Posted by Ame Sans Vie on August 3, 2003, at 16:33:26
In reply to The effects of illegal drugs..., posted by Rickson Gracie on August 3, 2003, at 7:50:31
> Although I know alot about drugs used for mood disorders,I have no knowledge of illegal drugs.Not that I want to try them I was wondering which neurotransmitters they effect in the brain.
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HOW DOES LSD GIVE HALLUCINATIONS AND THE MIND-ALTERING EFFECTS?
First of all, it may be helpful to know that drugs such as LSD-25, dimethyltriptamine (DMT), and psilocybin (the active constituent of "magic mushrooms") are all part of a class called indoleamines. Id est, they all contain indole rings in their molecular structures that closely resemble the makeup of serotonin. It is due to this similarity that these drugs are able to mimic serotonin in the central nervous system and act at its receptors, thus inhibiting the firing of serotonin neurons.
The effects of LSD are primarily exerted in the serotonergic systems of the raphne nuclei (R.N.) and locus coeruleus (L.C.) parts of the brain. On the serotonin neurons themselves, there seem to be two main types of receptors to which LSD and 5-HT both can attach. The two types are known as the 5HT1 receptors, usually part of pre-synaptic neurons, and the 5HT2 receptors, which are usually on the post-synaptic neuron. When a molecule becomes chemically attached to 5HT1 receptors of the serotonin producing neurons, the neuron slows or stops its production of serotonin, creating a negative feedback loop, where excess serotonin will halt further production. When a molecule binds to the 5HT2 receptors, the post-synaptic neuron is inhibited, and it is more difficult for it to generate an action potential. Apparently, serotonin will attach itself to either of these two receptors with equal frequency, but it has been proposed that LSD prefers the 5HT1 type to the 5HT2 type.
Much of LSD's action is hypothesized to take place in the R.N., a small area of the brain which contains most of the brain's serotonergic cells. The R.N. is connected to many other areas of the brain, which could explain why such a tiny dose of this potent substance can cause such mind-blowing experiences.
The first postulated mechanism for the action of LSD involved its possible affinity for pre-synaptic 5HT1 receptors. It was believed that the presence of LSD would flood the 5HT1 receptors, which would force the serotonergic pre-synaptic neuron to cease serotonin production. This would lead to an increase in post-synaptic activity. All effects of LSD were believed to have their roots in this theorized suppression of serotonin.
Among researchers, much importance is placed on the effects of LSD in the R.N., because it is a small area of the brain which contains most of the brain's serotonergic cells. Part of the function of the R.N. is postulated to be the protection of the brain from over-stimulation and sensory overload. It is also connected to many other areas of the brain, which if LSD action is truly based in the R.N., would explain how such small doses can create such wide-ranging sensory and hallucinatory effects.
LSD's effects on 5HT2 receptors have been a subject of considerable debate. This debate mainly circles around whether LSD inhibits the 5HT2 receptors' uptake of serotonin, or whether it facilitates the uptake. In other words, we are currently unsure whether it is agonistic or antagonistic at these receptors.
The current theory, which is attempting to resolve the debate without going against the accumulated evidence, is that LSD is only a partial agonist. According this this explanation, the LSD molecule is more attracted to the post-synaptic 5HT2 receptors than the 5HT molecule. Once it is attached to the 5HT2 receptor, LSD can cause the same effect as normal serotonin (i.e. the dampening of post-synaptic neural activity), but it would do so much less effectively than serotonin. Thus, in experiments where the synapses being tested were devoid of natural serotonin, LSD appeared to be agonistic, functioning as serotonin. However, when judged against the normal activity of serotonin, the LSD, with the higher receptor affinity, blocked the serotonin and the system behaved as if serotonin was reduced, because the less effective LSD was acting instead of the more effective serotonin. This theory of partial agonism seems to be the most promising currently.
Regarding LSD's mechanism of action in causing "hallucinations" (more properly referred to as "sensory abnormalities" or "visuals", since true hallucinations require that the subject not know that what they are sensing isn't really there -- most users of LSD realize that it is only a trip), as mentioned earlier, much of LSD's action is within the R.N., which is part of the ascending reticular activing system. Serotonin inhibits ascending traffic in the reticular system, most likely to protect the brain from sensory overload. Obviously, interruption in normal serotonin activity would result in excitation of various sensory modalities, resulting in "hallucinations" and altered sensory perception in other ways.
LSD may have other modi operandi than those outline above -- it seems to have an affinity for histamine, acetylcholine, dopamine, epinephrine, and norepinephrine receptors as well as serotonin. Further research is needed.
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HOW DOES MDMA GIVE INTENSE FEELINGS OF LOVE?
MDMA, like the indoleamines, is a primarily serotonergic drug. It blocks the reuptake of serotonin (5HT), similar in this regard to SRI-type drugs (e.g. Prozac, Zoloft, Anafranil). Unlike these drugs, however, MDMA appears to enter the neuron, either via passive diffusion or directly through the reuptake transporter, and causes the release of 5HT. The resulting released 5HT then enters the synaptic cleft through the 5HT transporter; thus, MDMA acts on 5HT similarly to the way amphetamines act on dopamine. As MDMA is a substituted amphetamine (3,4-methylenedioxy-N-methamphetamine), this comes as little surprise.
It is postulated that this efflux of 5HT into the synaptic cleft, and subsequent action of this 5HT on pre- and post-synaptic binding sites, is central to MDMA’s neuropharmacology. MDMA, however, has micromolar potency for the 5HT2, muscarinic M1, alpha-2 adrenergic, and histamine H1 receptors. Agonist properties at the 5HT2 receptor have been found to be fairly universally associated with classical psychedelic drugs (i.e. LSD, psilocybin, mescaline). It is possible that some of MDMA’s “psychedelic effect”, however limited that effect may be (at least in low-normal doses of around 75-150mg) occurs due to interactions with this receptor.
The alpha-2 adrenergic receptor is more than likely associated with some of cardiovascular effects of MDMA.
MDMA also releases dopamine, which may be central to both its psychological action and to its neurotoxicity in animal studies. Pre-treatment of an animal with a drug which blocks dopamine release will also block MDMA neurotoxicity. Also, serotonin-specific releasing agents which are non-dopaminergic have been synthesized and found to be devoid of MDMA’s neurotoxicity in animals. They have also been found to be devoid of MDMA’s psychological effects. MDMA tends to indirectly *inhibit* the firing and release of dopamine in nigrostriatal dopamine neurons (neurons projecting from the substantia nigra to the striatum) due to local 5HT release.
MDMA doses of around 20mg per kg of body weight in animals have been shown to reduce levels of tryptophan hydroxylase, which is the rate-limiting enzyme in 5HT synthesis. It is thought that this occus because of oxidative stress which MDMA places on the neuron. This oxidative stress may occur through several channels (i.e. the metabolism of MDMA into a toxic Quinoid, 5HT derived toxins, 5HT-mediated cellular events, temporary inhibition of monoamine oxidase) and the exact mechanism is presently unknown. It is hypothesized that this oxidative stress also leads to the neurodegenerative destruction of 5HT axons which is observed to occur with large doses of MDMA in animals. Anti oxidants, anti-dopaminergic agents, agents which block intracellular calcium increases, and pre- or post-treatment with fluoxetine all block MDMA’s neurotoxicity. Research is ongoing to determine the exact mechanism of MDMA-induced toxicity.
It is most likely MDMA’s release of a flood of serotonin into the brain that accounts for its empathogenic qualities (i.e. intense feelings of love, peace, and harmony).
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HOW IS THE HIGH FROM HEROIN ESTABLISHED?
Heroin has effects not at all unlike other common opioids drugs. There are three important neurotransmitters that relate to heroin: dopamine, norepinephrine, and the endorphins.
Dopamine helps to control human appetites for both food and sex. Large amounts of this substance are also associated with being out-going and exuberant. Parkinson's Disease and often depression are related to having too little dopamine in the brain whereas schizophrenia is related to having too much. Heroin, like nearly all drugs that cause a high, causes a release of dopamine.
Norepinephrine governs the sympathetic nervous system—the nerves of the body that cannot be voluntarily controlled. Its primary purpose is to stabilize blood pressure so that it does not get too low. When a provocative situation arises, the brain's release of this substance stimulates the “fight or flight” response. Heroin depresses the middle brain—the locus coeruleus, in particular—and so provides the user with the opposite feelings: safety and contentment.
There are sites in the body—primarily in the brain and spinal cord—called opioid receptors which are involved in happiness and feelings of safety. These sites were originally discovered by scientists searching for mechanisms that allowed morphine to cause pleasure and relieve pain. All of the opioids (e.g. morphine, codeine, meperidine, pentazocine, oxymorphine, tramadol) attach to these sites where their effects are felt. There are at least five different types of opioid receptors, but only four that are closely associated with the effects of the opioids: mu (µ), kappa (κ), delta (δ), and sigma (σ). The µ and κ sites affect pain relief, the δ sites are involved with feelings of euphoria, and the σ sites relieve depression. In the body, diacetylmorphine (heroin) is converted rather quickly into morphine, which is the principal medical alkaloid of opium. Its effect at the µ-receptors in the central nervous system is said to be responsible for analgesia, euphoria, dependence potential and respiratory depressions. Morphine also binds with κ-receptors which mediate spinal analgesia, miosis and sedation.
It makes sense that the body would not have these receptors unless it created its own chemicals which would fit into these sites and before long, scientists had discovered endorphins—morphine-like chemicals used by the body for many purposes but primarily to modulate mood, promote pleasure, and manage reactions to stress.
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HOW DOES GHB AFFECT THE BRAIN TO PRODUCE EUPHORIA?
Although many neurotransmitter systems are affected by treatment with γ-Hydroxybutyrate (GHB), the dopaminergic system is consistently altered by GHB. Treatment with GHB has been mainly shown to inhibit dopamine release. Although some studies have shown that GHB initially inhibits dopamine release and then causes a time-dependent release, this has subsequently been found to have been a result of experimental errors (i.e. ignoring the effects of anaesthetics, or having unusually high levels of Ca2+ in the growth medium).
The mechanism of how GHB affects dopamine and the CNS in general is unclear, but it is almost certainly mediated by either the GABA-B receptor or the putative GHB receptor. The evidence that GHB affects the GABA-B receptor is threefold. On a behavioral level, antagonizing the GABA-B receptor stops animals from identifying GHB in drug-discrimination tests3. On a cellular level, GHB causes a pronounced hyperpolarization of nerve cells, and this effect is blocked by GABA-B antagonists but not by GHB receptor antagonists. Finally, on a molecular level GHB binds (although weakly) to the GABA-B receptor, showing its own innate agonistic properties. It is possible that GHB could also be metabolized to GABA (although this seems unlikely) or releases GABA in pathways expressing the GABA-B receptor.
The putative GHB receptor is a novel binding site, showing its own properties, as far as agonists, antagonists and binding profiles are concerned, and is now widely believed to be a molecularly distinct receptor, although its sequence has not been identified. Importantly, the putative GHB receptor exhibits an extremely high affinity to GHB. Certain frontal lobe neurons become hyperactive in animals treated with GHB, presumably because the cells are normally inhibited by dopamine, but due GHB's lowering of the release of dopamine, this inhibition is partially ablated. This hyper activity can be attributed GHB receptor activation, because when the animal is then treated with the selective GHB-receptor antagonist NCS-382, the cells dose-dependantly revert to their normal firing rate.
Both the GHB and GABA-B receptor systems have been shown to be inhibitory in nature (meaning that increasing activation of these receptors reduces the activity of associated systems), explaining many of GHB’s actions. It also explains why GHB can be so dangerous in combination with alcohol, benzodiazepines, barbiturates and other GABAergic sedatives. Although the exact nature of the putative GHB receptor has not been identified, it is known to be distributed in the hippocampus, cortex and dopaminergic structures and hence would be consistent with areas implicated by the known effects of GHB. Even though the GHB receptor may be responsible for GHB's ability to induce seizures, it seems that the GHB receptor is not the main mediator of GHB's subjective effects. A recent report showed that most behavioral effects of GHB were not significantly affected by GHB receptor antagonists. Interestingly, it has been shown that GHB receptor antagonists inhibit GHB's effect on dopamine, and hence, GHB's effect on dopamine is not considered important in mediating GHB's behavioral effects.
Although the scientific community isn't in agreement, in light of the evidence available to date, it seems that GHB's subjective "high" and behavioral effect is due mainly to its effect on the GABA-B receptor and not the GHB receptor or dopamine blockade and release. Although the GHB receptor appears to be responsible for many physiological changes seen during treatment with GHB, the ultimate mediator of the response is the GABA-B receptor. How GHB affects the GABAB receptor is unclear: It may be through metabolism of GHB to GABA, or more likely, via release of GABA. It is possible that there may be sub-groups of GHB receptors, or that GHB is an allosteric modulator of the GABA-B receptor. It is likely that the question of GHB's exact mechanism will remain unanswered until the GHB receptor is isolated and sequenced, and its properties are better understood.
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HOW DOES ALCOHOL AFFECT YOUR MIND TO GET YOU DRUNK?
Ethanol affects different cerebral neurotransmitters. One of them is the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
The interaction between ethanol and the GABA receptor is evident in studies showing decrease in the symptoms of alcoholic-withdrawal syndrome by the use of substances that increase GABA activity, like GABA-reuptake blockers and benzodiazepines, thus demonstrating the possible influence of the GABAergic system on the physiopathology of human alcoholism.
Ethanol potentiates GABA-receptor actions via a mechanism independent of benzodiazepine-receptor.
Low alcohol concentrations could promote facilitation of GABAergic inhibition on the cerebral cortex and spinal cord.
Some phenomena observed in alcoholism, such as tolerance and dependence, could be explained by the effects consequent to chronic ethanol exposure.
The quick tolerance to the increased chloride influx mediated by GABA begins already in the first hours and becomes established during chronic alcohol use.
Alcohol selectively modifies the cerebral synaptic action of glutamate. The glutamatergic system, whose neurons use glutamate as neurotransmitter, and is one of the main excitatory pathways in the central nervous system, also seems to play a relevant role in the nervous alterations induced by ethanol. Glutamate is the major neuroexcitatory neurotransmitter in the brain, accounting for 40% of all synapses.
Post-synaptic actions of glutamate in the central nervous system are mediated through two types of receptor: One of them is the inotropic receptor, related to ionic channels causing neuronal depolarization. The second type of receptor is the metabotropic (since its answers need cellular signalization metabolic steps); its intracellular actions are mediated by G-protein.
One of the inotropic glutamate receptors has two families diferentially identified by their pharmacological, biophysical, and molecular characteristics. In the first family we find the NMDA (n-metil-D-aspartate receptor), voltage-dependent, that sustains the currents, and is associated with ion channels permeable to calcium, sodium and potassium. In the second family of glutamate receptors we find the AMPA/Ka, whose preferental agonist is a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
Glutamate participates in synaptic plasticity and in long term potentiation, and it seems to play a critical role in memory and cognition.
The prevailing eletrophysiological effect of ethanol is the reduction of excitatory glutamatergic neurotransmission. It has been observed that low concentrations of ethanol can inhibit the stimulating actions mediated by NMDA upon hippocampal cells in culture.
In concentrations associated to "in vivo" intoxication, ethanol inhibits NMDA receptor current.
These findings could also explaim part of the genesis of physical dependence to alcohol, through a process that is the opposite to that of GABA. That means that when ethanol is interrupted, glutamatergic pathways induce overexcitement of the central nervous system, causing convulsions, anxiety, and delirium.
Calcium influx into the cells has an important function in the release of neurotransmitters in the synaptic cleft, as well as in the activity of cellular second messengers. Ethanol, in concentrations of 25mM, seems to inhibit calcium flow through ionic channels, thus decreasing neurotransmitters release. This could also be one of the mechanisms responsible for dependence and tolerance, because when alcohol-intake is stopped these ionic channels would increase calcium influx and, consequently, neurotransmission, giving rise to signs and symptoms of withdrawal syndrome.
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I KNOW COCAINE IS A DOPAMINE AGONIST, BUT THAT’S ALL I KNOW.
You’re certainly right about that – methylbenzoylecgonine (cocaine) is a powerful dopamine agonist, amongst other things.
Cocaine acts primarily on the sympathetic nervous system, the part of the CNS that is responsible for the familiar “fight or flight” response. It does not exert effects in the more rational areas of the brain known as the cortex, whose function is to inhibit the more primitive areas of the brain (i.e. the sympathetic nervous system).
The rewarding effects of cocaine are mediated by its activation of dopamine in the mesolimbic and mesocortical pathways. Cocaine results in increased release and/or blocking of the reuptake of neurotransmitters such as dopamine and norepinephrine from nerve cells. More specifically:
1. Cocaine blocks the reuptake of dopamine, norepinephrine, and serotonin.
2. Cocaine creates increased synaptic dopamine levels.
3. Cocaine causes increased dopamine neurotransmission.
4. Cocaine causes subsensitivity of postsynaptic dopamine, norepinephrine, and serotonin receptors.These effects lead to chronic alterations in neurotransmitter production and reuptake:
1. Supersensitivity to dopamine, norepinephrine, and serotonin receptors.
2. Increased numbers of post-synaptic dopamine receptors.
3. Decreased brain dopamine metabolites.
4. Inhibited dopamine vesicle binding.
5. Increased tyrosine hydroxylase activityThrough reuptake blockade, cocaine allows neurotransmitters (particularly dopamine) to remain in the synapse and provide more intense neural stimulation. This results in an increase in the number and sensitivity of post-synaptic neurotransmitter receptors. However, cocaine-induced blockade of neurotransmitter re-uptake impairs production, causing a chronic depletion. The sustained neurophysiologic changes in the dopamingergic/noradrenergic systems (which regulate mood states) are responsible for the psychological symptoms of cocaine addiction and withdrawal.
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HOW IS IT THESE DRUGS CREATE SUCH EUPHORIC STATE, WHILE SOME SEROTONIN (SSRI’S), TCA’S, AND OTHER PSYCHIATRIC DRUGS DO NOT GIVE THE SAME FEELINGS AS ILLEGAL SUBSTANCES?
Many principles apply here, one being delayed gratification. SSRIs, TCAs, MAOIs, etc., while they may possess some of the same pharmacological qualities as illicit drugs, take weeks to take effect. This is in contrast to illicit drugs, which exert immediate effects, thus the user is instantly gratified and can easily make a comparison between the “high” state they’re currently in with the sober state they were in an hour or two earlier.
Another very important factor is that psychiatric medications are prescribed for a reason—you have a dysfunction in one or more neurotransmitter systems to begin with. Thus, the effects of these drugs will just be to normalize your state of well-being, while in non-mentally ill persons (and even in some mentally ill persons), some of these drugs *may* cause feelings of euphoria (i.e. Effexor, MAOIs).
> I am interested in how these drugs affect certain neurotransmitters.....Serotonin,NE,Dopamine,GABA
> Or do they hit other thing in your body?
> I am in no way condoning the use of these drugs but am curious on how they work.
> ThanksWell, I hope the above answered your questions... anything else you'd like to know or think that I've left out, feel free to ask. :-)
poster:Ame Sans Vie
thread:247730
URL: http://www.dr-bob.org/babble/20030802/msgs/247806.html