TOPIC

6: NEUROPHARMALOGICAL ACTIONS

THE NEURON
BACKGROUND
• Early philosophers knew that the ability of animals to change their behaviour in response to
external events must be mediated by some form of communication along biological material
• Early “balloonist” theories
o Rene Descartes: expansion of fluids within the brain and spine were transduced into
muscle movements
• Galvani: electrical induction of muscle movements in frogs’ legs indicated that electrical
energy mediated the transduction of sensory information into muscular activity (behaviour)
o Frog sees a fly (sensory information) so it jumps (muscular activity behaviour) to
catch it
o Communication between sensory (visual) neurons and motor neurons occurs via
electrical energy which runs along a “neural pathway”
• Camillo Golgi: discovered a method for staining brain cells
o Involved fixing black silver chromate particles into the neuron membrane. This results
in a stark black deposit which provides clear and well contrasted picture of the
neuron
o The ability of visualise separate neurons led to the eventual acceptance of the
‘neuron theory’
• Staining methods have now been used to identify lots of different types of brain cells which
do different things within the nervous system

STRUCTURE
• Dendrites: branch-like structures that receive
information/signals from other neurons
• Cell body (soma): control region which contains the
machinery that keeps the neuron alive and functioning
• Axon hillock: where the excitatory and inhibitory input
from other cells are summated to determine whether the
cell will ‘fire’ (aka action potential) or not
• Axon: thin fibre extending from the soma which is involved
in transmitting electrical signals to other neurons (via an
action potential)
• Myelin sheath: is a fatty layer that covers portions of the
axon which speeds up electrical conduction down the
axon
• Nodes of Ranvier: allows the electrical charge to jump to
each node, speeding conduction
• Terminal buttons: passes the electrical signal to the
dendrite of a neighbouring cell (via neurotransmitter
release)

NEURON POTENTIALS
RESTING POTENTIAL
• Resting membrane potential: voltage of a neuron when it is not ‘firing’
+
• Maintained by pumping positively charged sodium ion (Na ) out of the cell and potassium ions
+
(K ) into the cell
o More positive ions outside compared to inside the cell – creates a negative
electrical charge inside the cell (-70mV)
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ACTION POTENTIAL
• Action potential: the process by which an electrical signal is transmitted along an axon
• Andrew Huxley: breakthrough in understanding the action potential using the giant squid axon
as his experimental model
• Occurs when a neurotransmitter (stimulus) from another cell, or a drug, causes sodium
channels to open which allows sodium ions to flood inside the cell
o Creates a brief positive charge (‘fires’) inside the cell before the sodium ions are
pumped out again
o This brief positive electrical charge within the cell causes neighbouring voltage-gated
sodium ions channels on the axon to open, allowing the positive electrical signal to
move down the length of the neuron like a Mexican wave
• Myelin sheath acts like an electrical insulator. It blocks the transit of ions across the cell
membrane except at the nodes of Ranvier. This enables the electrical signal to pump down
the neuron at a much faster speed than without the myelin sheath.

 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

NEUROTRANSMISSION
SYNAPSE
• The action potential may continue into the next cell through a process known as
neurotransmission or synaptic communication
• Synaptic cleft (gap): space between the terminal button and the dendrite (spine) of the target
(neighbouring) cell
• Changes in neurotransmission at the synaptic cleft are the basis for learning and behavior,
and it is here that drugs act to create addiction
• When an action potential reaches an axon terminal, it stimulates the release of
neurotransmitter molecules from sacs called vesicles. These molecules cross the synaptic
gap and bind to receptor sites on the receiving neuron. This allows electrically charged
atoms (not pictured here) to enter the receiving neuron and excite or inhibit a new action
potential

• The sending neuron normally reabsorbs excess neurotransmitter molecules, a process called
reuptake

EXCITATORY AND INHIBITORY SYNAPTIC POTENTIALS

+
• Excitatory neurotransmitter: opens sodium (Na ) channels allowing sodium ions to enter the
postsynaptic cell which creates a positive internal charge increasing the probability of an
action potential
o Excitatory postsynaptic potential (EPSP)
+
• Inhibitory neurotransmitter: opens potassium (K ) channels releasing potassium ions trapped
within the postsynaptic cell which creates a negative internal charge decreasing the
probability of an action potential
o Inhibitory postsynaptic potential (IPSP)
• Excitatory and inhibitory inputs compete (summate) to determine whether the cell ‘fires’ or not
o Drugs act by modifying these processes to change cell firing rates
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NEUROTRANSMITTERS
• Excite or inhibit neurons
• 7 neurotransmitters are important in addiction
o Primary site of action of an addictive drug
o Form a crucial part of the downstream cascade that drives the formation of addictive
behavior
1. Dopamine 5. GABA
2. Serotonin 6. Glutamate
3. Endorphin 7. Endocannabinoid
4. Acetylcholine
• Drugs act on primary ‘target’ neurotransmitter receptor
o Sets in motion a cascade of ‘downstream’ neural communication
• The inability of drugs to release dopamine, either directly or indirectly, is crucial for addiction
o Cocaine and amphetamines act primarily on the dopamine system
o Unique properties of other drugs, arising from their target receptor specificity, makes
them attractive for different reasons
§ Nicotine is a cognitive enhancer mediated by the acetylcholine system
§ MDMA is a positive mood enhancer through its action on serotonin
§ Opiates produce euphoria via opioid receptors
§ Alcohol is a relaxant through its targeting of GABA and glutamate
§ Cannabis has sedative properties through its action on the endocannabinoid
system

AGONIST AND ANTAGONIST DRUGS

• Ion channels are opened or closed by neurotransmitters
o Depending upon what ions these channels allow to flow in which direction, the
neurotransmitters either excite or inhibit the cell
• Drugs modify cell activity by virtue of having a molecular shape that is similar to the shape of
a neurotransmitter molecule
o Drugs are classified as agonistic if they fit a receptor perfectly and thus cause the
linked channel to open or close
o Drugs are classified as antagonistic if they fit a receptor imperfectly and thus block
the action of the neurotransmitter
• Drugs may be both agonists and antagonists at different receptors, creating complex effects
in different parts of the brain
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

DOSE RESPONSE CURVE

• Dose-response curves plot the response ot drugs, indexed by a measure of behaviour or
experience (e.g. pain relief) against the dose of the drug administered
o Typically S shaped
§ At low doeses there is little response as the dose increases so does the
response, until an upper limit is reached where further increases in dose
produce no additional response
§ Effective dose (ED) 50 is the dose at which 50% of the maximum response
is achieved
o The S shape dose-response curve may reflect the underlying physiological limits of
cell firing rates, which are also S shaped

DOPAMINE
• Mesolimbic pathway: ventral tegmental area (VTA) to the nucleus accumbens
o Key for drug reward learning
o Common path for drugs to produce their rewarding effects
• Olds and Milner (1954): early evidence for the role of dopamine in reward
o Rats favoured the location of the box in which they had received electrical
stimulation of the medical forebrain bundle (midpoint of the mesolimbic pathway)
o Found that rats would learn to press a lever to obtain this electrical stimulation,
indicating this stimulation was rewarding
o Conceivably this may underpin drug addiction
• Roy Wise (1996): found that electricl self-stimulation reward was mediated by mesolimbic
dopamine pathway
o Measured the change in rats’ rate of lever pressing to obtain electrical stimulation
across different frequencies of stimulation
o Higher frequencies of stimulation were more rewarding and supported higher rates of
lever pressing to obtain the stimulation
o Administration of amphetamine (DA agonist) shiftend the curve to the left, making a
lower frequency of stimulation more rewarding
o Administration of Pimozide (DA antagonist) shifted the curve to the right, requiring
higher levels of stimulation to achieve the same level of reward
o Indicates that behaviours which cause an increase in dopamine activity will increase
to the extent that dopamine is released
o Addiction appears to form by virtue of drugs releasing dopamine
• The self-adminstration procedure is used to model human addiction in rats
o Rats are given access to a lever which if pressed causes the infusion of a drug into
the blood stream
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

o The fact that rats acquire the self-administration response to obtain drugs indicate
that drugs are rewarding
o The mesolimbic dopamine pathway has been implicated in drug reward by the fining
that lesions of the nucleus accumbens abolishes cocaine (Roberts et al. 1980) and
amphetamine self-administration (Lyness et al. 1979)
o Thus, drugs must activate dopamine in the nucleus accumbens in order to stamp-in
self-administration behaviour

DOPAMINE AGONISTS
• Cocaine and amphetamine are dopamine (DA) agonists
o Increase the amount of DA presence in the synaptic cleft (via different mechanisms)
• Cocaine blocks DA reuptake
• Amphetamine causes DA to be released from synaptic vesicles into the terminal button
o And, reverses the direction of the DA reuptake transporter
• Supernormal increase in DA availability within the synaptic cleft

SEROTONIN
• Cell bodies for neurons that express serotonin (5-HT) are located in the raphe nuclei of the
brain system
o Axons project extensively across the brain – consistent with 5-HT having a
modulatory role on total brain function
• 5-HT neurons in the raphe nuclei play an important role in maintaining conscious arousal
level (wakefulness)
o these cells are inhibited during sleep

MULTIPLE ROLES
• Multiple roles in synaptic communication
o Acts on different ion channels to produce excitatory and inhibitory transmission of
action potentials
o Diffuses into the extracellular fluid to excite neighbouring neurons (neuromodulation)
o Interacts with other neurotransmitter systems including glutamate and GABA to
influence learning and memory
§ Important for cognition
§ Ogren et al 2008; Kehagia et al 2010

MOOD
• 5-HT is best known for its role in positive mood
o Evidence: the main antidepressant medications all influence 5-HT neurotransmission
to increase the availability of 5-HT in the synaptic cleft (i.e. they are agonists)
§ Increases positive mood
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

MDMA
• MDMA (ecstasy) has high affinity for blocking 5-HT reuptake from the synaptic cleft –
serotonin agonist
• Hallucinogens (psilocybin, mescaline, peyote, LSD) and stimulants (cocaine, amphetamine)
also block 5-HT reuptake
• Suggests that positive mood may be a common element amongst these drugs which helps
maintain their recreational use

MDMA: ADDICTIVE POTENTIAL

• MDMA (and hallucinogens) also release dopamine in the nucleus accumbens
o It is the dopamine enhancing effect of the drug which determines their addictive
potential (Ritz and Kuhar, 1989)
§ MDMA’s relatively lower affinity for releasing dopamine compared to
amphetamine and cocaine may explain why these compounds are ranked as
having a lower addiction potential than other drugs with higher dopamine
affinity (Nutt et al 2007)

ENDORPHINS (OPIOIDS)
• Endorphins: (neuropeptide) play a key role in pain reduction (analgesia) and subjective
pleasure (euphoria)
o Receptors are called opioid receptors because they respond to opiods/opiates
§ Receptors are locaed throughout the spine and sensory-motor pathways of
the brain
o Either open K+ channels or close Na+ channels reducing the likelihood of action
potentials carrying pain signals
• Endorphins are released by the pituitary gloand during a fight or flight response to stress
o Reduce pain sensation
• Endorphins are also located within the VTA of the mesolimbic dopamine pathway
o They inhibit inhibitory GABA neurons causing an increase in dopamine release in the
nucleus accumbens (Spanagel et al. 1990)

HEROIN AND DOPAMINE

• Release of dopamine in the nucleus accumbens is crucial to maintain heroin self-
administration
• Zito et al (1985)
o Rats self-administered heroin until their behaviour had stabilised
o Lesioned the nucleus accumbens and measure the percent decline in self-
administration behaviour relative to the pre-lesion baseline
o Animals ranked as having the greatest accumbens damage (2-4) showed the smalled
percent of self-administration relative to pre-lesion (20-60%), whereas animals
ranked as having little accumbens damage and sham animals who had no damage,
showed self-administration rates which were closer or matched their pre-lesion
baseline
• Nucleus accumbens is essential for heroin self-administration
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

PAIN AND PLEASURE

• Hedonic recactions procedure: an animal model of subjective emotional experience
o A sweet (pleasant) or bitter (unpleasant) solution is squirted into a rat’s mouth –
facial reaction is recorded with a close up camera
• Facial reactions to pleasant and unpleasant solutions
o Liking is associated with a licking reaction
o Disliking is associated with a gaping reaction
• Berridge and Kringelback (2008)
o Explore the neural mechanisms underpinning subjective reactions to opiates
o Whether injections of opiates into different locations within the nucleus accumbens
inceased sweet liking (liking increase), decreased bitter disliking (disliking decrease)
or decreased sweet liking
• In response to opiates, a large region (purple) decreased disliking, a smaller region (red)
increased liking, and a very small region (blue) decreased liking
o Accords with human subjective reports of opiates that unpleasantness melts away
and pleasure is overwhelming

ACETYLCHOLINE
• Has a role in cognitive capacity
o Sensitivity to sensory events, memory, speed of responding, etc.
o Evidence: Alzheimer’s disease is marked by broad impairments in cognitive capacity
and characterised by destruction of acetylcholine cell bodies (Auld et al. 2002)
o These cells project broadly across the cortex, they are believed to modulate higher
cortical functions as a whole

COGNITIVE FUNCTION
• Acetylcholine functions as a cognitive enhancer, improving attention and reactivity to
environmental events
• At the cellular level, acetylcholine increases the signal ot noise ratio in the firing rate
response to stimulation
o Cells have a background firing rate, and increase this rate in response to appropriate
stimulation (aka tuning)
o The difference between the signal and the noise (background) is crucial for detection
and responding to environmental events
• Sillito and Kemp (1983)
o Cells in the visual cortex of anesthetised cats are tuned to respond preferentially to
bars of light moving across the visual field in a particular direction (left or right)
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

o Selectivity of this tuining is weak in the control (anesthetised) animals. Hwoever,

when acetylcholine is applied (Ach), the tuning of the cells become much more
selective ot the preferred stimulation.

NICOTINE
• Nicotine is an acetylcholine agonist
o Binds to acetylcholine receptors on the post-synaptic call
§ These receptors are coupled to sodium channels, which open in response to
binding, exciting the cell and thus increasing the probability of an action
potential
• Nicotine also binds to pre-synaptic acetylcholine receptors located on the terminal button of
cells which express endorphins (Berrendero, 2010) and dopamine (Sidhoura et al 2007; Nisell
et all 1994)
• Cells in the VTA (mesolimbic dopamine pathway) increase firing rate in response to tobacco
smoke (TS)
o Activation is essential for nicotine to maintain self-administration behaviour (David et
al 2006)
• Addictive potential of nicotine stems from its three main actions
o Increasing cognitive function by activating the acetylcholine system (Levin et al.
2006, Miwa et al 2011)
o Increasing pleasure, wellbeing or pain/stress relief by activating the endorphin system
(Gilbery 1979; Pomerieau et al 1984; Berrendero 2010)
o Increasing reward of self-administration behaviour by activating the dopamine system
(Wise, 2004)
• Foulds et al. (1996): had abstinent smokers and never-smokers complete a rapid visual
information processing (RVIP) task before and after an injection of nictone or placebo
o RVIP task: participants presented with a series of single digits on the computer
screen at a rate of 100 digits per minute for 10 minutes. Their job was to press a
button as soon as possible upon seeing a target, which was defined as three
consecutive odd or even digits
o Placebo injection: neither smokers or never-smokers showed an improvement in the
speed of target detection
o Nicotine injection: both groups showed an improvement of target detection
§ Accords with Sillito’s cat study
o Overall slower target detection of smokers compared to never-smokers is consistent
with a withdrawal or tolerance effect or neurocognitive damage from smoking
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

GABA
MULTIPLE ROLES
• GABA (gamma-amino butyric acid): the chief inhibitory neurotransmitter regulating neural
activity throughout the nervous system
• Release of GABA onto receptors causes a shift in ion channels which causes the cell to
hyperpolarise (negative charge) – decreases the probability of an action potential
• GABA cells often play the role of inhibitory ‘interneurons’
o Hold other cell groups inhibited (unless they are inhibited by another cell)
o Provide ‘negative feedback’ in the sense that excitatory cell firing rates cannot
exceed an upper limit
§ Capping of firing rate is important for cells to avoid excitotoxic death,
produced by overstimulation
• Support for the role of GABA in limiting the excitatory output of cells throughout the brain
comes from epilepsy
o Epilepsy:
§ A common disorder characterised by seizures affecting roughly 3% of the
population
§ Hallmark of seizures is a transition to a supernormal elvel of action
potentials within the brain as a whole shown in the EEG trace (electrical
activity recorded from the scalp)
§ Anticonvulsant drugs act to increase inhibition of brain cells by targeting
three main neural mechanisms
• Increase GABA availability (agonists)
• Block voltage-gated sodium channels to reduce action potentials
• Antagonise the actions of the main excitatory neurotransmitter
glutamate

GLUTAMATE
LEARNING
• Glutatmate is the most abundant neurotransmitter in the brain – present in over 50% of
nervous tissue
• It plays a crucial role in learning and memory
• Nuroplasticity: the process by which pathways and synapses in the brain are changed
(‘plastic’) as a result of experience
o Environment, behaviour, learning, drugs
• Two gunctions performed by glutamate receptors:
o AMPA and Kainate receptors: respond to glutamate release by opening Na+
channels thus initiating an action potential within the receiving cell
o NMDA receptors: respond to glutamate by opening calcium (Ca2+_ channels which
activates an intracellular process ‘second messenger system’
§ This increases the number of AMPA recepters and thus increases the
strength of the synaptic connection (long-term potentiation)
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

ALCOHOL
• Antagonises post-synaptic glutamate recptors and reduces the release of glutamate
o Reduces the overall level of excitation within the brain
o Impairs learning and memory (black-outs)
• GABA agonist: further reduces excitation levels, responsible for sedative effects, anxiety
reduction and motor incoordination
• Releases endorphins producing the euphoric and analgesic effect
o Opiate release partially responsible for alcohol reward because alcohol self-
administration can be reduced by opiate antagonists (e.g. naltrexone)
• Dopamine agonist: increases in Nucleus Accumbens
o Responsible for rewarding self-administration behaviour

CANNABINOID
RETROGRADE INHIBITION
• Anandamide: the neurotransmitter (endocannabinoid) which binds CB1 receptors
o Only recental discovered (Devane et al. 1992)
o One type of endocannabinoid now known to act on CB1
• CB1 receptors tend to be located on the pre-synaptic terminal button of neurons
o Exert an inhibitory effect on the release of neurotransmitters including acetylcholine,
dopamine, GABA and glutamate
o Produces increases or decreases in overall neural activity in different brain regions
depending upon the neurotransmitter effected (Iversen, 2003)
• Endocannabinoids are manufactured on demand by post-synaptic cells in response to
neurotransmitters binding from the pre-synaptic cell
o Retrograde messenger: information is carried back across the synapse to CB1
recepter (as opposed to pre-post)
o Feedback inhibits neurotransmitter release in pre-synaptic cell
• Increased dopamine activity in the mesolimbic pathway is thought to be mediated by THC
binding to CB1 receptor on GABA interneuron
o As a result, the GABA interneuron is inhibited. Dopamine cell firing is thus disinhibited
(increased) resulting in the experience of reard that drives the formation of addictive
behaviour

CANNABINOID AND THC

• THC binds to CB1 recepter (agonist)
• CB1 receptor has a broad distribution in the brain (Terry et al 2010)
o The various psychological effects of cannabis can to some extent be aatributed to
binding within particular regions (Glass et al 1997)
 TOPIC 6: NEUROPHARMALOGICAL ACTIONS

THC AND DOPAMINE

• THC administered to rats increases firing rate of dopamine cells in the VTA
o Projects to the nucleus accumbens
§ Crucial for the establishment of addictive behaviour
o The same activation in response ot THC can be seen in humans