mechanisms of action drugs

Question 1

A potentially addictive substance induces an increase in

Answer 1

dopaminergic transmission in the brain reward system

Question 2

Explain the path of the primary reinforcing effect of a drug

Answer 2

release of dopamine from the ventral tegmental area (vta) to the nucleus accumbens (NAc).W

Question 3

what is the vta?

Answer 3

The vta is a region extremely rich in DA (dopamine) neurons that resides in the midbrain

Question 4

Where is the Nac located (nucleus accumbens)

Answer 4

the NAc is officialy part of the striatum, a big structure that resides in the forebrain, where it comprises the ventral part of it

Question 5

What is the pathway called for dopamine that is responsible for reward?

Answer 5

mesolimbic pathway

Question 6

Name all the pathways where dopamine plays an important role

Answer 6

1. the mesolimbic pathway (reward)
2. the mesocortical pathway ( decision making)
3. the striatonigral pathway ( movement)
4. tuberoinfundibular pathway (prolactine production)

Question 7

What are natural drugs?

Answer 7

Natural drugs are substances extracted from plants, like cocaine and THC.The
natural ones are named the big five: cocaine, morphine, THC, alcohol and nicotine. Plants produce
these molecules (also named in many cases alkaloids) for protection.

Question 8

What are synthetic drugs?

Answer 8

. Synthetic drugs are (mostly
illegally) elaborated in the lab starting from a natural compound or elaborated from scratch. An example
is LSD. Another example is MDMA, which should sound familiar if you have watched Breaking bad.

Question 9

Name the big 5

Answer 9

big five: cocaine, morphine, THC, alcohol and nicotine

Question 10

Explain the protection mechanism of the nicotiana tabacum plants

Answer 10

an example of protection is nicotine for nicotiana tabacum plants. At high dosage nicotine is
an efficient paralyzing agent. Nicotiana tabacum plants are very exposed to bugs that like chewing the
leaves of that plant leading it to die. To protect itself nicotiana tabacum produces nicotine when a bug
attacks its leaves. The bug will eat the leave together with a ridiculous high amount of nicotine in it.
Result? The bug will die paralyzed

Question 11

Another drug classification is based on their effects, name them

Answer 11

stimulants (euphoria), depressants (sedation), hallucinogens (hallucinations), mixed

Question 12

Name examples of hallucination, euphoria, sedation and mixed effect drugs

Answer 12

hallucination: LSD and Psilocybin
euphoria: amphetamine and cocaine
sedation: alcohol, ghb and heroin
mixed effect: thc and mdma

Question 13

What drugs have the highest addictive potential?

Answer 13

Drugs that produce a strong enhancement in DA transmission (in particular in the VTA to NAc): this
effect produces intense to very intense reward when consumed (see rush/high).

Question 14

What drugs have lower addictive potential?

Answer 14

Other drugs are able to induce just a little DA release from the VTA to the NAc. They mostly act on other
pathways, like for MDMA that works more on serotonin than DA. These drugs have lower addictive
potential.

Question 15

Describe the difference in dopamine release between stimulants and depressants

Answer 15

Stimulants directly act on dopaminergic (VTA DA in this case) neurons, producing a direct
effect on DA transmission;
 Depressants (and in some cases mixed drugs) produce an increase in VTA to NAc DA release
disinhibiting DA neurons (thus indirectly).

Question 16

What is inhibitory and what is excitatory?

Answer 16

gaba is inhibitory and glutamate is excitatory

Question 17

Describe what happens when dopamine is inhibited

Answer 17

In case of a strong activity of a substance (for instance) on one of these projecting neurons, the situation
can dramatically change. For instance, imagine the case of a drug that blocks GABA transmission to
VTA DA neurons. In this case there will
not be a balanced excitation/inhibition
anymore. There will be a lot of
glutamate and nearly zero GABA. The
result is a massive excitation of VTA
DA neurons and a consequent very
high release of DA to the NAc

Question 18

Explain the indirect pathway on dopamine

Answer 18

This pathway is used for the depressants and the mixed drugs. Gaba is inhibited and this results into a stimulation of the vta dopamine in the NAc due to the difference in balance in gaba and glutamate

Question 19

Explain the pathway of cocaine

Answer 19

It blocks the DAT (the dopamine transporter enzymes that care about the reuptake of excessive dopamine from the synaptic cleft). This will increase the availability of dopamine that can activate the dopaminergic receptors expressed on post-sysnaptic neurons

Question 20

Explain the pathway of amphetamine

Answer 20

Also amphetamine blocks DAT (dopamine transport enzymes). So, an increase of dopamine transmission to the NAc and euphoria. On top of this, it also augments the packaging of dopamine in the presynaptic cleft. The packaging is done by VMAT (vesicular monoamine transporters). Amphetamine increases the activity of VMAT. so, an increase in the dopamine released and a decrease in the dopamine reuptake

Question 21

Explain the Nicotine pathway

Answer 21

Nicotine is an agonist (versterker) at the level of the nicotinic acetylcholine receptors. In the brain, nAChRs are strongly expressed in the cortical regions and in the brain reward/limbic system. Hence, nicotine (activating these receptors)
exerts its functions as cognitive enhancing substance (in the cortex) and rewarding/addictive substance
(in the brain reward system). In the brain reward system nAChRs are massively expressed both on DA neurons from the VTA to the NAc and in their projecting neurons. AChRs are coupled with an ion-channel that,
when active, allows the influx of positive ions like sodium (Na+) and calcium (Ca2+). When nicotine
binds to these receptors it exerts an increase of positive ions in the dopaminergic axon terminals. This
effect excites the terminals, allowing a higher packaging of dopamine into vesicles (2) and release of
dopamine to the NAc (3). This produces the rewarding/reinforcing effects of nicotine.

Question 22

What is the function of the nicotinic acetylcholine receptors?

Answer 22

These receptors are normally expressed in our brain to respond to the release of
acetylcholine (Ach), an important neurotransmitter involved in cognitive functions and movement. Ach
is also released in the periphery where it promotes the activity of both smooth and voluntary muscles. It
is, in fact, the molecule that allows our muscles to contract/relax, allowing movement.In the brain, nAChRs are strongly expressed in the cortical regions (that´s why Ach is involved in
cognitive functions) and in the brain reward/limbic system. Hence, nicotine (activating these receptors)
exerts its functions as cognitive enhancing substance (in the cortex) and rewarding/addictive substance
(in the brain reward system).

Question 23

Explain the heroin pathway

Answer 23

It acts on receptors in the brain reward system, named mu-opioid receptors. These release endorphins. Activating these receptors will lead to suppressing the release of gaba to the vta da neurons. This results into hyper-excitation and an increase in the release of dopamine to the Nac. Mu-opiod receptors block the gaba release, because they belong to the gi-coupled receptors. which means when these receptors are activated (by endorphins or heroin) they induce metabolic changes in the cell that lead to suppress its activity. Result is that GABA neurons,
deactivated by MuR stimulation, do not release GABA until these MuR are still active.

Question 24

What is heroin?

Answer 24

Heroin is a deacetylate form of morphine. Being deacetylate it gets much faster into the brain than
morphine. Both drugs (morphine and heroin) are opiates. They are thus classified as depressants as
once administered they cause sedation.

Question 25

What do mu-opiod receptors do?

Answer 25

These receptors are expressed in our brain to respond
to the natural release of endorphins. These molecules are mostly released when we feel pain and they
are responsible of that relief we experience after acute pain

Question 26

Explain the heroin pathway in short

Answer 26

heroin activates mu-opiod receptors. These are gi- coupled receptors and change the cell. They deactivate gaba neurons

Question 27

Explain the nicotinic pathway in short

Answer 27

Nicotine is at the level of nicotinic acetylcholine receptors. these are coupled with an ion channel that allows the influx of sodium and calcium ions. This excites the terminals and allows a higher packaging of dopamine into vesicles and higher release of dopamines to the nAc.

Question 28

Explain the effects of alcohol

Answer 28

Alcohol activates the GABA receptors. When these are activated, they allow the influx of negative ions such as chloride. This will suppress the gaba release from the neurons projecting to the vta dopamine neurons. This effect is responsible of an indirect release of dopamine to the NAc

Question 29

Explain the pathway of thc

Answer 29

THC acts on the cannabinoid receptors (cb1rs). These respond to the release of 2 endogenous molecules we name endocannabinoid (anandamide and 2ag). THC mimics the effect of these molecules binding to the same CB1 receptors (with less affinity though). In the brain reward system, these receptors, once activated, suppress GABA release from GABAergic
projections to the VTA dopamine neurons, because they work using basically the same inhibitory mechanism of MuRs. Result is more dopamine released from the VTA to the NAc.

Question 30

What is the function of anandamide and 2ag?

Answer 30

These molecules are
produced and released from our neurons to protect our brain against insults (stroke, inflammation).

Question 31

Explain the hallucinogens pathway

Answer 31

They act on serotonin (5ht) transmission and the overstimulation of serotonin receptors in some brain regions which mostly reside outside the brain reward circuitry is thought to cause hallucinations.

Question 32

Why are hallucinoegens known for their lower addictive property?

Answer 32

Hallucinogens like LSD are mostly known for their lower addictive property. This is because they
produce a modest (to none) release of dopamine to the NAc and the rest of the brain reward system
when compared with other drugs (like cocaine).

Question 33

What is the function of serotonin?

Answer 33

Serotonin (aka 5HT) is an important neurotransmitter for the regulation of the mood and for
other vital functions (see body temperature)

Question 34

Explain mdma

Answer 34

MDMA is not considered a hallucinogen. However, it works on the same serotonin receptor. Result
is good feeling derived by more serotonin released. As serotonin also plays a role in vital functions (for
instance, due to its activity on the hypothalamus), the overdose of MDMA can cause serious troubles
that may lead to death (see serotonin syndrome, high fever and dehydration).