IBRO CIHR & UNESCO ADVANCED BEHVIOURAL NEUROSCEINCE SCHOOL KENYA 2008 SYNAPTIC FUNCTION & DRUG ACTION Associate Professor Laurie Kellaway Faculty of Health Sciences University of Cape Town
WHAT DOES A CHEMICAL SYNAPSE LOOK LIKE?
Hippocampal neuron stained for F-actin using rhodaminelabeled phalloidin
Classification criteria of synapses Type 1 Type 2 asymmetric synaptic density postsynaptic material prominent & dense rounded vesicles Wide synaptic cleft Usually EXCITATORY symmetrical synaptic density Flattened pleomorphic vesicles Narrow synaptic cleft Usually INHIBITORY NB: Associated dense material of Type 2 may form only a thin layer or limited to small area Vesicles must be associated with dense areas to classify as a synaptic complex
D = dendrite with 2 spines SA = spine apparatus S= spines receiving axon terminals A = astroglial processes x31 000
MAJOR NEUROTRANSMITTERS ACETYLCHOLINE : SPINAL CORD NUERONS- CONTROLS MUSCLES, CENTRALLY - MEMORY REGULATION close assoc with Hc (MOSTLY EXCITATORY) selective attention DOPAMINE: NTx INVOLVED IN REWARD SYSTEM OF THE BRAIN - MUTIPLE FUNCTIONS DEPENDING ON WHERE IT ACTS - (MOSTLY INHIBITORY). Motor performance and sustained alertness ( via frontal regions) GABA - WIDESPREAD - MAJOR INHIBITORY NTx GLUTAMATE - UBIQUITOUS EXCITATORY NTx GLYCINE - MAINLY IN SPINAL CORD - INHIBITORY NTx NOREPINEPHRINE - NTx & HORMONE FUNCTION. FUNCTIONS IN ANS: MOSTLY EXCITATORY - INHIBITORY IN SOME BRAIN AREAS SEROTONIN- MANY AREAS- general regulator; FUNCTIONS in MOOD APPETIE AND SENSORY PERCEPTION ; IN SP.CORD IT IS INHIBITORY IN PAIN PATHWAYS HISTAMINE: widely projecting system: involved in sleep-wake state, temperature contol, CVS control, eating & release of stress hormone (CRF), and argenine vasopressin AVP- receptors are all G-protein coupled receptors
BASIC MECHANISM OF NTx RELEASE AP - VOLTAGE GATED Ca ++ channels NTx stored in presynaptic vesicles released Effects a local change to postsynaptic membrane EXOCITOSIS promoted by Ca ++ Several pools of NTx -different stages of availability Ca ++ recruits vesicles from cytoskeleton - mobile pool Ca ++ /Calmodulin dependent protein kinase phosphorylation of synapsin - primes vesicle Adhesion of vesicle to presyn.membrane mediated by synaptobrevin & SNARE protiens Synaptotagmin directly activated by Ca ++, participates in final step of secretion
Post synaptic mechanism NTx diffuse across synaptic cleft - binds to specific ionotropic /and or metabotropic Rs in postsynatic membrane. conformational change - opening of ion channel If NT is excitatory eg Glutamate activation of NMDA Rs ( or Ach activation of Nicotinic Rs) - causes Na + to enter cell - fewer K + flows out - net effect = depolarization. If NT is inhibitory: eg GABA activation of GABA A R : allows Cl - ions to flow into cell: Effect = hyperpolarization Effects are integrated at the axon hillock = fire or not Metabotropic R: effect last longer ms, days, years Interact with G-Pr that in turn activate second messenger eg adenyl cyclase, Ca ++ to generate camp G- Proteins - act directly on channel to open or close them. 2nd messengers: activate protein kinases that can phosphorylate (activate or inactivate) ion channels and change membrane conductance Similarly can phosphorylate transcription factors = gene transcription, thus increasing or synthesis of ions channels or factors affecting ion channels
DRUGS & NEUROTRANSMISSION DRUGS AFFECT SYNAPSES AT VARIETY OF SITES & NUMBER OF WAYS INCREASED NUMBER OF IMPULSES (FIRING RATE). RELEASE OF NTx FROM VESICLES - WITH OR WITHOUT IMPULSES. BLOCK REUPTAKE OF NTx OR BLOCK RECEPTORS. PRODUCE MORE OR LESS NTx. PREVENT VESICLE FROM RELEASING NTx.
Drug action on synapses Direct agonists and antagonists bind to post-synaptic Rs: activates it or blocks it Many synapses both pre and post synaptic Rs NTx at presynaptic membrane is INHIBITORYfeedback control of release - if its action is EXCITATORY at the postsynaptic membrane - then easy to see two Rs are different. DRUGS may act only at the presynaptic R - thus a presynaptic agonist decreases amount of NT released, whereas presynaptic antagonist will increase amount of NT Drugs may augment effect of endogenous Nt by INIHIB of elimination of NT from synaptic cleft.(enzymic e.g. Ach) Or via presynaptic re-uptake which used to scavenge most small NTx molecules. Within presynaptic neuron DRUGS may alter synthesis, breakdown, vesicle accumulation altered Net effect - short term release, long term depletion of NTs
Methamphetamine alters DA transmission ENTERS DA VESICLE IN AXON TERMINAL CAUSING RELEASE OF DA BLOCKS DA TRANSPORTERS, THUS DA NOT PUPMED BACK INTO TERMINAL - EXCESSIVCE DA IN CLEFT THIS CAUSES EXCESSIVE FIRING IN POST- SYNAPTIC NEURON THUS STIMULATION OF MESOLIMBIC SYSTEM - RESULTANT FEELING OF EUPHORIA. COCAINE HAS SIMILAR MANNER OF ACTION
NICOTINE NIOCTINE INCREASES DOPAMINE RELEASE (SIMILAR EFFECTS TO METAMPHETAMINE & COCAINE ADMINISTRATION) NICOTINE BINDS TO RECEPTORS ON PRESYNAPTIC NEURON STIMULATES NEURON TO FIRE INCREASED APs - DA release is increased Increases the number of synaptic vesicles released
Alcohol Multiple effects on neurons - alters ion channels, membranes enzymes and receptors Binds to Rs for acetylecholine,serotonin, GABA, glutamate Focussing on GABA receptor
There are many different chemicals in the brain that function as neurotransmitters, but a small handful do most of the work. Neurotransmitter What it does What drugs affect it?? Dopamine Involved in regulation of movement, reward and punishment, pleasure, energy Every drug that affects feelings of pleasure, including Cocaine, Amphetamine, opiates, marijuana, heroin and PCP Epinephrine (also called Adrenaline) Excitatory neurotransmitter involved in arousal and alertness Norepinephrine (also called Noradrenaline) Involved in arousal and alertness,
Serotonin: Involved in regulation of mood and impulsivity Drugs: Alcohol, Hallucinogens: Stimulants, Anti-depressants Acetylcholine Inhibitory neurotransmitter involved in movement, memory function, motivation and sleep: Drugs: PCP and hallucinogens, Marijuana, Stimulants GABA (Gamma Aminobutyric Acid) Inhibitory neurotransmitter involved in arousal, judgment and impulsiveness Depressant drugs, Marijuana Glutamate Excitatory neurotransmitter Endorphins Substances involved in pain relief and reward/punishment Drugs: Opioids, Depressants
Noradrenergic & adrenergic projections
Cholinergic projections
Serotonergic projections
Locus coeruleus - Noradrenergic group
HISTAMINERGIC PROJECTIONS
Mecha nisms Of Specific Drug Activit y: Depressant Drugs: Alcohol, Benzodiazepines, Barbiturate s and other central nervous system depressant drugs act primarily on a neurotransmitter substa nce known a s GABA (Gamma Aminobutyric Acid ). GABA is an in hibitory neurotransmitter that m a kes other n eurons le ss likely to activate. The depressant dru gs are GABA agonists, acting to help GABA reduce neuronal activation more efficiently than it u sually wo uld. Alcohol also in hi bits (acts a s an antago nist agai nst ) another excitatory neurotransmitter (Glutam ate ), making it harder for Glutamate to get the ner vous system excited.
Stimulant Drugs Amphetamines have their primary effects on the neurotransmitter Dopamine. Amphetamines both induce the terminal button of Dopamineproducing neurons to let more Dopamine out than normal, and also keep that Dopamine out in the synapse longer than it normally would be allowed to stay. Amphetamine also acts agonistically on receptors for a different neurotransmitter, Norepinephrine, by competing with Norepinephrine for postsynaptic receptors and turning those postsynaptic receptors on. Cocaine has its major effect by blocking the re-uptake of the neurotransmitters Dopamine
Opioid Drugs: Opioid drugs bind to special endorphin receptors in the brain (the 'mu', 'kappa', 'sigma' 'delta' and 'gamma' receptors) that have to do with pain. When these receptors are occupied and activated, the perception of pain lessens. Drug treatments for opioid addictions sometimes include the administration of Naltrexone, which is an opioid antagonist. Naltrexone competes with the opioids for their receptor sites, but is not itself capable of activating those receptor sites. An opioid addict on Naltrexone is thus rendered more or less incapable of getting high from their opioid drug of choice; they may take an opioid, but it will be blocked from the opioid receptors by the Naltrexone, and will not have its effect
Cannabinoids: Marijuana has a complex set of effects. It acts on the neurotransmitters Serotonin, Dopamine and Acetylcholine. It also binds to a receptor for a recently discovered neurotransmitter known as Anadamide. Hallucinogens: LSD is known to antagonize Serotonin by blocking its release.
ADDICTION ADDICTION
Drug addiction and consequences There is no doubt any more that it negatively affects brain function Neuroadaptive changes Tolerance Physical dependence Mood alteration Relief of distress It is a chronic relapsing brain disease of uncontrollable drug-seeking behaviour & use; even knowing and experiencing the negative consequences on health and social interaction
Areas of the brain involved in addiction RESULTS FROM BRAIN IMAGING STUDIES (fmri): A LESS RESPONSIVE PREFRONTAL CORTEX SETS UP ADDICTS TO BECOME MORE IMPULSIVE