Neuropharmacology of CNS & Substance Abuse

Neuropharmacology of CNS & Substance Abuse • Story of MPTP (1-methyl-4-phenyl 1,2,3,5-tetrahydropyridine) • Monoamine oxidase (MAO) in astrocytes • Oxidative phosphorylation

Anatomy of the nervous system • Neurons • Interstitial cells • Astrocytes • Oligodendrocytes, Neurolemma, Schwan cells • Myelin Sheaths • Nodes of Ranvier • Anterograde, Retrograde, Microtubules • Motor proteins • Kinesin, Dynein • Microglials, phagocytic cells macrophage/monocyte

Morphological considerations • Nutritional and biochemical aspects • Brain-blood-barrier • Tight junctions, Endothelial • Anoxic or hypoglycemic

The Synapse • Three elements: Presynaptic, Postsynpatic, Synaptic cleft • 4 steps: 1. synthesis storage; 2. transmitter release; 3. receptor activation; 4. neurotransmitter inactivation

Specific neurotransmitter system • Acetylcholine • Muscarinic, • Nicotinic • Glutamate- excitatory • AMPA, Kainate, NMDA • GABA - inhibitory • Subtype A and B • Glycine- inhibitory, Spinal cord, strychnine

Substance abuse Background main types of abused drugs Table no insulin or penicillin "junkies"

Tolerance • diminishing drug effect following repeated administration. Higher doses are needed to produce the same effect. • May be pharmacokinetic or pharmacodynamic tolerance • pharmacokinetic : induction of hepatic metabolic enzymes e.g. barbiturates; • pharmacodynamic: alteration at receptor levels e.g. decrease of GABA receptors followed by increase of barbiturate administration; morphine and its receptor. • Tolerance may be developed only one effect of the drug but not the others; e.g. in opiates, euphoric and analgesic effects are tolerated but the respiratory depression is not.

Cross-tolerance Cross-tolerance means that individuals tolerant to one drug will be tolerant to other drugs in the same class, but not to drugs in other class.

Drug dependence • signs and symptoms upon withdrawal when drug levels fall

drug dependence with opiates • 1. opiates inhibits the firing of locus ceruleus (LC) neurons by interacting with m receptors. • 2. long term opiate administration causes molecular adaptations in the signaling properties of neurons. • 3. decrease signaling; without decreasing the numbers or affinity of the receptors. • 4. cAMP cascade is up-regulated, phosphorylation of a slow depolarizing Na+ channel, neuronal excitability. • 5. hyper-excitable state becomes manifested when withdrawn

withdrawal symptoms vary with drugs. barbiturates, alcohol, possible death • cross-dependence : drug A that show cross-tolerance with drug B of the same class also support the dependence of B .

Caffeine • competitive antagoinst of adenosine receptors • sedative • caffeine is an addicting drug because it shows reinforcement and its withdrawal induces symptoms: headache, drowsiness, fatigue, decreased performance, depression

Methadone maintenance • opiate agonist, analgesic, to replace the addict's heroine • maintenance basis (same dose, chronic use), withdrawal basis (gradually reducing dose, 1-6 months)

cocaine, • HCl, freebase, crack, 1-2 min peak CNS effects • dopamine receptor agonists

Addiction Liability • animal behavior paradigm self-administer • Table of Addiction risk of major psychoactive drugs • reward pathway center, dopaminergic neurons ventral tegmental area; forebrain, • euphoria reinforcement cycle

War on drugs • a perceived threat, moral principle • Table. Number of yearly drug-related deaths • Tobacco, Alcohol >> Cocaine, Heroine, Aspirin

Descriminalization • Netherlands, soft and hard drugs coffee shop 4.6% use cannabis vs 4.8% in U.S.

Drugs in Sports • Background • not drug abuse but illicit use of banned substances • History • Scandinavian warriors, muscarine, psychoactive alkaloids • 1800s amphetamine, strychnine and ephedrine commercially available • IOC ban (1) substances of selected groups; (2) doping methods. • rationales : clearly enhanced performance, medical safety, social acceptability

Stimulants • amphetamine, cocaine and strychnine • delay onset of fatigue • caffeine, phenylpropanolamine, ephedrine • problem for legitimate health medication • Rick DeMont episode • alternatives salbutamol terbutalin by inhaler only

Narcotics • morphine, pain killers, alternative • OTC cold cough remedies contain dextromethorphan

Anabolic agents • anabolic androgenic steroids (AAS) testosterone and its derivatives • treatment bone marrow failure anemias • moderately high dose  gain 13 lbs pure muscle • side effects females masculinization low vocie • use of AAS in international sports competitions • urine test testosterone:epitestosterone T:E ratio • b-2 agonist asthma relief clenbuterol • livestock industry growth promote • drug treated meat • Alekey Petrov story

Diuretics • urine excretion conceal evidence of the misuse of drugs • rapid weight loss • weight classes boxing wrestling • masking agents probenecid prevent secretion of AAS • epitestosterone T:E ratio • absolute level : no more than 200 ng/ml

Miscellaneous drugs • b-blockers,  blood pressure • cardiac output, hypertension, cardiac arrythmia, angina • shooting archery • chorionic gonadotropin  androgenic steorids • testosterone  • corticotropin (adrenal stimulatory trophic hormone) corticosteroids • erythropoetin (EPO) red blood cell production blood samples

Blood doping • oxygen-carrying capacity • technique • withdrawing 1 liter blood, store frozen 9-12 weeks • hemoglobin return, reintroduce

搖頭丸 俗稱或快樂丸的毒品事實上屬於安非他命的衍生物，英文叫作MDMA(3,4-methylenedioxy-methamphetamine)或Ecstasy. 搖頭丸是在1914年，由德國默克(E. Merk)公司合成為減肥藥用途，後來發現此藥最主要作用與興奮劑及迷幻效藥物類似。因此，未能上市。直到了1980年，雖然FDA未能通過，卻有不少此類藥物，被用來作精神治療的輔助劑。自從1983年起，搖頭丸逐漸的被美國大學生廣泛的使用。美國政府乃在1985年，加以立法管制。國內自1990年起安非他命廣泛流行後，最近幾年來在舞廳及，才開始流行搖頭丸。事實上市面上販售的搖頭丸有些不只含有MDMA的成份，更有添潻加甲基安非他命及安非他命、或咖啡因等成份‧會增加其毒性作用。

Flunitrazepam (FM2) commonly abused benzodiazepines drugs such as Flunitrazepam (FM2), Diazepam (Valium), Triazolam (Halcion), Lorazepam, and Oxazepam

RU468 abortion drug, anti-progesterone effect

望找到的資料是老師所要的... • 白板 : • 來源：屬禁用之安眠鎮靜類製劑。 • 性狀：主成分為Methaqualone(Mandrax)甲口奎酮，白色結晶性粉末製成錠劑。 • 醫藥用途:沒有 • 濫用方式：口服。常被混在酒精、鎮定劑、可待因及大麻中服用。 • 毒害：抑制中樞神經，成癮者服用後感到高潮式快感，隨之有平靜祥和感，發生感覺異常及異常出血現象、流鼻血、白血球稀少及再生不良性貧血等致命併發症。為達更大快感，增加劑量後產生之中毒現象如：全身痙攣式抽搐、肌張力增加、瞳孔放大、發抖、支氣管分泌及唾液增多，肺水腫。造成低血壓、呼吸抑制、休克現象，如未及時急救會導致死亡。停藥三至五天後產生頭痛、噁心、厭食、腹絞痛、發抖、失眠等禁斷症候。

Neuropharmacology of CNS & Substance Abuse