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

Cross-tolerance

Drug dependence

• signs and symptoms upon withdrawal when drug levels fall

1. opiates inhibits the firing of locus ceruleus (LC) neurons by interacting with 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 hyper-excitable state becomes manifested when withdrawn

drug dependence with opiates

• 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 -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

-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

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。

搖頭丸

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

Flunitrazepam (FM2)

RU468abortion 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。