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.

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

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.

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

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

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.

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

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.

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

Cholinergic Synapse

Serotonin and Norepinephrine Pharmacology Corner

Reuptake of Dopamine

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

Co-Release of Neurotransmitters From Neuroscience: Promiscuous vesicles John T. Williams Nature 490, 178–179 (11 October 2012) doi:10.1038/490178a

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).

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.

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.

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

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

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

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

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

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.

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)

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):377-85. Ben Amar M (2007) J Psychoactive Drugs. 39(2):131-42.