Neurotransmitters

Definition They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons Peripherally,adjacent effector's cell may be a muscle or glandular cell

Differences Hormones: produced by ductless glands,secreted into circulation, go to distance target cells,to act via specific protein receptors at these cells e.g: Aldosterone,Insulin,ADH,Thyroxin Autacoids : act on target cells close to their site of release,called “local hormones” or “paracrine secretions” e.g: Histamine,prostaglandin

Criteria The substance must be present within the presynaptic neuron The substance must be released in response to presynaptic depolarization, and the release must be Ca2+-dependent Specific receptors for the substance must be present on the postsynaptic cell

Major classes of NT Amino Acids Acetylcholine (excitatory) Glutamate (excitatory) GABA (inhibitory) Acetylcholine (excitatory) Monoamine (excitatory) Catecholamine: Dopamine, Norepinephrine Indolamine: Serotonin

Neural organization of NT systems I, II, & III are different CNS areas, e.g. cortex, brainstem, spinal cord I II III Communication (GLT & GABA) Coordination (GLT & GABA) Modulation (Ach, NE, DA,5HT

1. Amino acids Glutamate (GLT) & ɣ-aminobutyric acid (GABA) Main excitatory (GLT) and inhibitory (GABA) NTs in CNS Found throughout CNS in long axon and intrinsic neurons Interacts with / modulate activity within other NT systems

AA synthesis and metabolism Glucose OR glutamine Kribs cycle Glutamate (GLT) Glutamic acid decarboxylase (GAD) γ- aminobutyric acid (GABA) Metabolism Reuptake by presynaptic neuron and glial cells Recycled into glutamate (& GABA)

Glutamate receptors Ionotropic (fast): Na+ in AMPA: fast excitatory signals Kainate: fast excitatory, autoreceptor (↑ GLT release) Ionotropic (slow): Na+, Ca2+ in NMDA: sustained, high-frequency excitatory signals Activated by repeated excitatory stimulation: escalation Metabotropic (slow): K+ out; Ca2+ in

Glutamate Receptors

GLT function & effect Main excitatory NT within CNS Pain perception: Acute: AMPA / kainate (co-transmission substance P) Chronic (neuropathic): NMDA Memory: long-term potentiation (LTP) Epilepsy, excitotoxicity (ischemic episodes)

GABA Major inhibitory neurotransmitter in CNS Hyperpolarizes postsynaptic membrane Two types of GABA Receptors: GABA-A Cl- channel  binding Cl- conductance in presynaptic neurons “fast” response (1msec) Benzodiazepines, barbiturates GABA-B G-protein coupled receptor K+ conductance “slow” response (1sec) The first nt that I am going to discuss is GABA…

GABA Receptors This slide shows a schematic diagram of the GABA A receptor. As you can see, it is made up of 5 membrane spanning subunits. This diagram also shows some of its pharmacological binding sites.

GABA functions & effect Main inhibitory NT within CNS synchronize local neural activity modulation of motor control in basal ganglia broad distribution underlies importance of tonic inhibition in CNS Dysfunction = Epilepsy

2. Acetylcholine (Ach) Earliest discovered neurotransmitter NT @ ALL first synapses outside CNS (autonomic ganglia) Terminal NT: parasympathetic NS; skeletal muscle 2 receptor families Muscarinic: metabotropic PNS: parasympathetic NS terminals CNS cortex, hippocampus (HC), striatum Nicotonic: ionotropic (Na+ in) CNS cortex, hippocampus (HC), ventral tegmental area (VTA) PNS: autonomic ganglia, skeletal muscle junctions

ACh synthesis and metabolism choline Choline acetyltransferase (ChAT) acetylcholine (ACh) Acetylcholinesterase (AChE) choline [reuptake into presynaptic neuron] + acetate [to blood]

Ach function & effect (brain) Pedunculopontine – lateral dorsal pathway Sleep / wake (REM sleep); motor (ACh →DA) Basal forebrain cholinergic pathways Medial septal nucleus →HC + amygdala Learning and memory Nucleus basalis of Maynert → cortex Attention and memory

Ach circuit in brain

3. Monoamines Catecholamines Indolamine(s)

Dopamine (DA) Found only in CNS (not PNS): widely distributed via pathways ascending from midbrain Can be excitatory or inhibitory [location, receptors,interactions w other NTs] 2 receptor families: D1 (D5) & D2 (D3, D4) D1 striatum; (D5) hippocampus, hypothalamus D2 striatum; substantia nigra (SN) & VTA [autoreceptors] D3 limbic, striatum, cortex; SN [autoreceptors] D4 limbic, frontal cortex

DA synthesis and metabolism Tyrosine (amino acid from diet) Tyrosine hydroxylase Dopa Dopa decarboxylase on postsynaptic membrane Dopamine (DA) Monoamine oxidase (MAO) in presynaptic neuron [after reuptake] Catechol-O-methyl transferase (COMT) DOPAC + HVA

Wait a minute !! If dopamine is too polar to cross the BBB, how can L-DOPA cross it?

Answer ! L-DOPA is transported across the BBB by an amino acid transport system (same one used for tyrosine and phenylalanine)

DA function & effect Nigrostriatal pathway Motor function Mesolimbic and Mesocortical pathways Pleasure & Reward, reinforcement, motivation Attentional and behavioural control Endocrine regulation (Prolactin) Psychosis Schizophrenia, hallucinatory drugs

DA circuit in brain

Reward circuitry Prefrontal cortex nucleus accumbens VTA dopamine SLIDE 16: Introduce the pleasure centres of the brain affected by drugs: This is a mid-sagittal view of the brain, as seen if you were to cut down the middle of the brain. The major structures of the reward pathway are the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex. When you are engaged in something pleasurable, this circuitry of your brain is activated causing you to experience pleasure and thus making it more likely that you will engage in this pleasurable activity again. The nucleus accumbens plays a central role in the reward circuit. Its operation is based chiefly on two essential neurotransmitters: dopamine, which promotes desire (Well, the specific role of dopamine in this reward circuit is not fully known. Dopamine promotes the link between behavior and learned rewarding stimuli, rather than having a direct association with pleasure), and serotonin, whose effects include satiety and inhibition. Many animal studies have shown that all drugs increase the production of dopamine in the nucleus accumbens, while reducing that of serotonin. The nucleus accumbens maintains close relations the ventral tegmental area (VTA). Located in the midbrain, at the top of the brainstem, the VTA is one of the most primitive parts of the brain. It is the neurons of the VTA that synthesize dopamine, which their axons then send to the nucleus accumbens. The VTA is also influenced by endorphins whose receptors are targeted by opiate drugs such as heroin and morphine. Another structure involved in pleasure mechanisms is the prefrontal cortex, whose role in planning and motivating action. The prefrontal cortex is a significant relay in the reward circuit and also is modulated by dopamine. Taken from http://www.thebrain.mcgill.ca   VTA dopamine

? Reward Pathway SLIDE 17: How the reward pathway was discovered: The pleasure and reward pathway of the brain was discovered through research on laboratory rats. In these experiments researchers implanted electrodes into the structures of the rat reward pathway, such as the nucleus accumbens. This allowed them to administer small electrical stimuli to these structures that were reinforcing to the animals. Rats were then trained to press a lever in order to obtain the rewarding electrical stimulation. This reward proved so powerful that the animals would lever press at very high rates (> 6,000 times per hour). Moreover, this reinforcement was more potent than other rewards, such as food or water. For example, in a classic experiment, animals suffered self-imposed starvation when forced to make a choice whether to obtain food and water or electrical brain stimulation. Research has shown that electrical stimulation of the pleasure and reward pathway is intensely pleasurable to humans, as well. So to summarize, both natural and artificial rewards exert their reinforcing effects through activating the pleasure and reward circuitry of the brain. Activation of this circuitry causes us to experience pleasure, and increases the likelihood of our repeating the behavior that led to that pleasurable experience. When a drug causes an activation of the pleasure and reward pathway, it initiates changes in the brain that reinforce the use of the drug. We know many drugs that can cause addiction. Even you can name a few (ask the students). For example: nicotine in cigarettes, alcohol, opiates like heroin and morphine, marijuana (yes, it does), cocaine and its derivatives, ecstasy, etc. In the next few slides, we’ll see how drugs can lead to addiction.

Norepinephrine (NE) Found in both PNS (sympathetic NS), and widely distributed in CNS 3 receptor families (all metabotropic): Alpha-1: excitatory postsynaptic (↑Ca2+ flow) Alpha-2: inhibitory presynaptic [autoreceptor] (↑K+, ↓Ca2+) Beta: excitatory presynaptic [autoreceptors] & postsynaptic Synthesized from DA in NE axon terminals; metabolized (after reuptake) by MAO / COMT

NE in PNS: Autonomic (sympathetic) NS Sympathetic NS terminals and adrenal medulla Fight-or-flight response

NE pathways in brain 2 major groups of NE neurons ascending from pontine locus coeruleus (LC) and lateral tegmental nuclei (LTN) some overlap, together innervate whole brain

NE function & effect Arousal: LC sleep/wake state Arousal ↔ attention Tonic NE activity in LC = vigilant attention Scanning, high behavioural flexibility Phasic NE activity in LC = focused attention Selective attention, response inhibition Also involved in nociception, memory, and control of autonomic & endocrine function

Serotonin (5-HT) 5-hydroxytryptamine Found in both PNS and CNS CNS contains < 2% total 5-HT in body Outside CNS: broad range physiological functions 7 (!) receptor subtypes (ionotropic and metabotropic) Not clearly associated with specific brain regions Some functional specificity (with overlap)

Serotonin Receptors 5-HT1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, thermoregulation, anxiety) 5-HT1B CNS: presynaptic inhibition, behavioral effects; vascular: pulmonary vasoconstriction ergotamine 5-HT1D CNS: locomotion; vascular: cerebral vasoconstriction 5-HT2A CNS: neuronal excitation, behavioral effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT 5-HT2B stomach: contraction α-methyl-5-HT 5-HT2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD 5-HT3 CNS, PNS: neuronal excitation, anxiety, emesis 5-HT4 GIT, CNS: neuronal excitation, gastrointestinal motility 5-Ht5 CNS: unknown 5-Ht6 CNS: unknown 5-HT7 CNS, GIT, blood vessels: unknown There are many 5HT receptors subtypes found with in and outside the nervous system. Different receptor subtypes are implicated in mediating various functions. Please do not try to memorize this chart! A few of these subtypes you will hear about repeatedly. For example, the 5HT 1A receptor….., the 5HT 1B R….., the 5HT 2AR…., and the 5HT 2C R….

5-HT synthesis and metabolism Tryptophan (amino acid from diet) Tryptophan hydroxylase 5-hydroxytryptophan L-aromatic acid decarboxylase Serotonin (5-HT) Monoamine oxidase (MAO) in presynaptic neuron [after reuptake] Aldehyde dehydrogenase 5-HIAA

5-HT functions: ‘body’ Coordinate physiological functioning Physiological regulation Thermoregulation, appetite and digestion, cardiovascular activity, sexual functioning, pain perception Circadian rhythms Sleep/wake cycle: precursor of melatonin (pineal gland)

5-HT functions: ‘mind’ Affect regulation and cognitive function Learned helplessness Anticipatory anxiety Inhibit pain sensation 5-HT contributes to (declarative) memory, particularly for emotional stimuli

Summary Neural signaling occurs via electrical impulse down the axon, causing NT release Amino acids glutamate and GABA are the major excitatory and inhibitory NTs in the CNS, modulating activity via long-axon and intrinsic neurons Ach, DA, NE, and 5-HT systems originate in subcortical nuclei and project along organized pathways to modulate brain activity; although interactive, each is associated with certain functions and neuromodulatory disorders