Lecture 5- CNS stimulants and Psychotomimetric drugs 1

Question 1

Describe:
Psychomotor stimulants
Psychotomimetics

Answer 1

Psychomotor: affect motor control (usually promote motor activity) as well as well being of brain. Dopaminergic system.

Psychotomimetrics- similar to psychomotor but don’t have motor effect. Targets they’re hitting are similar. But not so heavily involved in dopaminergic system. More serotinergic system which is not so involved in locomotion.

Question 2

Why don’t nicotine and cannabis affect locomotion much?

Answer 2

Nicotine and cannabis don’t affect motor as much because not hitting dopamine

Question 3

What kind of drugs are psychomotor stimulants?

Answer 3

Amphetamine and related drugs:

Amphetamine, methamphetamine, ecstasy (MDMA), cocaine – variants: crack, etc

Question 4

What are the effects of psychomotor stimulants?

Answer 4

1. Marked effect on mental function and behaviour. Dependent on how much you can get into nervous system how quickly because this mimicks the reward system’s quick release of dopamine.
2. Induce euphoria, reduced sense of fatigue
3. Increase motor output
4. Act on central modulatory catecholaminegic pathways (esp. Dopamine) and other similar paths
5. May have peripheral as well as central actions (e.g. blood pressure, heart rate, bladder control)

Question 5

Describe tolerance, dependence and withdrawal?

Answer 5

Need greater and greater concentration to get same effect- tolerance
Dependence- you feel worse when you stop taking the drug than before.
Withdrawal- have symptoms when you stop.

These happen with lots of drugs, not just recreational. Because the brain changes to compensate for presence of the drug.

Question 6

Describe the structure of amphetamine and related compounds?

Answer 6

Small ring structure with proximal amine group. Like noradrenaline and dopamine!
Noradrenaline and dopamine have almost exactly same structure apart from noradrenaline has the hydroxyl group.

Question 7

Are amphetamines blocking dopamine and noradrenaline receptors? Explain…

Answer 7

Receptors are very specific. However other molecules which handle these are not so specific. E.g. reuptake mechanisms. Not mimicking dopamine binding to receptors.
But they’re getting in the way of re-uptake and packaging into vesicles at the synapses so they’re affecting transmission at the synapses, which is how they have their effect. Disturbs signalling.

Question 8

What is the mode of action of the amphetamines?

Answer 8

1. Block the re-uptake transporter proteins.
2. They block to some extent the vesicular transporters. So prevent the transmitter once its made, being packaged. So the transmitter content of the synapse increases.
3. Binds to monoamine oxidase enzyme that normally looks for dopamine and noradrenaline.

So you’re blocking re-uptake, there’s more in the cleft. The amount you do uptake you’re blocking its breakdown, you’re blocking packaging of new transmitter so transmitter content of cytosol of terminal increases , which can actually force this transporter to work in reverse. More transmitter in cytosol the concentration gradient pushes the transmitter outwards into the synaptic cleft. Destroyed the signalling of the neurone.

Question 9

Behavioural effects of amphetamines?

Answer 9

Locomotor stimulation
Euphoria and excitement
Insomnia
Increased stamina
Anorexia
(peripheral effects include raised BP and inhibition of gastric motility)

Question 10

Clinical uses of amphetamine related drugs?

Answer 10

-Amphetamine to counteract narcolepsy (not a cure!)

-Methylphenidate - Ritalin- treat ADHD (controlled drug, if used incorrectly can have effects like amphetamines
atomoxetine= new drug for adhd. Its a selective noradrenaline reuptake inhibitor (can be used in combination with methyphenidate)

-Modafinil- study drug, keep you awake. (May just be good marketing) (a “cognitive enhancer”) is a more general amine reuptake inhibitor

Question 11

Why might you want to mix two of the clinical drugs?

Answer 11

Sometimes if you take two drugs at lower doses can get the benefits without the side effects, rather than a lot of one drug.
The problem is how do you decide which drugs to mix together.
(Limited use of these amphetamine related drugs basically.)

Question 12

If taken repeatedly over a short period, what can amphetamine induce?

Answer 12

“amphetamine psychosis”, much like acute schizophrenia – hallucinations, paranoid symptoms and aggressive behaviour

Repetitive sterotypical behaviours may develop (known as “punding” this can include self-biting, scratching or even shoe polishing!)

Question 13

How do you know rodents get dependant on amphetamines?

Answer 13

In the rodent model of this behaviour, animals will self-administer until the cardiovascular side effects cause death.

Question 14

Cocaine

Main features

Answer 14

Plant alkaloid from coca plant, historically used as tonic and to allay fatigue
Was a constituent of Coca-Cola until 1903
Banned in the USA in 1914 as a “dangerous narcotic”
Very little medicinal use; widely misused (as it is wrongly believed to be harmless and non-addictive!)
Affects dopamine transporter. Increases dopamine like the others.

Question 15

Cocaine mechanism?

Answer 15

Cocaine acts similarly to amphetamine (as well as being a local anaesthetic), but acts equally on uptake of noradrenaline, dopamine and 5HT.

Question 16

How is cocaine taken?

Answer 16

Cocaine is rapidly absorbed and is often taken nasally or by IV – the former destroys local tissue (by vaso-constriction, resulting in a perforated nasal septum) while the latter gives a more intense “high”

The free base (which can be prepared from the salt) vaporises at ~90°C and so can be “smoked” – crack, which has a more intense, faster effect than nasal administration

It is metabolized rapidly in the liver and one metabolite is measureable in human hair. Lasts in the hair as long as the hair lasts. Good for testing.

Question 17

Effects of cocaine.

And dependance

Answer 17

Toxic effects are common, mainly cardiovascular, which can be acute or chronic

Can produce strong psychological dependence (results in “substance dependence” not true addiction, as with opiates) particularly with rapid routes of administration

Can produce foetal malformation if used in pregnancy

Question 18

Summary of cocaine

Answer 18

Psychomotor stimulants act by increasing available noradrenaline, dopamine and/or 5HT

Administration results in euphoria, increased stamina, increased motor output

Possess central and peripheral actions (which add to the toxicity)

Little medical use

Question 19

Caffeine mode of action?

Answer 19

1. Inhibit central adenosine receptors (A1 and A2) (antagonist).
   Normally activation of these receptors inhibits CNS. So antagonising the adenosine system so can’t be inhibitory.

Adenosine and ATP are modulatory, acting to fine-tune the actions of many other neurotrnasmitter systems, generally resulting in decreased CNS activity

2. Also inhibits phosphodiesterase enzyme, which normally breaks down cAMP so this increases local cAMP (much like β receptor agonists).
   cAMP is made by adenylate cyclase. Big amplification. So small change in camp early on has big effect on cell.
   caffeine blocks phosphodiesterase so lots more cAMP.

Question 20

Caffeine effects?

Answer 20

Caffeine does not have psychomimetic functions, nor induce stereotypic actions

Mental functions are improved by moderate doses (~200mg or 2 cups of filter coffee), but impaired at higher doses

Tolerance/habituation can occur, Tolerance due to more phosphodiesterase being made so if you stop taking caffeine, not enough cAMP so get withdrawal.
But…

Caffeine, unlike amphetamine and cocaine, is not self-administered by animals and is not regarded as a dependence producing drug.

Question 21

Caffeine summary?

Answer 21

Psychomotor stimulation by caffeine due to block of central adenosine receptors

Administration results in mild euphoria, increased urine output

Not addictive, but social “dependence” can occur

Traditionally has been (widely) used to increase concentration/ offset sleep

Question 22

Psychotomimetics summary

Answer 22

Psychedelic or hallucinogenic
Affect thought, perception and mood
No psychomotor stimulation or depression
Minimal intellectual or memory impairment
Autonomic side-effects low
(Surprisingly?) little or no dependence liability

LSD, psilocybin (magic mushrooms), mescaline, ecstasy, ketamine, phencyclidine, even cannabis…

Question 23

LSD (Psychotomimetric) pharmacological effects?

Answer 23

Psychotomimetic functions of LSD probably via potent partial AGONIST activity at 5HT2A receptors possibly within the cingulate cortex. Binds and activates 5ht2a receptor.

Activation of 5HT2A receptors may indirectly block glutamate activation of NMDA receptors.

LSD also activates 5HT1A autoreceptors on 5HT cells in the Raphe nucleus, slowing their firing rate.

Question 24

Mescaline and Psylocibin (psychotomimetric) pharmacological effects?

Answer 24

Mescaline may also act on 5HT2A receptors, but other actions are not well understood and may include actions on amine transporters

Psylocibin is metabolised to a compound active at several 5HT receptors.

Question 25

How do we measure psychotomimetric drug effects?

Answer 25

Pharmacologically, it is difficult to measure the effects of psychotomimetics in animals, as effects are “subjective” – we can’t measure changes in consciousness or hallucinations! Animals tend not to self –administer….

Question 26

Ecstasy?

Answer 26

MDMA - more than just an amphetamine derivative.

Gives the euphoria as amphetamine, but adds mild hallucinogenic actions. Because double ring structure similar to serotonin (?)

Considered to be like taking amphetamine with “mild” LSD

Used in the 1950’s by American military trying to discover a “truth serum”!

Question 27

Ketamine and Phenycyclidine?

Answer 27

Ketamine (“Special K”) is a dissociative anaesthetic agent used in veterinary practice and science (medically rarely used in humans)
Phencyclidine (PCP, “Angel Dust”) is an analogue of ketamine, less available/used

Both produce euphoria and can give rise to hallucinations at higher doses, along with detachment, disorientation. PCP can cause psychotic episodes
Both block NMDA receptor. We’ve found now that reduced NMDA action is foudn in schyzophrenic people.

Question 28

Ketamine and phenycyclidine mode of action?

Answer 28

Block NMDA receptor (voltage sensitive Glu-activated ionotropic receptor)

Question 29

Side effects of ketamine and phenycyclidine?

Answer 29

Long term use can result in paradoxical bladder defects

Dangerous in overdose, often taken in combination with other drugs such as alcohol, barbiturates or heroin