1. The Chemistry of Behavior: Neurotransmitters and Neuropharmacology
Neurochemistry focuses on the basic chemical composition and processes of the nervous system.
Neuropharmacology is the study of compounds that selectively affect the nervous system.
Endogenous—occurs naturally within the body:
Endogenous ligands: substances that the brain produces
Exogenous—introduced from outside the body
Exogenous ligands: used throughout human history to affect our physiology and behavior.

2. Many Chemical Neurotransmitters Have Been Identified
Table 4.1 Transmitters
Neurochemistry focuses on the basic chemical composition and processes of the nervous system.
Neuropharmacology is the study of compounds that selectively affect the nervous system.
Exogenous substances are molecules from outside our own bodies, used throughout human history to affect our physiology and behavior.
Endogenous—occurs naturally within the body:
Endogenous ligands—substances that the brain produces
Exogenous—introduced from outside the body
Criteria for neurotransmitters—chemicals released onto target cells:
Substance exists in presynaptic axon terminals
Is synthesized in presynaptic cells
Is released when action potentials reach axon terminals
Receptors for the substance exist on postsynaptic membrane.
When applied, substance produces changes in postsynaptic cells.
Blocking substance release prevents changes in postsynaptic cell.
Types of neurotransmitters:
Amine neurotransmitters—acetylcholine, dopamine, serotonin
Amino acid neurotransmitters—GABA, glutamate
Peptide neurotransmitters (or neurotransmitters)
Gas neurotransmitters—nitric oxide, carbon dioxide

3. Cholinergic Pathways in the Brain
Cholinergic nerve cell bodies and projections contain ACh.
Acetylcholine (ACh) was mapped by the enzymes involved in its synthesis.
Cholinergic nerve cell bodies and projections contain ACh.

4. Dopaminergic Pathways in the Brain
Dopamine (DA) is found in neurons in: the mesostriatal pathway which originates in the midbrain, specifically the substantia nigra and innervates the striatum

5. Noradrenergic Pathways in the Brain
Noradrenergic fibers from the locus coeruleus project broadly

6. Serotonergic Pathways in the Brain
Serotonin (5-hydroxytryptamine, 5-HT) cell bodies are mainly found
in the raphe nuclei, and their serotonergic fibers project widely.

7. Synaptic Transmission Requires a Sequence of Events
The sequence of synaptic transmission:
Action potential travels down the axon to the axon terminal.
An action potential causes Voltage-gated calcium channels open and calcium ions (Ca2+) enter.
Ca2+ causes Synaptic vesicles fuse with membrane and release transmitter into the cleft a process known as exocytosis
Transmitters diffuse across the cleft and bind to postsynaptic receptors and cause an EPSP or IPSP.
EPSPs or IPSPs spread toward the postsynaptic axon hillock.
Transmitter is inactivated (by enzymatic degradation) or removed (by transporters for reuptake and recycling)—action is brief.
Transmitter may activate presynaptic autoreceptors, decreasing release

8. Fig 3.12 Synapse The sequence of transmission:
Action potential travels down the axon to the axon terminal.
Voltage-gated calcium channels open and calcium ions (Ca2+) enter.
Synaptic vesicles fuse with membrane and release transmitter into the cleft.
Transmitters cross the cleft and bind to postsynaptic receptors and cause an EPSP or IPSP.
EPSPs or IPSPs spread toward the postsynaptic axon hillock.
Transmitter is inactivated (by enzymatic degradation) or removed (by transporters for reuptake and recycling)—action is brief.
Transmitter may activate presynaptic autoreceptors, decreasing release.
An action potential causes Ca2+ channels to open in the axon terminal and allow Ca2+ into the cell.
Ca2+ causes synaptic vesicles to fuse with the presynaptic membrane and release neurotransmitter into the cleft, a process known as exocytosis.
Transmitter action is brief and can occur in two ways:
1. Degradation is the rapid breakdown and inactivation of transmitter by an enzyme.
Example: acetylcholinesterase (AChE) breaks down ACh and recycles it
2. Reuptake—transmitter is taken up into the presynaptic cell
Transporters are special presynaptic receptors involved in reuptake.
Some neurotransmitter molecules do not cross the cleft and bind to autoreceptors that inform the presynaptic cell about the net concentration of neurotransmitter in the cleft.

9. Synaptic Transmission Requires a Sequence of Events
Transmitter action is brief because of:
1. Degradation is the rapid breakdown and inactivation of transmitter by an enzyme.
For example: acetylcholinesterase (AChE) breaks down ACh and recycles it
2. Reuptake—transmitter is taken up into the presynaptic cell
Transporters are special presynaptic protein receptors involved in reuptake.
For example: dopamine is transported back into the presynaptic terminal

10. Cholinergic Synapse

11. Serotonin and Norepinephrine
Pharmacology Corner

12. Reuptake of Dopamine

13. Co-Release of Neurotransmitters
Dale's Principle
a rule attributed to the English neuroscientist Henry Hallett Dale in the 1930’s
a neuron performs the same chemical action at all of its synaptic connections to other cells
overturned by many examples of co-release
Co-release of neurotransmitters
May be true for most neurons
For example: Acetylcholine and glutamate
Stored in separate vesicles
Amount of release of each can vary independently

14. Co-Release of Neurotransmitters
From Neuroscience: Promiscuous vesicles
John T. Williams Nature 490, 178–179 (11 October 2012) doi: /490178a

15. Fig 3.13 Nicotinic Acetylcholine
Exogenous Ligands fit receptors exactly
neurotransmitters or hormones
Exogenous ligands drugs and toxins from outside the body
Usually do not fit the receptor exactly
Ligands fit receptors exactly and activate or block them:
Endogenous ligands—neurotransmitters and hormones
Exogenous ligands—drugs and toxins from outside the body
A synapse that uses acetylcholine (ACh) has ligand-binding sites for ACh in the receptor molecules in the postsynaptic membrane.
ACh can be excitatory, and open channels for Na+ and K+, or inhibitory, and open channels for Cl−.
Some chemicals can fit on cholinergic receptors and block the action of ACh:
Curare (plant-derived) and bungarotoxin (from venom of snakes in the cobra family) block ACh receptors—are antagonists
However, muscarine and nicotine mimic ACh and are agonists of the receptor.
Most muscarinic ACh receptors are found in the brain and are also found on organs innervated by the parasympathetic division of the autonomic system.
These receptors played a role in the discovery of neurotransmitters in a famous experiment conducted by Otto Loewi (which helped him win the Nobel Prize in 1936).

16. Figure 4.2 The Agonistic and Antagonistic Actions of Drugs
A ligand is a substance that binds to a receptor and has one of three effects:
An agonist initiates the normal effects of the receptor.
An antagonist blocks the receptor from being activated by other ligands.
An inverse agonist initiates an effect that is the opposite of the normal function.
Drugs that act as either agonists, antagonists or inverse agonists are known as competitive ligands (bind to the same part of receptor molecule as endogenous ligand).
Noncompetitive ligands (or neuromodulators) bind to modulatory sites that are not part of the receptor complex that normally binds the transmitter.

17. Fig 3.15 Ionotropic - Metabotropic
Neurotransmitters affect targets by acting on receptors—protein molecules in the postsynaptic membrane.
Ionotropic receptors are fast—open an ion channel when the transmitter molecule binds.
Metabotropic receptors are slow—when activated they alter chemical reactions in the cell, such as a G protein system, to open an ion channel.
Receptor subtypes—the same neurotransmitter may bind to a variety of subtypes, which trigger different responses
Receptors control ion channels in two ways:
Ionotropic receptors open when bound by a transmitter (also called a ligand-gated ion channel).
Metabotropic receptors recognize the transmitter but instead activate G proteins.
G proteins, sometimes open channels or may activate another chemical to affect ion channels.
The chemical is known as the second messenger—it amplifies the effects of the G protein and may lead to changes in membrane potential (The first messenger is the neurotransmitter).
Neurotransmitters affect targets by acting on receptors—protein molecules in the postsynaptic membrane.
Ionotropic receptors are fast—open an ion channel when the transmitter molecule binds.
Metabotropic receptors are slow—when activated they alter chemical reactions in the cell, such as a G protein system, to open an ion channel.

18. Fig 4.1 Versatility of Neurotransmitters
Acetylcholine
Acetylcholine
Muscarinic
Receptor type
Nicotinic
Receptor type
Receptor subtypes—the same neurotransmitter may bind to a variety of subtypes, which trigger different responses
However, muscarine and nicotine mimic ACh and are agonists of the receptor.
Most muscarinic ACh receptors are found in the brain and are also found on organs innervated by the parasympathetic division of the autonomic system.
These receptors played a role in the discovery of neurotransmitters in a famous experiment conducted by Otto Loewi (which helped him win the Nobel Prize in 1936).
ACh can be excitatory, and open channels for Na+ and K+, or inhibitory, and open channels for Cl−.
Some chemicals can fit on cholinergic receptors and block the action of ACh:
Curare (plant-derived) and bungarotoxin (from venom of snakes in the cobra family) block ACh receptors—are antagonists

19. Pharmacology of Marijuana
Marijuana or cannabis, refers to preparations from the Cannabis plant
Δ9-tetrahydrocannabinol (THC) is the major psychoactive chemical
There are many other cannabinoids such as cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabivarin (THCV)
Cannabinoid receptors are G protein-coupled with two subtypes
CB1- expressed mainly in the central nervous system
Effects include relaxation, mood alteration, stimulation, hallucination, and paranoia
CB2 - expressed in the immune system
Receptors can be activated by either:
endogenous ligands the endocannabinoids
exogenous plant cannabinoids such as THC

20. Fig 4.15 Cannabinoid Receptors
The brain contains cannabinoid receptors to mediate the effects of THC and other compounds.
Cannabinoid receptors are concentrated in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex.
The brain contains cannabinoid receptors to mediate the effects of THC and other compounds.
Cannabinoid receptors are concentrated in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex

21. Medical Marijuana Reduces nausea and vomiting from chemotherapy
Stimulation of hunger in AIDS patients
Lowered intraocular eye pressure (shown to be effective for treating glaucoma)
General analgesic effects (pain relief)
Anxiety
low doses tend to induce anxiolytic-like effects, i.e. reduce anxiety
high doses often cause the opposite effect, can increase anxiety
Synthetic cannabinoids are available as prescription drugs
Dronabinol (Marinol) synthetic THC, used to treat nausea and vomiting caused by chemotherapy
Nabilone (Cesamet) used as an antiemetic and as an adjunct analgesic

22. The endocannabinoid system plays a homeostatic role
Medical Marijuana
The endocannabinoid system plays a homeostatic role
activated after transient or chronic
stress
neuronal damage, and neuroinflammation
experiences that strengthen synaptic
motivational and affective processes
regulating local levels of other neurochemical signals
new therapeutic drugs
that can selectively manipulate the levels of endocannabinoids at their targets

23. Negative Effects of Marijuana
Short-term: many different effects because cannabinoid CB1 receptors are located throughout the CNS
problems with memory and learning
distorted perception
trouble with thinking and problem solving
loss of motor coordination
increased heart rate
Increased anxiety ???
Long-term:
Increased cancer risk – from smoking
Respiratory problems – also obviously from smoking
Suppressed immune system (usually a small amount) from CB2 receptors activation
These are all controversial claims with some studies finding no increased problems with any of these health problems.

24. Addiction to Marijuana
Cannabis withdrawal syndrome
similar magnitude to tobacco
characterized by negative mood (irritability, anxiety, misery), muscle pain, chills, and decreased food intake
usually goes away in a week even in heavy users
Activation of the Reward Circuit
Nonhuman animals (rats) do not readily work for THC which indicates that the reward circuits are not getting much activation
Usually done in an operant chamber with rats bar pressing for THC
Special circumstances such as prior drug experience and food deprivation can increased amount of bar pressing for THC
Psychological Dependence
Reports of psychological craving but mild for most individuals
However much worse in some individuals
Probably related to predisposition for mental illness (see next slide)

25. Marijuana and Mental Illness
Reefer Madness
Increased risk of psychotic symptoms
a greater risk in people who used cannabis most frequently (daily use)
stronger in those with any predisposition for psychosis
Although individuals may start using cannabis because of predisposition for mental illness recent studies show a cause and effect relationship
Le Bec PY (2009) Encephale. 35(4):
Ben Amar M (2007) J Psychoactive Drugs. 39(2):