 Dopamine (DA): Dopaminergic neurons produces both
EPSP's and IPSP's depending on the nature of the
postsynaptic receptor.
 Dopamine can only be obtained from phenylalanine derived
from a protein-rich diet.
 This is then converted into the amino acid tyrosine which
then creates L-Dopa by the actions of Tyrosine hydroxylase.
 The actions of the enzyme DOPA decarboxylase finally
converts L-Dopa into Dopamine.
 At least 5 types of dopamine receptors have been identified
so far referred to as D1 - D5 each with differing properties.
Dopamine (continued).
 Dopamine has been implicated in several important
functions including movement, attention and learning.
 Degeneration of dopaminergic neurons in the substantia
nigra (part of the basal ganglia) causes Parkinson's
disease, some symptoms of which can be alleviated by the
drug L-Dopa.
 Dopamine may also play a role in schizophrenia as drugs
that block the activity of dopamine alleviate the more
serious symptoms of this disorder and drugs which increase
dopamine production increase such symptoms.
Norepinephrine (NA).
 This is also called noradrenalin and is created within
dopamine-containing synaptic vesicles by dopamine hydroxylase.
 In the brain, noradrenergic synapses are involved in the
control of alertness and wakefulness and produce IPSP's.
 In the target organs of the sympathetic nervous system
noradrenergic synapses have excitatory effects.
 There are several types of noradrenergic receptors which are
usually referred to as adrenergic because they are also
sensitive to epinephrine (adrenalin).
 In the CNS there are 1, 2, 1 and 2-adrenergic receptors.
These are coupled to G-proteins that generate the secondary
messenger cyclic AMP and are metabotropic.
 Catecholamine synthesis is regulated by the enzyme
monoamine oxidase (MAO).
The Indoleamines.
 Serotonin (5-Hydroxytryptamine or 5-HT): The precursor of
serotonin is the amino acid tryptophan.
 The enzyme tryptophan hydroxylase converts tryptophan
into 5-hydroxytryptophan (5-HTP).
 Another enzyme 5-HTP decarboxylase then produces 5-HT
(serotonin).
 At most serotonergic synapses this transmitter produces
IPSP’s and its behavioural effects are also inhibitory. It
plays a key role in mood; eating; pain; sleep and dreaming;
and arousal.
 There are at least 7 different types of serotonergic
receptors 5-HT1A-1D and 5-HT2-4 all being metabotropic
except for the 5-HT3 receptor.
Other Transmitters.
 Some neurons use amino acids as transmitter substances,
the most important being:
 1. Glutamate: Also known as glutamic acid and is found
throughout the brain. It produces EPSP's in the postsynaptic
membrane but also directly affects axons by lowering their
threshold of excitation, thus increasing the rate at which
action potentials occur.
 Some Oriental foods contain high levels of monosodium
glutamate and this can cause mild neurological symptoms.
 There are several ionotropic and metabotropic glutamate
receptors.
 The ionotropic NMDA receptor seems to involved in the
synaptic changes underlying learning and memory.
Other Transmitters (continued)
 2. GABA (gamma-aminobutyric acid): Produced from
glutamic acid by the actions of an enzyme called glutamic
acid decarboxylase (GAD).
 It is inhibitory and is widely distributed throughout the
brain and spine and some investigators believe that it is the
widespread presence of GABA that prevents epilepsy.
 Two GABA receptors have been identified - the ionotropic
GABAA and the metabotropic GABAB.
 The GABAA receptors contain bindings sites for at least 3
different substances, one being for GABA, the second being
for benzodiazepines and third being for alcohol and
barbiturates each of which have inhibitory effects.
Other Transmitters (continued)
 3. Peptides: Neurons in the CNS also release peptides.
 One of the most important are the endogenous opiates
discovered by Pert et al., (1975).
 They discovered that that the reason that drugs such as
morphine and heroin are so addictive is that they act on the
naturally-occurring opioid synapses that are normally
stimulated by the brain’s own substances.
 These natural opiates are called enkephalins and appear to
be important for pain relief and pleasure.
Pharmacology of Synapses.
 Many natural substances affect the functioning of the
synapses.
 Key drugs of abuse are derived from plants or grains (e.g.
alcohol, nicotine, opium, caffeine, cocaine).
 Effective drugs either increase or decrease the effects of a
neurotransmitter.
 A drug that blocks the effects of a neurotransmitter is an
antagonist, while a drug that mimics or increases its effects
is an agonist.
 Whether a drug is an agonist or an antagonist is
determined by its affinity (the strength of its binding to the
receptor) and its efficacy (how well it activates the
receptor).
Individual Differences.
 Everyone’s brain uses the same neurotransmitters which
gives the impression that drugs will have the same effects
on everyone.
 Clearly this is not so. There are large individual differences
in drug responsiveness, and these are determined by the
fact that different receptors are found in different numbers
and sensitivities, determined by genetic and environmental
factors.
 E.g someone may have a large number of dopamine D4
receptors and few D1 or D2 receptors, but someone else
may have more of the latter and fewer of the former (Kalat,
2001).
 Synaptic function can be affected by different drugs in
several ways:
1. Production of the Transmitter.
 A transmitter substance must first be synthesised from a
precursor and this process is controlled by enzymes.
 Drugs that affect these enzymes can thus influence the
production of the transmitter substance. E.g:
 L-Dopa is a dopamine agonist as it increases the rate at
which dopamine is synthesised.
 The drug PCPA prevents the enzyme tryptophan from
making serotonin (it is thus an antagonist) and is often
used to halt the progress of certain tumours that derive
from serotonergic neurons.
2. Storage and Release.
 Reserpine (snakebite cure) makes the synaptic vesicles
that contain monoamines leak and the molecules of
neurotransmitter are mopped up by MAO before being
released. Reserpine is thus an antagonist.
 Other substances do not affect the storage of the
transmitters but prevent their release.
 E.g Botulinum toxin causes paralysis by preventing the
release of ACh.
 Other drugs, such as the venom of the black widow spider
cause the release of too much ACh which can be fatal in the
very young and old.
3. Effects on Receptors.
 Once a neurotransmitter is released, it must stimulate the
postsynaptic receptors.
 Nicotine mimics the effects of ACh at the nicotinic receptors
and is thus an agonist.
 Atropine (Belladonna) blocks the acetylcholinergic
muscarinic receptors and causes paralysis in the autonomic
nervous system, it is an antagonist.
 The plant toxin curare blocks the nicotinic receptors found
in the muscles and causes paralysis, it was originally used
as a hunting weapon but is now used during surgery to
prevent muscle contraction.
4. Reuptake and Destruction.
 Cocaine prevents the
reuptake of NA and DA and is
thus an agonist.
 Physostigmine prevents the
enzymes that destroy ACh
from working and is also
agonistic.
 Iproniazid inactivates MAO
allowing more monoamines to
be released when the axon
fires. It is a potent
antidepressant as it acts as a
serotonergic agonist.
Carlson, (1994), p 73
Drugs of Abuse.
 Highly addictive drugs produce their pleasurable effects because
they increase activity in dopamine receptors in the nucleus
accumbens.
Axons from nucleus
accumbens
Nucleus
accumbens
Kalat (2001) p 70
Drugs of Abuse.
 i) Amphetamine: Stimulates dopaminergic synapses by
increasing the release of dopamine at the presynaptic
terminal. Effects are short-lived and are usually followed by
depression as dopamine is then released at a much lower
rate than normal.
 ii) Cocaine: Blocks reuptake of dopamine, norepinephrine
and serotonin. Again, the effects are short-lived and are
followed by reduced neurotransmitter release.
 Cocaine users rapidly develop a tolerance to the drug and
have to take more and more to achieve the same effects.
 Permanent alterations are also caused to the dopamine
system which alters brain metabolism and blood flow
increasing the risks of stroke and epilepsy.
Drugs of Abuse (continued)
 iii) MDMA (methylenedioxymethamphetamine or Ecstasy):
Stimulates dopamine release at low doses (mimicking
cocaine or amphetamine). At higher doses it stimulates
serotonergic synapses producing sensory hallucinations
and mood changes.
 The highly stimulating nature of the drug also destroys the
same synapses over time.
 iv) Nicotine: Stimulates acetylcholinergic nicotine receptors
in the nucleus accumbens. It is rapid-acting, highly
addictive, and also produces pronounced withdrawal
effects.
Drugs of Abuse (continued)
 v) Marijuana: The leaves of the cannabis plant contain
cannabinoids such as D9-tetrahydrocannabinol.
 These are rapidly absorbed but leave the body slowly which
is why the drug has weak withdrawal effects.
 Cannabinoid receptors are found in the hippocampus and
basal ganglia (which is why memory and movement are
affected) and in the pain centres.
 vi) LSD (lysergic acid diethylamide): This hallucinogenic
drugs mimics the effects of serotonin though exactly how
its causes distortions in perception and mood are not yet
understood.
Drugs of Abuse (continued)
 vii) Caffeine: This interferes with the effects of the
inhibitory substance
adenosine which acts upon
presynaptic terminals to prevent the release of dopamine
and acetylcholine.
 By blocking the inhibitory effects of adenosine more
dopamine and acetylcholine are released.
 viii) Alcohol: This has many effects on the nervous system
but it principally:
 Inhibits the flow of sodium across the neuronal membrane.
 Decreases serotonin activity.
 Facilitates the response of the GABAA receptor.
 Increases dopamine activity.
 Blocks the actions of glutamate.
Reference and Bibliography.
 Carlson, N.R. (1996). Physiology of Behaviour.
 Kalat, J.W. (2001). Biological Psychology.
 Pert, C.B., Snowman, A.M., & Snyder, S.H. (1974).
Localization of opiate receptor binding in presynaptic
membranes of rat brain. Brain Research, 70: 184-188.