Psychopharmacology

Chemical Signaling by Neurotransmitters & Hormones- Chapter 3

Chemical Signaling Between Neurons (Fig 3.1)
Presynaptic cell- the cell delivering the message
Postsynaptic cell- the cell receiving the message
Usually a chemical stimulus (neurotransmitter) is passed from the pre- to postsynaptic
cell (rarely use direct electrical connections)
Neurotransmitters are stored in vesicles in the axon terminal, and released into the
synapse when the AP reaches the axon terminal

Types of Synapses (Fig 3.2)

Axodendritic: most common, axon terminates on dendrite of postsynaptic cell (produce
EPSP/IPSP)
Axosomatic: axon terminates on soma of postsynaptic cell (produce EPSP/IPSP)
Axoaxonic: axon terminates on axon terminal of postsynaptic cell (usually allows pre-
cell to modify NT release and type of post- neuron)
Presynaptic inhibition: reduces NT release from postsynaptic terminal
Presynaptic excitataion: increases NT release from postsynaptic terminal
Dendroaxonic: messenger from dendrite of post- cell diffuses presynaptically to affect
how the axon terminal releases NT (usually gaseous NTs)
Neuromuscular junction: presynaptic axon terminal releases ACh onto postsynaptic
muscle (affects nicotinic ACh receptors)- causes muscle contraction

Neurotransmitters (Table 3.1, Fig 3.3, 3.4)

Chemical messenger between neurons, currently over 100 substances
Must meet following criteria:
Pre- cell must contain the substance and method to manufacture it.
A mechanism must be present to inactivate the substance.
Substance must be released from the axon terminal when the neuron is
stimulated by an AP.
There should be receptors for the substance on the post- cell.
Direct application for the substance or agonist drug on its receptors on the post-
neuron should have the same effect as stimulating the pre- neuron.
Applying an antagonist drug that blocks receptors should inhibit the action of the
applied substance, as well as the effect of stimulating the pre- neuron.
NTs fall into several classes:
Amino acids: (glutamate, GABA)
Monoamines: (epinephrine, norepi, dopamine, serotonin) These are derived from
amino acids after removal of the acidic part (-COOH)
Small classical NTs: include acetylcholine, epi, norepi, dopamine, serotonin,
and amino acid NTs
Neuropeptides: 3 to 40 amino acids long, usually act as neuromodulators
(substance P, endorphins, corticotropin-releasing factor (CRF))
Lipids: usually have direct intracellular effects (anandimide affects cannabanoid
receptors)
Gaseous NTs: not stored in vesicles, and often work on the pre- neuron
Most NTs are synthesized near sites of use
Enzymes shipped throughout cell, so they can be manufactured anywhere
Can be replenished quickly
Neuropeptides are manufactured in soma on Nissl substance due to size and need for
mRNA and ribosomes
 Neuropeptides are packaged into vesicles and shipped to axon terminals via
anterograde axoplasmic transport
Cannot be replenished until more is shipped to axon terminal

Gaseous Neurotransmitters (Box 3.1)

Evidence for both nitric oxide (NO) and carbon monoxide (CO)
NO produced from amino acid argenine and nitrix oxide synthase (NOS) in endothelial
and postsynaptic cells
NOS activated by increased Ca++ in cell (usually via NMDA receptors for
glutamate)
NO is unusual because it is made postsynaptically, is a gas and not stored in a vesicle,
can spread rapidly over a fairly large area, and it diffuses across the synapse to the
presynaptic cell to cause changes
Usually increases # of vesicles of NT released by pre- cell, meaning the
postsynaptic cell is more strongly stimulated the next time an AP is generated
Utilized in long-term potentiation (LTP)

Presynaptic Events of Vesicular Release (Fig 3.5, 3.6)

1. Nerve impulse arrives at the synaptic knob
2. V-gated Ca2+ channels open and Ca2+ diffuses into the synaptic knob
3. Ca2+ triggers exocytosis of synaptic vesicles docked to the membrane in active
zone; SNAREs operate, vesicular contents released
4. After releasing NT, empty vesicles drop back into synaptic knob and can be
reloaded (if using classical NT)
5. Ca2+/calmodulin also causes reserve synaptic vesicles to detach from the
cytoskeleton and dock with SNAREs on inside of plasma membrane.

SNARE Proteins
SNARE= Soluble NSF Attachment Protein Receptors
Vesicles in releasable pool already attached to axon terminal membrane in active zone
via SNARE proteins
Other vesicles in storage pool attached to cytoskeleton away from active zone
SNARES composed of 3 types of proteins:
Cytoplasmic proteins: NSF and SNAP
Vesicular membrane: v-SNARE (synaptotagmin) and VAMP (synaptobrevin)
Target or terminal membrane: t-SNARE (syntaxin) and SNAP-25
When Ca+ enters axon terminal, Ca++ binds to synaptotagmin, causing it to change
shape
This causes the SNARE proteins to rotate and twist, forming a fusion pore- which will
either flutter open and shut, or invert the vesicle of NT, allowing NT into the synapse
High Ca++ also binds to calmodulin, forming Ca++/calmodulin complexes, which
phosphorylates another protein called synapsin I
When synapsin I is phosphorylated, it releases vesicles in the storage pool from
the cytoskeleton, and moves them up to unoccupied t-SNARES for future release
If enough Ca++ is still present, activates synaptotagmin again, releasing more
NT

Controls on NT Release by Neurons (Fig 3.7)

Rate of APs in pre- neuron (more APs = more NT release)
 Probability of NT release from axon terminal (Ca++ dependent), but Ca++ doesnt
always cause NT release when present- variable probabilities
Autoreceptors: a receptor for the same NT the pre- neuron releases on the pre- neurons
axon terminal or soma membrane- these affects how much NT the neuron releases
Terminal autoreceptors: on axon terminal, when stimulated, they decrease the
amount of NT released
Somatodendritic autoreceptors: on soma or dendrites, when stimulated, they
decrease the cellular response by allowing fewer channels to open
These are protections for overstimulation, and offer a neuron feedback as to how
much NT is currently in use and affecting nearby cells
Heteroceptors: receptors on an axon terminal that can be stimulated by another
axon/cell to affect how much NT it releases

Fates of Released NTs (Fig 3.8)

Enzymatic breakdown: the NT is modified/cut apart in such a way it is inactivated (ACh,
catecholamines, gaseous NTs, lipid NTs, some neuropeptides)
Example: MAO breaks down dopamine, epi, norepi
Transporters: in astrocytes or axon terminals (reuptake), the NT is transported into
another cell, where it can be repackaged and/or enzymatically degraded (usually for
neuropeptides, catecholamines, or amino acid NTs)
Example: Cocaine blocks transporters for dopamine, serotonin, and norepi,
antidepressants block serotonin reuptake
Diffuse away from synapse

Types of Receptors (Table 3.2, Fig 3.9, 3.10, 3.11, 3.12)

Ionotropic: work very rapidly, and produce short-term change in Vm
Usually allow flow of ions across membrane (Na+, K+, Cl-, Ca++, etc).
Composed of 4 or 5 protein subunits in arrangement that makes a pore in the
center that can be opened or closed based on presence of ligand.
Metabotropic: work more slowly, cause series of biochemical events inside cell for effect
Made up of seven transmembrane domain proteins
They activate G proteins inside the cell, can do one of two things:
Stimulate or inhibit channels in plasma membrane (ACh, dopamine, NE,
serotonin, GABA, endorphins)
Stimulate or inhibit effector enzymes in cell membrane, which usually
involve a second messenger (first messenger = NT, 2 nd messenger = other
chemical produced by effector enzyme).

Postsynaptic Ionotropic Receptor Effects

6. NT diffuses across synaptic cleft and binds to receptor on postsynaptic
membrane
7. Receptors acts as a ligand-gated Na+ channel. Channel opens, Na+ moves in,
depolarizing the cell.
Can also be inhibitory, and cause IPSP, in which case Cl- channel opens and Cl-
moves into cell
8. Na+ diffuses along inner face of plasma membrane partially depolarizing it and
causing a local EPSP (post-synaptic potential).
Or Cl- diffuses along inner face of plasma membrane, producing IPSP
9. EPSP spreads along the membrane and stimulates axon hillock area of axon to
initiate an AP if the voltage change is of sufficient strength upon arrival there.

Postsynaptic Metabotropic Receptor Effects

6. NT binds to receptor on postsynaptic neuron
 7. Receptor activates a G protein which hydrolyzes GTP and migrates along the
interior of the plasma membrane
8. G protein binds to adenylate cyclase (or other enzyme)
9. Adenylate cyclase removes two phosphate groups (PP) from ATP, producing cAMP.
10. cAMP activates a protein kinase
11. Protein kinase phosphorylates other cytoplasmic enzymes. This can lead to any
of the following effects.
11a. Activated enzymes trigger genetic transcription and synthesis of new
proteins
11b. Activated enzymes trigger other metabolic pathways
11c. Activated enzymes open ligand-gated ion channels in the plasma
membrane, allowing Na+ (or K+ or Cl-)to enter the cell and create a PSP.

Second Messengers (Table 3.3)

2nd messengers usually activate protein kinases- enzymes that phosphorylate (add
PO42-) other proteins.
Target protein could be a channel, enzyme, NT receptor, transporter, structural
protein, etc.
Can also affect phosphorylate proteins in nucleus of cell, that turn on or turn
off genes.
Famous 2nd messengers:
cAMP: stimulates protein kinase A (PKA)
cGMP: stumlated by nitric oxide (NO), stimulates protein kinase G (PKG)
Phosphoinositide 2nd messenger pathway: activates protein kinase C (PKC), as
well as increase Ca++ levels in post- cell
Calcium: can be increased by PKC activity, opening v-g Ca++ channels, and
ionotropic receptors. It requires the presence of a protein called calmodulin to
have effects. Ca++/calmodulin activates calcium/calmodulin kinase (CaMK).

Tyrosine Kinase Receptors (Fig 3.13)

These mediate the effects of neurotrophic factors (proteins that stimulate survival and
growth of neurons during development, and involved in neuronal signaling).
Neurotrophic factors (NTFs) include nerve growth factor (NGF- uses trkA), brain-
derived neurotrophic factor (BDNF- uses trkB), neurotrophin-3 and -4 (NT-3 and
NT-4- use trkC).
These factors utilize tyrosine kinase receptors (trk)
NTFs bind to receptor, and two tyrosine kinase (trk) molecules come together in
the cell membrane
trks phosphorylate each other on tyrosine residues located in cytoplasmic region
of each receptor
This triggers other protein kinases in the cytoplasm, which produce long-term
changes in the way the cells physiology works (gene expression)

Pharmacology of Synaptic Transmission (see fig 3.14 in your book for summary)
1. precursor: L-DOPA is precursor for dopamine
2. inhibit NT synthesis: alpha-methyl-para-tyrosine inhibits tyrosine hydroxylase, so
dopamine and NE are not made
3. block storage of NT in vesicles: reserpine blocks storage of dopamine, NE, and
serotonin
4. stimulate release: amphetamine increases release of dopamine and NE from axon
terminal
5. inhibit release: botulinum inhibits release of NT (degrades SNAP-25)
6. agonist for receptor: nicotine for nicotinic ACh receptors
 7. antagonist for receptor: curare is competitive antagonist for nicotinic ACh receptors
8. stimulate autoreceptors (inhibit NT release): apomorphine reduces dopamine release
9. block autoreceptors (increase NT release): pindolol increases blocks receptor,
increases serotonin release
10. inhibits NT degradation: physostigmine blocks acetylcholinesterase (AChE) so ACh
levels increase, or phenelzine blocks MAO so levels of dopamine, NE, and serotonin
increase in the synapse
11. blocks reuptake of drug: cocaine blocks transporters for dopamine, NE, and
serotonin

Endocrine System (Fig 3.15, 3.16)

Endocrine glands synthesize and release hormones into the bloodstream
Hormones typically have effects far from site of origin, and usually produce long-term
effects
Some substances are both NTs AND hormones (epinephrine and NE for example)

Important Endocrine Glands and Hormones (Fig 3.17, 3.18)

Adrenal glands:
Adrenal medulla: inner layer, chromaffin cells secrete epi and NE into blood
during sympathetic responses
Adrenal cortex: secrete steroid glucocorticoids in response to stress (in humans,
cortisol).
Gonads: testes and ovaries (steroid hormones)
Ovaries: secrete estradiols and progesterone
Testes: secrete testosterone (and other androgens, such as inhibin)
Pancreas: involved in regulation of blood glucose (BG)- large peptide hormones
Alpha cells: secrete glucagon, increase BG as it is released by tissues
Beta cells: secrete insulin, lowers BG as it is taken up by tissues
Delta cells: secrete somatostatin, fine tune knob for insulin and glucagon
Thyroid gland: regulator of metabolic rate and body temp
Follicles make thyroxine (T4) and triiodothyronine (T3) which circulate in the
blood. T3 is active form. Both are steroid hormones.
Pineal gland: above superior colliculus between cerebral hemispheres
Makes melatonin which is involved in activity cycles and photoperiod regulation
Pituitary gland: located below hypothalamus of diencephalon
Pituitary stalk: connects hypothalamus with pituitary, neuroendocrine cells in
hypothalamus release hypothalamic-releasing factors (neuropeptides) which
travel down portal vascular system in median eminance to anterior pituitary
Thyrotropin-releasing hormone (TRH): stimulates TSH release
Corticotropin-releasing hormone (CRH): stimulates ACTH release
Gonadotropin-releasing hormone (GnRH): stimulates FSH and LH release
Anterior Pituitary: makes and secretes peptide trophic hormones into blood:
Thyroid stimulating hormone (TSH): increases T3 and T4 secretion by
thyroid
Adrenocorticotropic hormone (ACTH): stimulates cortisol release
Follicle-stimulating hormone (FSH) and leutinizing hormone (LH): involved
in reproductive endocrinology in both males and females. LH promotes
sex steroid secretion in males and females
Growth Hormone (GH): stimulates production of insulin-like growth factor 1
(IGF-1) which is important for skeletal and muscular growth
Prolactin: promotes milk production by mammary glands
Posterior pituitary: release peptide hormones:
 Vasopressin (aka antidiuretic hormone ADH): acts on kidney aquaporin
channels for water to increase water retention
Oxytoxin: stimulates uterine contractions during childbirth, and milk
letdown from breasts during lactation
Both have been found to play role in parenting and affiliative behaviors

Mechanisms of Hormone Action (Fig 3.19)

Peptide hormones: work on metabotropic membrane receptors and second messenger
systems
Some, like insulin work on receptors similar to the trk receptors
Steroid and lipid hormones: use intracellular receptors generally located in the cell
nucleus
These bind to transcription factors which turn on or off expression of genes (and
therefore what kinds of protein products the cell makes)

So What is the Big Deal About Hormones??? (Fig 3.20)

Drugs can alter secretion of many hormones, causing pathology.
Ex: Alcohol causes reproductive hormone disruption in both men and women.
Hormones can alter behavioral responses to drugs.
Ex: Glucocorticoids increase response to cocaine and amphetamines, and cause
subject to administer drug more often. (Box 3.2 in text)
Some hormones can have psychoactive properties, similar to a drug.
Ex: sedative effect of melatonin, thyroid hormones reduce depression.
Secretion of pituitary hormones dependent on brain neurotransmitter activity.
If a drug causes change in pituitary hormone axis, shows drug has wide-ranging
effects.
Ex: Fenfluramine increases serotonin release from axon terminals, and
downstream it increases prolactin secretion.
MDMA (ectasy) damages the serotonin system in the brain
Give fenfluramine to people who had used MDMA before and monitor prolactin
levels in the blood. MDMA showed NO increase in prolactin levels in blood, even
after 12 months abstinence.
Shows abnormalities in serotonergic system with MDMA use.