Chapter 6 B Neurotransmitter Systems Continued

Dale's Principle (or Dale's Law) is a rule attributed to the English neuroscientist Henry Hallett Dale (We first mentioned him in the first section of this chapter.). The principle states that a neuron does the same thing at all of its synaptic connections to other cells, regardless of the identity of the target cell. The concept is generally true, but there are exceptions in many cells that have peptide neurotransmitters.

Theodor Karl Gustav von Leber was a German ophthalmologist who studied the neurology of the eye. He also identified the disease now named after him, Leber’s Disease.

Glutamate Receptors - synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body. Glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation. Glutamate receptors are implicated in the pathologies of several neurodegenerative diseases. It is believed their relationship to these disesases is due to their role in excitotoxicity. Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through the process of excitotoxicity. Excessive glutamate, or exogenous excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors, causing high calcium ions influx into the postsynaptic cell.

Neurogenerative diseases or conditions thought to be mediated (at least partially) through excessive stimulation of glutamate receptors: 1.Alzheimer’s disease: 2.amyotrophic lateral sclerosis (ALS) – “Lou Gehrig's Disease” - the degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement. 3.drug addiction, tolerance, and dependency 4.glaucoma – excessive pressures in the humors of the eye may lead to excessive stimulation of glutamate receptors, leading to retinal failure.

5.Huntington’s disease – a mutated form of the Huntingtin gene produces an abnormal protein that can cause glutamate toxicity. 6.Leber’s disease – a genetic condition where there is loss of visual acuity due to the toxic overstimulation of the glutamate receptors in the retina. 7.Parkinsonism – an atypical form of Parkinson’s Disease that is often the result of exogenous neurotoxicity. Parkinsonism was shown in the 1990 film “Awakenings” which dramatized the efforts of neuroscientist Oliver Sachs (played by Robin Williams).

There are three known types of glutamate receptors. Each type responds to glutamate, but differentially responds to their specific exogenous molecule as well: AMPA NMDA Kainate The different receptor subtypes are located in different regions of the brain and are associated with different glutamate related neural disorders.

A farmer harvesting opium poppies. Top Image: A farmer harvesting opium resin from cut opium poppies. Lower Image: A fellow smoking opium in a water pipe. Opioid receptors – a group of G protein-coupled receptors with opioids as ligand molecules. The drug opium, is an agonist of this receptor class. The endogenous opioids are: dynorphins Enkephalins endorphins endomorphins nociceptin These five compounds all affect pain sensation and modulation.

Cholinergic (ACh) Neurons - synthesis involves the enzyme (ChAT) (choline acetyletransferase) - the rate limiting step in synthesis is the amount of uptake of choline in the axon terminal - Acetylcholinesterase (AchE) is an enzyme used to degrade Ach in the synapse for reuse

Catecholaminergic Neurons – Involved in movement, mood, attention, and visceral function – Tyrosine is the precursor for the three most prevelant catecholamines: – Dopamine (DA) – Norepinephrine (NE) – Epinephrine (E, adrenaline)

Serotonergic (5-HT) Neurons – Derived from tryptophan – Regulates mood, emotional behavior, sleep Selective serotonin reuptake inhibitors (SSRIs) – Antidepressants – Synthesis of serotonin is via the enzyme tryptophan hydroxylase.

Amino Acidergic Neurons

Other Neurotransmitter Candidates and Intercellular Messengers – ATP: Excites neurons – Endocannabinoids – Other retrograde messengers lipid molecules that may function to allow the postsynaptic neuron to decrease release of neurotransmitter from the presynaptic neuron

Consumption of Cannabis: Effect is due to its ability to alter neural activity most notably in slowing the release of neurotransmitters that interact with the cannabinoid receptors associated with the endocannabanoids. Function is still largely not understood and is a very active avenue of research. Endocannabainoids are endogenously produced neurotransmitters or retrograde neurotransmitter agents. Cannabis (marijuana) is a plant that produces structurally similar compounds to the endocannabinoids.

Conclusion Neurotransmitters – Transmit information between neurons – Essential link between neurons and effector cells Signaling pathways – Inputs vary temporally and spatially to increase and/or decrease drive (first part of Chapter 6) – Delicately balanced – Signals regulate signals- drugs can shift the balance of signaling power (first part of Chatper 6)