The major ways drugs induce pleasure in the human brain (Psychopharmacology)

Discussion in 'Psychedelics' started by etkearne, Feb 25, 2012.

  1. etkearne

    etkearne Resident Pharmacologist

    Ok. So I wanted to make this topic for a long time and unfortunately I only have my iPad at my disposal the very day that I got the motivation to write it up (ie: today!). But nonetheless, I will attempt to write a decent topic.

    What I aim to address is the most fundamental question about the drugs we take: HOW do these drugs induce pleasure in our minds? I am taking a strictly materialist position to writing this, mainly to simplify things, but also because I am a pretty strong materialist when it comes to our minds.

    I will write the drug class and then write a short but throrough description of how they work. It is helpful to know some basic things about neural signaling. I would look up the following phrases on Wikipedia to understand this better:

    - Neurotransmitter
    - Receptor
    - Agonist
    - Antagonist

    Ok. So here we go...

    1. Opiates/ Opioids (examples: Hydrocodone, Oxycodone, Heroin, Morphine)

    When a person ingests an opioid drug, it is quickly absorbed by the bloodstream and the opioid molecules enter the central nervous system and eventually the brain. It is in the brain alone that opioid pleasure is induced.

    There exist a range of receptors called the mu, delta, and kappa opioid receptors. When an opioid molecule binds to the recptor as an agonist, it activates it. When activated, these receptors act to inhibit neural flow on the neuron on which they are found upon. So, if these receptors were distributed evenly in the brain, we would expect a net effect that would not be interesting. The excitability (due to inhibition of inhibitory neurons) would be cancelled by the inhibition.

    Lucky for us, opioid receptors are found in just the right places. Regarding pleasure, we focus on two areas- the locus coeruleus and nucleus Accumbens. The LC is the root of all neurons in the brain that use Norepinephrine. The transmitter causes cardiovascular stimulation which is generally unwanted. So the inhibition by the opioid molecule calms the body and mind. It also suppresses stress hormones that emit from the LC.

    But this is not the only root of pleasure. In the NucAcc, GABA neurons feed into the shell of the NucAcc. GABA is inhibitory. It "dampens" excitability from dopamine. However, when an opioid inhibits the GABA neuron, it (think hard here, it is really abstract IMO) inhibits inhibition leading to excitation via the disinhibition of dopamine. Thus, the locked up dopamine rushes through the NucAcc and the entire tract of the brain from the amygdala to the frontal Cortex lights up. This is what we call euphoria.

    So, combining the calming of the LC and the dopamine rush in the Mesolimbic tract of the brain, we experience euphoria from the opioid.

    2. Stimulants (examples: amphetamine, cocaine)

    Similar to opioids, stimulants begin exerting their pleasurable effects in the brain. When the stimulant molecule enters the central nervous system, it will not be of much value unless it can alter the normal functioning of some part of the brain. So we examine the Monoamine Transporter. Monoamines are basic Neurotransmitters like serotonin, norepinephrine, and dopamine.

    The transporter acts by recycling excess levels of the Monoamines in the brain. After all, the brain is an efficient machine, and too much of anything is wasteful. We will look at two Monoamien transporters: Norepinephrine Transpoter (NET) and Dopamine Transporter (DAT). Stimulants act by inhibiting and/or reversing the flow of the NET or DAT. Cocaine inhibits them from doing the recycling but amphetamine actually reverses their flow leading to the release of NE and DA.

    So what good is all of this excess Norepinephrine and Dopamine? Well, excess dopamine, as we know from the opioids section above, when found in the Mesolimbic tract of the brain, causes acute euphoria. Pretty good. Ok. So what about the Norepinephrine? Well, excess levels of NE activate the cardiovascular system, leading to improved endurance, sense of energy, and motivation to keep doing tasks. While this in itself isn't anything exciting, IF we couple that WITH the euphoria of the Mesolimbic activity, we end up with what is considered the most direct and strong euphoria of any drugs on earth.

    However, their euphoria is not the be all and end all, because unlike opioids which lead you to be CONTENT and EUPHORIC, stimulants are more euphoric but do NOT give you a sense of peace or contentment. The excess NE activity actually makes you want to just repeat the experience right away. But nothing can take away that stimulants are incredibly strong euphoriants.

    3. Downers (examples: benzos like Valium and Xanax, barbiturates, and alcohol)

    These drugs all have a very similar action on the brain and central nervous system. Upon entering the brain, these drugs act by being positive modulators, or binding to and activating (in other words) to the GABA-A receptor. They do nothing else (except alcohol only which enhances dopamine and opioid activity as well). So, what good is this?

    GABA is the second most common neurotransmitter in the brain. A size able minority of all neurons are GABA neurons. When GABA passes between neurons, it acts to inhibit signaling. It acts as a "dampener" on the nervous system. Unlike opioids and stimulants, GABA neurons are widespread in the brain. So, if you think about it, any excited process in the brain can be "dampened" or "cancelled out" by increasing GABA levels.

    Now here is the key. Unlike stimulants and opioids, downers are not intrinsically euphoric. Just "turning down" the brain's volume does not lead to pleasure. UNLESS the person is experiencing overly intense stimulation or intrusive thinking such as anxiety, insomnia, jitteriness, etc. in those states, norepinephrine has controlled the brain and it is overly excited. But by taking a downer, this excessive activity can be turned down so that the user is left in a non-euphoric, but certainly CONTENT and relaxed state.

    This is why downers are not as maliciously addictive as opioids or stimulants.

    4. Cannabis

    Cannabis and other cannabinoids such as the famous JWH chemicals all share a common mechanism once reaching the central nervous system. They all bind tightly to receptors aptly (and rather in-inspired-ly) named Cannabinoid receptors. There are two types and we will focus on CB1 as it is the one responsible for the high.

    Worth noting is that one of the reasons people want real medical Marijuana is that many chemicals in Cannabis are CB2 agonists which are responsible for many of the plant's seemingly miraculous physical cures. Marketing just THC leaves out many useful compounds.

    CB1 receptors are actually very similar to opioid receptors. They act by inhibiting the normal flow of Neurotransmitters on the neurons on which they lay. But the difference between these and opioid receptors is that CB1 receptors show up in many completely different brain regions than the opioid ones.

    Now, it is imperative to note that, like mu opioid receptors, CB1 receptors are located in the Nucleus Accumbens and can disinhibition dopamine in the Mesolimbic pathway. This is the reason Cannabis makes you feel content and happy. However, let's look at some of the other areas affected.

    In the mid-brain, there exists neurons which communicate using Acetylcholine. So, for a message to make it to the next neuron, acetylcholine must pass the synapse. Interestingly, these brain regions are implicated in memory formation, time sensation, and spatial orientation. So, CB1 receptors, when activated by something like THC, inhibits the flow of acetylcholine in this region.

    So what? Well, it means that signals relating to processing the sensory input of the environment are disrupted. It means that some setting that you have been in a hundred times can seem like it is brand new. This is a euphoria-neutral effect. It can actually lead to the paranoia associated with Cannabis excess consumption because you end up depersonalized and confused.

    But it is important to note that CB1 receptors are NOT located in the brain stem (unlike opioid receptors) which means that your vital signs will not be "dampened" to the point of death. Thus, pot is very safe physically (and generally mentally).

    One other interesting thing is the love for music that pot smokers profess. Possible explanation for this is that when listening to a song stoned, since the normal sensory gating mechanism is disrupted, the sounds seem novel and amazingly complex. Combine this with opioid-esque euphoria and you could have an amazing musical experience.

    5. Empathogens and Psychedelics (MDMA, MDA, LSD, shrooms)

    I will attempt to "lump" together these two rathe broad categories of drugs because they share a key similarity in how they work. Whereas so far, our focus on euphoria from drugs has been on the neurotransmitter Dopamine, or to a lesser extent, Norepinephrine. But now we are going to look at the "neglected" Monoamine called SEROTONIN. Just like the other Monoamines, there is the neurotransmitter Serotonin, and there are Serotonin receptors. These receptors are activated by serotonin AND agonist molecules.

    Empathogens like MDMA act to flood the brain with the neurotransmitter serotonin. But the psychedelics like shrooms work as agonists to serotonin receptors. This is a key difference and we will thus examine it. But I will focus, like I said in my thesis, on drug induced euphoria. We all know that psychedelics are not known for simple euphoria but for their more subtle aspects. We will not discuss them simply because I could write a book on that!

    So empathogenic drugs work as Serotonin Releasing Agents. Remember the SERT protein? It is the recycling molecule for serotonin. If too much serotonin is in the synapse, SERT cleans it up and recycles the molecule. Ok. So what? Well, just like Amphetamine reverses the action of DAT, flooding the brain with unnatural levels of Dopamine. But SERT inhibition by things like MDMA flood the brain with immense surges of the transmitter Serotonin. what!? Well we have to look at what excess serotonin does. The post synaptic serotonin receptors need to be examined. About 90 percent of serotonin receptors are of the 5-HT1A variety. So, naturally, if there is a flood of serotonin in the brain, these receptors will be activated, as serotonin is their natural agonist. So what do these receptors do? Well, they do a few things. First, they inhibit excess cortisol and norepinephrine, leading to a calm and serene state (recall opioids do this too...). Second, they release in great quantities certain hormones. Mainly they lead to the release of Oxytocin. This hormone promotes social togetherness and bonding between people. NOW we are starting to see some MDMA related stuff.

    In addition to Oxytocin, excess testosterone is inhibited and vasopressin is regulated and normalized. All of this together leads to incredibly serene and tranquil states of mind that are very conducive to peaceful social situations.

    Also, MDMA is a mild dopamine releasing agent, so combining that with this 5-HT1A business leads to the unique euphoria of the empathogens.

    Psychedelics (well technically just the serotonErgic ones like LSD, DMT, and Shrooms) act as agonists (well technically partial agonists) of a select collection of serotonin receptors. Interestingly, they act on the serotonin receptors that are uncommon in the brain. Unlike the 5-HT1A, these drugs act on things like the 5-HT2A and 2C. Again, I will not explain how the psychedelia of these drugs is achieved. I will explain it if someone in the thread wants to find out. It is rather complex however, but I am sure you can understand it. Pharmacology should not be restricted to the "elites." I think all people can and should understand it.

    So, to conclude, the psychedelic euphoria is mainly a subjective euphoria. The insights and epiphanies gained under their influence can unlock some amazing cognitive functions and ways of thinking. These epiphanies, while not innately euphoric in a dopaminergic sense, are incredibly important and valuable.

    This is the last update to the main post. Thank you!
  2. Great read! I'll be looking froward to your future postings on the subject.
  3. walsh

    walsh Senior Member

    Nice thread.

    It might be a bit confusing to people when you refer to 'GABA neurons'. GABA is just a neurotransmitter, but you make it sound like there are neurons specifically devoted to their storage and release.
  4. etkearne

    etkearne Resident Pharmacologist

    There are GABA neurons. By that, it means that they are neurons for which the primary receptor present on their axons and synapses is the GABA receptor.

    I hope that clears it up for everyone.
  5. guerillabedlam

    guerillabedlam _|=|-|=|_

    Interesting thread and it has already answered a question I was pondering a few days ago. I assume that the activation of Dopamine by inhibiting Gaba can also play a role in why opiates can be addicting as Dopamine is generally regarded as a 'reward' neurotransmitter.

    I do have a couple questions though...

    1) Salvia Divinorum is also a potent Kappa Opioid agonist and generally is not regarded as euphoric, is this because it's not an alkaloid or is there any other theories you can posit on why that may be?

    2) Opioids are well known for relieving pain, Pain receptors are located throughout the body, so how do opiates work at doing this?
  6. etkearne

    etkearne Resident Pharmacologist

    Kappa opioid receptors act in different regions than the mu receptors. They are not in the NucAcc or Mesolimbic system. They are mainly on Glutamate bearing neurons. So, since they inhibit, the kappa opioid agonists are basically glutamate antagonists, or NMDA antagonists. That is why Salvia is a dissociative

    Opioids kill pain because they inhibit neurons coming to the brain from the spinal cord carrying pain messages via Substance P (a neurotransmitter). Thus, the pain signal never reaches the cortex, so we don't process why we are in pain, thus, we experience analgesia. I find opioids fascinating in their mechanism of action, even completely independent of their euphoric properties.

    I think you will like my description of MDMA which is coming soon!
  7. guerillabedlam

    guerillabedlam _|=|-|=|_

    I don't know much regarding opiates but from what I've read, Oxycodone acts as a kappa opioid agonist as well, surely you wouldn't classify that as a disassociative?
  8. etkearne

    etkearne Resident Pharmacologist

    This commonly cited statement about OC being a kappa agonist is based off of an old (I believe Japanese) study that hypothesized OC acted on kappa receptors. However, MOST mainstream phamacologists I have encountered in peer reviewed journal articles I have read dismiss this study because OC shows all of the hallmark traits of being primarily a mu agonist.

    However, it is theorized that certain people react to different opioids erratically. The opioid Demerol is a good example. It is conclusively shown to be both a mu and kappa agonist. For some people, it barely touches the kappa and for others, their raving hallucinations and delusions (due to kappa activity) make the drug impossible to use.

    I find it all fascinating! I wish they would do more conclusive studies on Oxycodone simply because so many people take it for pain management.

    Also worth noting is that kappa antagonists are good antidepressants on their own.
  9. etkearne

    etkearne Resident Pharmacologist

    Ok. I just finished writing my last update to the main post at the top. I will now take questions on what was presented, concerns, and corrections.

    More importantly, I will also take requests to explain the pharmacology of specific drugs you may be curious about but that I did not cover. So please, have fun reading, and keep the conversations going.

    If this can be stickied, I would immensely appreciate it.
  10. NoxiousGas

    NoxiousGas Old Fart

    nice :2thumbsup:
  11. etkearne

    etkearne Resident Pharmacologist


    Dissociatives: (such as Ketamine, Dextromethorphan, PCP)

    These drugs have absolutely fascinating effects on the mind, but to keep with the theme here, I am only going to discuss the methods by which they induce euphoria or good-feelings. Now, similarly to my post on Psychedelics, these drugs are radically different from the opioids and stimulants as euphoria is NOT their main effect, and in fact, one can have a completely wonderful and meaningful dissociative experience with absolutely no euphoria. It is rather subjective.

    However, pharmacologically-speaking, there ARE some things that point to euphoria in these substances. So lets take a look at a new group of receptors in the brain: The NMDA-Glutamate Receptors. These are literally the most common receptors in the Central Nervous System. What they do, normally, is act as a coincidence detector. For a 'positive' signal to pass down the lane in the brain, most neurons utilize glutamate. It is thus an 'excitatory' transmitter. That doesn't mean it excites the person, but simply that it allows for messages to be continuously passed down the lane.

    But for NMDA receptors to activate, spilling their glutamate-guts down the lane, not only do they need glutamate to bind to it, but also glycine. This prevents the brain from sending FALSE SIGNALS. I think it is fucking brilliant that the human mind evolved something so clever, but I digress.

    How dissociatives work is by antagonizing NMDA receptors. They PREVENT signals from going 'down the lane.' So even if glycine is present, the NMDA receptor WON'T activate since it's glutamate is being tampered with by the drug, say Ketamine. So what does this do (say Ketamine)?

    Well, if Ketamine disrupts the brain's normal ability to send messages around itself, some 'funny' things occur. The brain gets rather confused by itself. One reaction is simply to 'depress' brain function leading to a quasi-comatose state (that is why you can o/d on Ketamine AND why they use it as anesthesia) Also, however, the brain can spontaneously 'make up' signals. This is the brain's half-assed way of 'guessing' what the previous neuron was trying to send.

    Why this is relevant to euphoria is that in this comatose, guessing-game state, the brain can come up with some pretty intense frameworks. In fact, it allows some subconscious ideas to come to the surface while completely REPRESSING usual, negative thinking patterns. Say you are typically a 'glass-half-empty' person. Your general outlook on life is a bit dreary and depressing.

    Well, with NMDA antagonization, your brain is able to "shed" that way of thinking and sort of "re-boot" itself. And in the process, new, more subconscious ways of thinking (for example, better coping skills) can surface. This is the essence of euphoria from a dissociative. It RE-BOOTS your brain.

    So, if you weren't a depressive to begin with, little euphoria would probably result. But, frankly, most people now-a-days are negative thinkers, so most people would experience positive mood lift on NMDA-antags. This is being picked up by experimental psychopharmacologists in places like Hopkins. They are giving low dose injections of Ketamine to treatment-resistant depression patients and the results are PROMISING!

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