Neuroscience Dr. Michael P. Gillespie Neurotransmitters

Neurotransmitter A neurotransmitter is defined as a chemical substance that is synthesized in a neuron, released at a synapse following depolarization of a nerve terminal, which binds to a postsynaptic terminal to elicit a specific response. Chemicals that relay and modulate messages between a neuron and an effector cell (neuron, muscle, gland). Dr. Michael P. Gillespie

Neurotransmitters Chemicals that are stored in and released from the synaptic boutons of neurons. Antitransmitters destroy the neurotransmitters in the synaptic cleft. They break them down so that the postsynaptic neuron can repolarize in order to fire again. Neurotransmitters can also be reabsorbed by the presynaptic terminal bouton (reuptake). Dr. Michael P. Gillespie

Neurochemical Basis for Human Behavior A large percentage of human behavior is modulated by the action of neurotransmitters in the brain. Behavioral pathology is largely due to imbalances in the neurotransmitter systems. Physical diseases can also be due to imbalances in neurotransmitter pathways (i.e. Parkinson’ disease). Dr. Michael P. Gillespie

Criteria For Identification The substance must be synthesized in the neuron and the enzymes needed for synthesis must be present in the neuron. The substance must be released in sufficient quantity to elicit a response from the post-synaptic neuron or cell located in the effector organ. Mechanisms for removal or inactivation of the neurotransmitter must exist. It should mimic the action of the endogenously released neurotransmitter when administered exogenously at or near a synapse. Dr. Michael P. Gillespie

Major Classes of Neurotransmitters Amino acids (eg Glutamate [GLU], gamma aminobutyric acid [GABA], aspartic acid, glycine). Peptides (eg, vasopressin, somatostatin). Monoamines (norepinephrine [NE], dopamine, serotonin). Acetylcholine Dr. Michael P. Gillespie

Mechanism of Neurotransmitter Release Exocytosis Recycling of Synaptic Vesicle Membranes Dr. Michael P. Gillespie

Neurotransmitter Systems There are multiple neurotransmitter systems in the brain and the enteric nervous system. Only two neurotransmitters are used in the peripheral nervous system (Ach and noripinephrine). Dr. Michael P. Gillespie

Function of Neurotransmitters http://www.youtube.com/watch?v=haNoq8UbSyc Dr. Michael P. Gillespie

Excitatory and Inhibitory Neurotransmitters can be either excitatory or inhibitory depending upon which receptors sites to which they bind. They act as the brake and accelerator systems of the brain. The only direct effect of a neurotransmitter is to activate one or more receptor types on the post synaptic cell. The effect on the post synaptic cell depends entirely upon the types of receptors present upon it. Dr. Michael P. Gillespie

Excitatory and Inhibitory continued… For some neurotransmitters (i.e. glutamate) the most important receptors all have excitatory effects. For some neurotransmitters (i.e. GABA) the most important receptors all have inhibitory effects. Some neurotransmitters have both excitatory and inhibitory receptors (i.e. acetylcholine). Some neurotransmitters produce metabolic pathways in the post synaptic cell that cannot be considered either excitatory or inhibitory. It is an oversimplification to call a neurotransmitter excitatory or inhibitory; however, it is sometimes convenient to do so. Dr. Michael P. Gillespie

Degradation and Elimination A neurotransmitter must be broken down once it reaches the post synaptic cell to prevent further excitatory or inhibitory signal transduction. Several methods are utilized for removal of the neurotransmitter: Diffusion Enzymatic degradation Uptake by cells Into the cells that released them (reuptake). Into neighboring glial cells (uptake). Dr. Michael P. Gillespie

Acetylcholine (ACh) ACh was the first neurotransmitter to be discovered. In the peripheral nervous system. ACh is the major neurotransmitter that controls muscle action. There are relatively few ACh neurotransmitters in the central nervous system. This neurotransmitter most often has excitatory effects. It exerts its effects at the neuromuscular junction. Dr. Michael P. Gillespie

Acetylcholine (ACh) continued… Excessive ACh results in dyskinesia. Dyskenesia is hyperkinetic motor activity characterized by involuntary motor contractions. Deficient ACh results in paralysis. In the CNS, ACh participates in the autonomic nervous system (i.e. regulation of heart rate). Two main classes of ACh: Fast acting receptor (nicotinic) Slow acting receptor (muscarinic) Dr. Michael P. Gillespie

Acetylcholine http://www.youtube.com/watch?v=AyoySswpvso&feature=r elated Dr. Michael P. Gillespie

Acetylcholinesterase Acetylcholinesterase is the antitransmitter that degrades acetylcholine. Nerve agents such as sarin gas (used in bioterrorism) inhibit acetylcholinesterase resulting in painful, continuous stimulation of muscles and glands. Many insecticides inhibit acetylcholinesterase in insects. Dr. Michael P. Gillespie

Nicotinic Blocking Agents Some snake venoms block nicotinic receptors and can cause paralysis. Curare is a nicotinic blocking agent extracted from plants. Curare has been used as a poison (placed on arrowheads). Dr. Michael P. Gillespie

Botulinum Toxin Botulin is a poison that blocks ACh and causes paralysis. Botox, which is a botulin derivative, has been used as a cosmetic treatment to diminish wrinkles by temporarily paralyzing the muscles. In April 2009, the FDA updated its mandatory boxed warning cautioning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism. In January 2009, the Canadian government warned that Botox can have the adverse effect of spreading to other parts of the body, which could cause muscle weakness, swallowing difficulties, pneumonia, speech disorders and breathing problems. Dr. Michael P. Gillespie

Botulinum Toxin Dr. Michael P. Gillespie

Botox Side Effects Paralysis of an unintended muscle group can occur. Inappropriate facial expression. Drooping eyelid Double vision Uneven smile Loss of the ability to close the eyes Allergic reaction can occur. Bruising can occur (typically lasting 7 – 11 days). Masseter muscle injection can result in reduction in power to chew foods. Headaches Dysphagia Flu-like symptoms Blurred vision Dry mouth Fatigue Swelling or redness at injection site. Botox can take away or dampen emotional feelings. Botox can hinder the ability to understand language (particularly language of emotions). Dr. Michael P. Gillespie

Alzheimer’s Disease A shortage of ACh in the brain is considered to be a contributing factor to Alzheimer’s disease. Some medicines that inhibit acetylcholinesterase have shown some effectiveness in treating the disease. Alzheimer’s disease is the most common form of dementia. There is no known cure. It worsens as it progresses. Early symptoms include loss of short term memory. Advanced symptoms include confusion, irritability, mood swings, aggression, trouble with language, and long term memory loss. Gradually, body functions are lost leading to death. Dr. Michael P. Gillespie

Alzheimer’s Disease http://www.youtube.com/user/jnjhealth?v=q1BkfV2h09g http://www.youtube.com/watch?v=IcuDz7tOL7E&feature=w atch_response_rev http://www.youtube.com/watch?v=7- P9lbTJ9Hw&feature=relmfu Late Stage Alzheimer’s Disease http://www.youtube.com/watch?v=oTEbq4h- kvQ&feature=fvwrel Dr. Michael P. Gillespie

Myasthenia Gravis Myasthenia gravis is an autoimmune disease characterized by muscle weakness and fatigue. The body produces antibodies against ACh receptors. ACh transmission is impaired. Drugs that inhibit acetylcholinesterase are often effective in treating myasthenia gravis. The hallmark of myasthenia gravis is fatigability. Muscles become progressively weaker during periods of activity and improve with rest. Muscles that control the eye and eyelid are particularly susceptible. In myasthenic crisis a paralysis of the respiratory muscles occurs. The heart muscle is regulated by the autonomic nervous system so it is generally unaffected by MG. Dr. Michael P. Gillespie

Myasthenia Gravis Strabismus and ptosis are notes in this individual with myasthenia gravis while trying to open the eyes. Dr. Michael P. Gillespie

Myasthenia Gravis http://www.youtube.com/watch?v=YtypsBCjuyQ http://www.youtube.com/watch?v=fTrWasKmHxY Dr. Michael P. Gillespie

Gamma Aminobutyric Acid (GABA) GABA is the major inhibitory neurotransmitter of the brain. It turns off the functions of the neurons. It acts as a brake for the excitatory neurotransmitters that can cause anxiety. Without GABA, brain cells would fire uncontrollably (as in epileptic seizures). GABA deficiency is implicated in anxiety disorders, insomnia, and epilepsy. GABA excess is implicated in memory loss and inability for new learning. Agents that can block GABA-B receptors may improve learning and memory. Dr. Michael P. Gillespie

GABA and Anxiety Disorders People who experience anxiety and panic attacks may have an imbalance in the GABA system and a depletion of GABA. Benzodiapines are a class of drugs eg, Xanax, Valium, Ativan) used to treat anxiety disorders. They enhance the effect of GABA on GABA-A receptors. Prolonged use results in adaptation. Down regulation occurs making the drug less effective over time. Larger doses are needed to provide relief from anxiety making the drug less effective over time. This is referred to as tolerance. Stopping the use of these drugs results in diminished sensitivity of GABA receptors, causing heightened anxiety. Dr. Michael P. Gillespie

GABA Supplementation Some dietary supplement companies are selling GABA as a sleep aid and anti-anxiety treatment. GABA does not penetrate the blood brain barrier. It is synthesized in the brain. Picamilon is a prodrug that is able to cross the blood-brain barrier. It is then hydrolized into GABA and niacin. The GABA will stimulate GABA receptors and potentially produce an anxiolytic response. Niacin is a potent vasodilator and may help with migraine headaches. Dr. Michael P. Gillespie

Glutamate (Glutamic Acid or GLU) Glutamate is the most common neurotransmitter in the CNS. It may account for up to half of the neurotransmitters in the brain. It is a major excitatory neurotransmitter. It is believed to play a major role in learning and memory. Some research has been done involving the use of glutamate to enhance learning and memory in patients with Alzheimer’s disease. Glutamate is a precursor for the synthesis of GABA. It is present in many foods and is responsible for the taste sense of umami. Sodium salt of glutamic acid (monosodium glutamate – MSG). Dr. Michael P. Gillespie

Epileptic Seizures Overactivity of glutamate may produce epileptic seizures. Epilepsy is an imbalance in brain chemistry involving over excitation. There is a delicate balance between excitation and inhibition in the brain. Dr. Michael P. Gillespie

Epileptic Seizure http://www.youtube.com/watch?v=MRZY2a2jnuw Dr. Michael P. Gillespie

Epilepsy http://www.youtube.com/watch?v=MNQlq004FkE&feature=r elmfu http://www.youtube.com/watch?v=6NcqQkKjqTI Dr. Michael P. Gillespie

Types of Epilepsy http://www.youtube.com/watch?v=otuaPazecDo&feature=re lated Dr. Michael P. Gillespie

Excitotoxicity Excess glutamate can cause excitotoxocity resulting in neuronal damage and cell death. Trauma to the brain (such as CVA and head injury) triggers an excessive release of glutamate. This can result in the death of many more neurons than occurred with the original trauma. In CVA, it is believed that not only hypoxia kills neurons, but also the release of too much glutamate. Dr. Michael P. Gillespie

Excitotoxicity continued… When the brain experiences a series of crises, glutamate is released 1000 times more than its normal level. This may be a method for the organism to facilitate a painless death after severe CNS damage occurs. Glutamate release is often responsible for the greatest amount of damage from TBIs and CVAs. Researchers are attempting to develop drugs that can prevent the release of glutamate after a severe brain injury. These drugs would have to be administered in the first few hours after the injury. Dr. Michael P. Gillespie

Dopamine (DA) Dopamine exerts effects in the areas of the motor system, cognition, and motivation / reward. There is no antitransmitter for dopamine. It is removed from the receptor site by reuptake into the presynaptic neuron, enzymatic breakdown, and diffusion out of the synaptic cleft. These processes take longer than the antitransmitter; therefore, dopamine exerts its effects for longer periods of time than other neurotransmitters. Dopamine is produced in the substantia nigra and the tegmentum of the midbrain. Dr. Michael P. Gillespie

Parkinson’s Disease Dopamine affects the basal ganglia and thus influences movement. Loss of dopamine from the substantia nigra is believed to be the primary cause of Parkinson’s disease. Parkinson’s disease causes paucity of movement, festinating gait, and masked face. Precursors to dopamine, such as L-dopa, can alleviate some of the symptoms of Parkinson’s disease. Dr. Michael P. Gillespie

Parkinson’s Disease Dr. Michael P. Gillespie

Parkinson’s Disease http://www.youtube.com/watch?v=jyBakRkzswU&feature=fv wrel http://www.youtube.com/watch?v=YVEv9ulfqd4&feature=rel ated http://www.youtube.com/watch?v=ol_pXf- FYJw&feature=related Dr. Michael P. Gillespie

Schizophrenia Too much dopamine has been implicated in Schizophrenia. Schizophrenia is characterized by hallucinations, delusions, disorganized thinking, and paucity of thought. Phenothiazines are antipsychotic drugs that block D2 dopamine receptors. Older classes of drugs used to treat Schizophrenia would often cause Parkinsonian-like symptoms. Called tardive dyskinesia (involuntary muscle contractions - lip smacking, repetitive tongue protrusion, blepharospasm). Dr. Michael P. Gillespie

Eugen Bleuler The term szhizophrenia was coined by Eugen Bleuler. Dr. Michael P. Gillespie

Schizophrenia http://www.youtube.com/watch?v=n_Zv59e68mU&feature=f vwrel http://www.youtube.com/watch?v=5I4yw2FyOHE Dr. Michael P. Gillespie

Reward System and Addiction Dopamine plays a significant role in the brain’s reward system. Dopamine is commonly released in response to highly pleasurable experiences such as eating and sexual activity. Drugs such as heroine, amphetamines, and cocaine increase dopamine levels to unnaturally high states. This is responsible for the high experienced from these addictive substances. The brain then decreases its natural production of dopamine, which causes a severe craving for the drugs. Dr. Michael P. Gillespie

Cognitive Function and Dopamine Dopamine disorders of the frontal lobes may be responsible for a decline in cognitive functions such as memory, attention, and problem solving. Diminished dopamine concentrations may be a contributing factor to attention deficit disorder (ADD). Diminished dopamine levels may also contribute to the negative symptoms of depression and schizophrenia. Dr. Michael P. Gillespie

Serotonin (5-HT) Serotonin is synthesized in the serotenergic neurons of the CNS and in the gastrointestinal tract. It is synthesized from the amino acid tryptophan. In the CNS neurons of the raphe nuclei in the medulla are the principle site of serotonin release. Dr. Michael P. Gillespie

Serotonin Functions Serotonin helps to regulate many body activities: Sleep Emotional control and equanimity Pain regulation Emesis (vomiting) Carbohydrate feeding behaviors (binging behaviors) Dr. Michael P. Gillespie

Serotonin and Circadian Rhythms Serotonin is more abundant in the pineal gland than anywhere else in the body. The pineal gland does not use serotonin as a neurotransmitter though. The pineal gland uses serotonin to synthesize melatonin. Melatonin helps to regulate circadian rhythms, diurnal patterns, and sleep-wake cycles. Low serotonin levels can disrupt circadian rhythms as seen in seasonal affective disorder. Dr. Michael P. Gillespie

Serotonin – Depression, Anger, OCD Low levels of serotonin are associated with depression and suicidal behavior. Serotonin Specific Reuptake Inhibitors (SSRIs) increase the brains level of serotonin by blocking the reuptake of serotonin by the presynaptic neuron. Low levels of serotonin are also linked to aggression, anger and violence. Too little serotonin has also been linked to obsessive-compulsive disorder (OCD). SSRIs have shown some success in treated all of these conditions. Dr. Michael P. Gillespie

Norepinephrine (NE) Also called noradrenaline. Norepinephrine and acetylcholine are the only two neurotransmitters used in the PNS. NE is released from the medulla of the adrenal glands as a hormone into the bloodstream. Norepinephrine does not have an antitransmitter and therefore its effects last longer than other neurotransmitters. Dr. Michael P. Gillespie

Norepinephrine and Alertness Norepinephrine plays a role in wakefulness / arousal. Norepinephrine is important in the active surveillance of one’s surroundings. It increases attention to sensory information from the environment. It is an agent in treatment of people with ADHD because it appears to enhance concentration and cognitive function. Psychostimulant medications such as Ritalin increase norepinephrine and dopamine levels in people with ADD / ADHD.. Dr. Michael P. Gillespie

Norepinephrine as a Stress Hormone Norepinephrine activates the sympathetic nervous system to produce the fight / flight response, increase the heart rate, release energy from fat storage, and increase muscle preparedness. Over activity of norepinephrine produces fear, anxiety, and panic. Beta blocking agents prevent norepinephrine from binding to beta receptors. This prevents sweating, tachycardia and other sympathetic signs that occur in stressful situations. Musicians, actors, and public speakers often use beta blockers to reduce sympathetic NS signs and enhance calmness. Dr. Michael P. Gillespie

Norepinephrine and Depression Low levels of norepinephrine have been linked to depression. Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressants that increase the amount of serotonin and norepinephrine in the brain. Dr. Michael P. Gillespie

Substance P Substance P is a neuropeptide that functions as both a neurotransmitter and a neuromodulator. Substance P is associated with mood regulation, anxiety, stress, neurogenesis, respiratory rhythm, neurotoxicity, vasodilation, nausea, emesis, and pain perception. Substance P is a neurotransmitter in the nociceptive pathway. It is involved in the transmission of pain. Substance P may play a role in fibromyalgia. The pain reliever capsaicin (active ingredient in peppers) has been shown to reduce Substance P levels. Dr. Michael P. Gillespie

Opioid Peptides Opioid peptides include endorphins, enkephalins, and dynorphins. These neurotransmitters are produced in the pituitary gland and hypothalamus. They also participate in the brain’s reward system as they have a major role in the perception of pleasure. Dr. Michael P. Gillespie

Opioids and Pain The primary action of opioids is the inhibition of nociceptive or pain information. The opioids resemble opiates (opium, morphine, heroin). They can produce analgesia and feelings of well-being. They are the body’s natural pain killers. The analgesic capsaicin stimulates the release of endorphins. Studies show that acupuncture stimulates the release of endorphins as well. Dr. Michael P. Gillespie

Opioid Peptides Other Functions Opioid peptides also play a role in cardiac, gastric, and vascular functions. Low levels of opioids are associated with anxiety and panic. Opioids play a role in satiety and appetite control. Dr. Michael P. Gillespie