- Neurotransmitters Of The Brain -

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Jerome Harris
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1 - Neurotransmitters Of The Brain - INTRODUCTION Synapsis: a specialized connection between two neurons that permits the transmission of signals in a one-way fashion (presynaptic postsynaptic). Types of synapsis: 1- Electrical (gap junction): Cardiac myocytes, astrocytes. 2- Chemical: Neuromuscular Junction. P.S.: The response of a postsynaptic neuron depends largely on the postsynaptic receptor rather than the type of neurotransmitter. Two families of receptors have been observed: 1- Ion channels 2- Second messenger coupled receptors (does not always imply a GPCR/cAMP pathway). We will be using the terms Excitation/Inhibition of a neuron rather than Depolarization/Hyperpolarization throughout this lecture: Na +, Ca ++ channels excitation K +, Cl - channels inhibition This use of terms is due to the fact that the activation of second messenger coupled receptors does not necessarily imply a change in the electrical gradient across the membrane, i.e., the response can be a change in the enzymatic activity, metabolic rate, or genetic profile within the neuron. Recall: The neuron s response depends on the receptor, not on the neurotransmitter. For example, Acetylcholine is a neurotransmitter found in different areas of the brain, yet its effect differs from one location to another. These different effects are due to different receptors responses depending on the location. NEUROTRANSMITTERS Q: Why do we consider the synthesis and degradation of neurotransmitters? A: Because in each biochemical pathway of a neurotransmitter there is a ratelimiting step that can be controlled or medically interfered. P.S.: The rate limiting steps are to be memorized. Recall: Neurotransmitters effects are terminated by way of two major mechanisms: Reuptake and Enzymatic Degradation.

2 Neurotransmitters will be discussed as two separate categories: Fast neurotransmitters and Neuromodulators. Fast Neurotransmitters 1- Glutamate: - Glutamate is found in 95% of all of the excitatory synapses of the brain. - Glutamate is the main excitatory neurotransmitter in the brain. It is involved in many physiological processes, such as memory and cognition. It is also of high significance in certain pathologies, such as Schizophrenia. - What is physiologically important regarding Glutamate is its receptors. - Recall: Autoreceptors are receptors found on the same presynaptic neuron. They regulate the same neuron from which they are released. They are mostly brake receptors (inhibit the release). - Glutamate has two main types of receptors: a- Inotropic: major type. b- Metabotropic: minor type, involves second messengers. - Inotropic receptors are further subdivided into 3 subtypes, namely NMDA, AMPA, and Kainate receptors. - They share the same property that they are Na + and Ca ++ channels. - However, Kainate receptors are mostly autoreceptors (presynaptic), whereas NMDA and AMPA are both postsynaptic. - P.S.:AMPA opens before NMDA, but NMDA enters more Ca ++ ions. NMDA opens later, but stays longer. - Thus, if glutamate is released rapidly for a short period of time, AMPA opens, but NMDA does not. - Note: Although kainate receptors are autoreceptors, they are not inhibitory. Recall that kainate receptors let Na + and Ca ++ in. Those ions are both excitatory; they cannot be inhibitory! - Termination of glutamate: by Reuptake. (Glutamate is degraded intracellularly.) - Ischemia can prevent the reuptake of glutamate. Decreased oxygenation of tissues, i.e., ischemia, leads to a decrease in [ATP]. Glutamate transporter is highly dependent on ATP. Decreased function of the transporter results in decreased reuptake. Decreased reuptake leads to hyperexcitation of NMDA and AMPA (mainly NMDA). Hyperexcitation of those receptors results in increased intracellular [Ca ++ ], which leads to APOPTOSIS. - There are some antagonists that target the NMDA/AMPA receptors. They are particularly useful in the first 20 minutes in a patient who has had a stroke. Those antagonists decrease the influx of Ca ++ by blocking the NMDA/AMPA receptors, thus inhibiting apoptosis. Notice that the drugs must be given in the first 20 minutes from the onset of stroke. The sooner you administer the drug the better the outcome will be.

3 2- GABA (Gamma AminoButyric Acid) - GABA is the main inhibitory neurotransmitter in the brain. - There are two types of receptors: a- Inotropic: fast Cl - channels. b- Metabotropic - Ionic receptors of GABA have multiple allosteric sites that molecules other than GABA can bind to. This is of high significance in pharmacology, where those are sites of certain drugs such as Benzodiazepam and Barbiturates. - Ethanol is a potent substrate that binds the GABA ionic receptors. This is the main acute effect of alcohol on brain. - A bridge to biochemistry: GABA and glutamate are precursors of each other. This regulates the excitatory and inhibitory signals within the brain. 3- Acetylcholine (ACh) - Two receptors are related to ACh: a- Nicotinic: ionic b- Muscarinic: second messenger system - ACh mainly leads to the influx of Na + and Ca ++ excitatory effect - ACh is synthesized within the brain in two distinct locations: a- Nucleus Basalis: goes directly to cortex b- Brainstem: goes indirectly to cortex, after passing through the thalamus. - Since ACh controls the gate of sensation, i.e. the thalamus, it has a critical role in sensation delivery to cortex. It also has a role in arousal, attention, and reward. - Related pathologies: Alzheimer s Disease. Neuromodulators - Their main effect is through second messenger system. - The most famous family is Biogenic amines (Dopamine, Norepinephrine, Serotonin). - Biogenic amines are similar in their synthesis, releasing mechanism, receptor binding, reuptake (specific vs. non-specific), and degradation. 1- Dopamine - Rate limiting step: Tyrosine Hydroxylase. - Dopamine receptors work through G proteins. Those receptors are divided into 5 subtypes, namely D1-D5.

4 - D1 and D5 receptors are excitatory. D2 is an inhibitory and an autoreceptor (presynaptic). D3 is postsynaptic and inhibitory. - When dopamine is released and bound to D3, the postsynaptic neuron will be inhibited. If we administer a D2 antagonist (presynaptic location), dopamine concentration in the synaptic cleft will increase, and D3 receptors will be more activated/exposed to dopamine and this will lead to inhibition of the postsynaptic neuron. - P.S.: always keep in mind where the location of the target receptor is. - Dopamine transporter has 2 binding sites: 1- one capable of binding Cocaine. Cocaine inhibits the transporter and increases dopamine concentration in the synapse. 2- the other is capable of binding Amphetamine. Amphetamine reverses the direction of action of dopamine transporter. The transporter gives off dopamine into the cleft rather than picking it up. - Dopamine is mainly synthesized in two areas within the brain: Substantia nigra, and ventral tegmental area. - Dopamine reaches every area of the brain. Nevertheless, we are only concerned with 3 pathways: 1- Nigrostriatal: susbtantia nigra Striatum 2- Mesolimbic: ventral tegmental area limbic system 3- Mesocortical: ventral tegmental area prefrontal area - A nigrostriatal pathway lesion will lead to Parkinson disease. - Overstimulation of the mesolimbic pathway leads to Schizophrenia. - Schizophrenia can manifest as either positive signs (hallucinations), or negative signs (social withdrawal). - P.S.: nucleus accumbens is a major target for dopamine. It is part of the limbic system. It is considered the pleasure/reward center. - Administering antidopmainergic drugs to treat positive symptoms of schizophrenia can sometimes lead to negative symptoms. This is because the drug reaches two sites; nucleus accumbens and prefrontal cortex. In nucleus accumbens, the drug terminates the positive symptoms, whereas in the prefrontal cortex, it will lead to negative symptoms. 2- Norepinephrine (NE) - α, β receptors are all metabotropic. - α2 receptors are presynaptic. - Norepinephrine transporter is the least selective transporter. - Norepinephrine is synthesized in locus coreleus in brainstem. From there, NE is spread over almost all areas of brain. - An external nucleus can stimulate the locus coreleus to synthesize and release NE. Overstimulation of locus coreleus leads to Anxiety. - NE has a physiological role in arousal and attention. - NE spreads to 3 major regions of the cortex: 1- Frontal cortex: decreased NE delivery to this region will lead to depression (action is mediated mainly byβ receptors).

5 2- Prefrontal cortex: area of attention, arousal, and memory. Decreased NE delivery to this region causes ADHD (Attention Deficit Hyperactivity Disorder). Action in this region is mediated mainly by α receptors. 3- Limbic system. 3- Serotonin (5-HT) - There are no rate limiting steps except for the presence of its precursor, Tryptophan. - Serotonin is widely spread in the brain. It is synthesized and released from Raphe nucleus. - There are 21 different subtypes of receptors. The ones to be memorized are: 5-HT1 Inhibits camp synthesis, thus inhibiting the neuron s activity. 5-HT2 Activates PLC (Phospholipase C), which leads to an increase in Ca ++ Concentration. It is mostly presynaptic. 5-HT3 Direct ion channels. - Serotonin is a critical neurotransmitter in the brain. It has a role in almost every function within the brain. It is related to a large number of pathologies as well. - Antipsychotic drugs pharmacological effects are mediated by serotonin pathways. Examples include Anxiolytics, Antiemetics, Antimigranes, and Antidepressants. - New psychiatric drugs can target multiple pathways regardless the type of neuromodulator involved. - The aforementioned neuromodulators; Dopamine,Norepinephrine, and Serotonin, heavily interact with each other. For example, Dopamine acts as an inhibitory neurotransmitter in the serotonin pathways and vice versa. Nitric Oxide (NO) - A non-traditional neurotransmitter. * Not stored in vesicles. * Works on pre- and postsynaptic neurons. - Glutamate is usually the neurotransmitter that activates the synthesis of NO. How does this happen? - NO synthase activation needs Ca ++. Glutamate receptors (NMDA) are Ca ++ channels that let a lot of Ca ++ ions in. Thus NO synthase gets activated, and NO is synthesized.

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