Neuropharmacology of CNS

1
Neuropharmacology of CNS Substance Abuse

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

2
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

3
Morphological considerations

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

4
The Synapse

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

5
Specific neurotransmitter system

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

6
Substance abuse

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

7
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.

8
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.
9
Drug dependence

• signs and symptoms upon withdrawal when drug
  levels fall

10
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withdrawn
11

• 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 .

12
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

13
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)

14

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

15
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

16
War on drugs

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

17
Descriminalization

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

18
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

19
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

20
Narcotics

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

21
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 testosteroneepitestosterone TE ratio
  
• b-2 agonist asthma relief clenbuterol
• livestock industry growth promote
• drug treated meat
• Alekey Petrov story

22
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 TE ratio
• absolute level no more than 200 ng/ml

23
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

24
Blood doping

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

25
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26
Flunitrazepam (FM2)
commonly abused benzodiazepines drugs such as
Flunitrazepam (FM2), Diazepam (Valium),
Triazolam (Halcion), Lorazepam, and Oxazepam
27
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28

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