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.

Table 4.1 Transmitters

Many Chemical Neurotransmitters Have Been Identified

Cholinergic Pathways in the BrainCholinergic nerve cell bodies and projections contain ACh.

Dopaminergic Pathways in the BrainDopamine (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 BrainNoradrenergic fibers from the locus coeruleus project broadly

Serotonergic Pathways in the BrainSerotonin (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:1.Action potential travels down the axon to the axon terminal.

2.An action potential causes Voltage-gated calcium channels open and calcium ions (Ca2+) enter.

3.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

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 exactlyneurotransmitters or hormones

Exogenous ligands drugs and toxins from outside the bodyUsually do not fit the receptor exactly

Figure 4.2 The Agonistic and Antagonistic Actions of Drugs

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.

Fig 4.1 Versatility of Neurotransmitters

Acetylcholine Acetylcholine

NicotinicReceptor type

MuscarinicReceptor type

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

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

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.