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Drugs & The Brain
Transcript of Drugs & The Brain
By: Olivia Paulo
The Drugs Focused on in this presentation:
How does marijuana work?
How does MDMA work?
THC is the active chemical in marijuana and it emulates anandamide. When it reaches the brain, it turns off inhibition by binding to the cannabinoid receptors. This allows for the release of dopamine, and because THC does not break down as easily as anandamide- the high.
The brain has inhibitory neurotransmitters that prevent the release of dopamine. Anandamide binds to cannabinoid receptors to stop the production of the inhibitory neurotransmitters for dopamine. Cannabinoid receptors are G-Protein receptors that are found in the Basal Ganglia, Hippocampus, and Cerebellum; thus they have an affect on short term memory, coordination, problem solving, and learning.
As a neurotransmitter, serotonin is responsible for the regulation of such things like sleep, temperature, mood, perception, appetite, and pain. The brain has serotonin transporters that eliminate the serotonin from the synaptic cleft once it has been used. The serotonin that is not taken up by receptors is taken up by transporters and back into the neuron (where it will be metabolized by enzymes). In order for this to happen, the transporter needs to bind with not only serotonin, but chloride and sodium. This trio causes a conformational change in the transporter and forces it to "flip" inside of the neuron and release the serotonin. Potassium on the inside will then bind to the empty transporter, causing it to go back to the synaptic cleft. (These transporters are known as SERTs or Serotonin reuptake transporters.) Once inside the neuron, serotonin will cause the cell body to send an electrical impulse down the axon. If enough serotonin is bound to receptors, then the stimulated neuron will release serotonin in the synapse.
How Does MDMA work?
When MDMA enters the brain, it mimics serotonin and binds to the serotonin transporters. MDMA, however, is a serotonin reuptake inhibitor (SSRI). By inhibiting the transporters, it leaves excess serotonin in the synaptic cleft. This excess activates more serotonin receptors. The more receptors being activated, the more serotonin that enters neurons.
The MDMA High
Length of the high: anywhere from 3-10 hours
Characteristics: increased pleasure in physical contact, heightened alertness, distortions in perception, empathetic, energized
"Imagine if you just won $100 million in the lottery, and everyone else around you has also won $100 million in the lottery- that's what it feels like to be on ecstasy. Where you feel this great high, everyone else is feeling this great high....You feel closer to other people."
-Dr. Robert Kiltzman
The Science Behind the High
The high that follows taking MDMA can be attributed to the increased levels of serotonin. Serotonin axons originate in "raphe nuclei," and the most common places they are found are in the medulla, midbrain, and pons- control centers for breathing, heartbeat, and blood pressure. It also has an affect on the limbic system- control center for emotion. During an ecstasy high, the plethora of serotonin is removed from the synapse by receptors, and sent to neurons throughout the body.
The high wears off because the reuptake transporters continue to remove serotonin from the synapse- there are less activated receptors, and less serotonin. (Monoamine oxidase metabolizes the neurotransmitter and breaks it down once it enters the neuron, regardless of decreasing levels.) During the come down, you begin to feel normal because the amount of serotonin now present is equal to the amount prior to MDMA. However, as is usually the case with MDMA, it continues to deplete serotonin levels so that they are drastically less than before the high. Many people will try to take more MDMA, this will not work because the "ecstacy feeling" was really a "serotonin feeling"- there is not enough serotonin in the system to produce that high again. This crash has been nicknamed "Suicide Tuesday." Serotonin does not replenish quickly for two reasons. The first is because it is made up of tryptophan- an amino acid that must go through a number of metabolic processes. And the second is that the brain was not made to produce a lot of serotonin at once.
Other Dangers of MDMA
Using ecstasy may cause serotonin receptors to go through "downregulation." Downregulation is a way for the brain to respond to an influx of serotonin. The receptors actually withdraw back into the dendritic membrane- basically temporarily shutting down. Different theories suggest that the brain does this to maintain a normal state, while others suggest that it prevents the receptors from being damaged. Downregulation can lead to depression because serotonin cannot bind to receptors that have been downregulated.
Neurotoxicity occurs after MDMA has depleted serotonin levels so the reuptake transporters are left empty. Dopamine is "hanging out" in the synapse and gets taken in by the empty reuptake transporters. Dopamine is harmful to serotonin cells because it gets broken down by monoamine oxidase into hydrogen peroxide. Hydrogen peroxide, in turn, uses oxygen to break down areas of the cell that are not typically subject to oxidation.
These pictures are of serotonin levels in the frontal lobe of monkey brains. Picture A is from before and picture B is after 10mg of MDMA everyday for 4 days.
HYPONATREMIA: a condition when water levels in the blood are dangerously high. MDMA uses are at risk for this because the drug releases a hormone that makes urinating challenging- thus they retain unhealthy amounts of water. This is problematic because when the blood reaches the brain, it can expand and push against the spinal cord.
HYPOTHERMIA: The hypothalamus serves as the body's innate thermostat. It is believed that excess serotonin in this area of the brain can impair temperature regulation/acknowledgement altogether. MDMA users typically overheat because they take it at hot, overcrowded raves or have an increased activity level because of the drug's effects. Failure to cool the body down has damaging effects on organs like the liver. Increased temperature leads to the denaturing of proteins- they bind together and cause the organ to shut down.
LIVER PROBLEMS: Drugs are detoxified in the liver. Our livers have an enzyme that break them down and send them to the kindeys to be released from the body. Some people don't have enough of this enzyme so the toxins from MDMA stay in the liver and damage the tissue.
MDMA releases this hormone throughout the enter body. Noradrenaline is the hormone responsible for "fight or flight". When nerve endings meet with muscles behind the eye, noradrenaline causes them to dialate. Similarly, noradrenaline also excites the jaw when the neuron and muscle meet. Many ecstasy users can be seen involuntarily clenching their jaw.
"The messier they look, the more fun they're having."
MDMA in Real Life
How Does Methamphetamine work?
Meth works very similarly to MDMA. Like serotonin, the brain has transporters for dopamine that remove any excess from the synapse. Meth mimics dopamine, but once it is inside the cell it enters the vesicles and pushes all the dopamine out. Because everything in nature wants to go from a high to low concentration, the high concentration of dopamine in the cell gets pushed out into the synapse. The more dopamine in the synapse, the more receptors will be activated and the more cells that will be stimulated.
The Science Behind the High
There are two receptors for THC- CB1 and CB2- they are both paired with G-proteins. As a team they regulate the synthesis of cAMP (Cyclic AMP). (Recall that cAMP is a second messenger so it relays the signal from the ligand to the cell.) THC and its receptors can reduce the amount of cAMP. Reduced amounts of cAMP stop the flow of calcium ions into the cells, this in turn, disturbs the creation of action potentials. The process of THC and its receptors explains the mellowed out feeling that is characteristic of a marijuana high.
Marijuana: is it helpful?
Professor Yosef Sarne of Tel Aviv University's Adelson Center for the Biology of Addictive Diseases at the Sackler Faculty of Medicine says: "(Marijuana) has neuroprotective qualities.... Extremely low doses of THC -- the psychoactive component of marijuana -- protects the brain from long-term cognitive damage in the wake of injury from hypoxia (lack of oxygen), seizures, or toxic drugs."
Hypothesis: doses of marijuana that are only the fraction of a marijuana cigarette given 1-7 days prior to head injury or 1-3 days after
Experiment: Sarne had 3 groups of mice; one group was injected with THC before head trauma, another after head trauma, and the third group had no THC. They were analyzed 3-7 weeks after injury.
Results: The mice that were injected with THC had a higher performance in tests that measured memory and learning.
Conclusion: THC can be used to almost build up the strenth of the brain. The drug, he believes, causes little damage and by "pre and post conditioning," it can build up a resistance in the brain that will protect it from more serious injuries.
There are high concentrations of cannabinoid receptors in the basal ganglia, cerebellum, and hippocampus. The basal ganglia and cerebellum control movement/coordination, which explains why they are debilitated during a high. The hippocampus is in charge of remembering recent events, thus marijuana use impairs short term memory.
"Dopamine Pathways: In the brain, dopamine plays an important role in the regulation of reward and movement. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the ventral tegmental area (VTA) and is released in the nucleus accumbens and the prefrontal cortex. Its motor functions are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the striatum."
Meth is one of the most addictive drugs
Studies explain that the first time someone gets high off of meth, it's a concious choice made in the frontal lobe. By the next few times it's used, the "decision" to get high is no longer voluntary.
Animals have a REWARD THRESHOLD, which is the minimum level a stimulus must be in order for it to be pleasurable. Each time meth is taken, the reward threshold increases so that more of the drug needs to be injested in order for it to be pleasurable.
"As addiction develops, there are also long-lasting changes in the reward circuitry. The result is a craving for the drug that is present independent of any pleasure associated with consumption" (Campbell, Reece 1082).
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The Human Brain