Dopamine Receptors And Their Behavioural Affects

[Neuroprotection]

Apologies if there’s already a thread discussing this, I am blind and using my phone to access the Internet, so I easily miss things.
Since dopamine modulates so many behaviours including but not limited to; pleasure, motivation, memory, sleep/wake cycle and addiction, I feel that dopamine deserves its own thread.
Whilst I would welcome any discussion about dopamine and its interactions with other neurotransmitters, I am hoping for this thread to focus predominantly on discussion of topics related to dopamine signalling and its receptors, downstream pathways of these receptors and their behavioural consequences.
Some key themes I think would be extremely useful to cover are as follows:

1) major behavioural effects attributed to D1 and D2 receptors and which aspects of psychostimulant drug affects they may generate.

2) downstream pathways of dopamine receptors and how they modulate neuronal function, especially in terms of synaptic strength and glutamate receptors.

3) to try and establish exactly which dopamine receptor is responsible for stimulant and schizophrenia related psychosis and which downstream signalling pathways are responsible for this. in this regard, it would also be useful to discuss possible ways of reversing psychosis related changes.

In my next post, I hope to contribute some knowledge and post some links, though I apologise for grammatical errors and if the links appear messy since my blindness makes the process very difficult.

 

[Neuroprotection]

okay, here’s the basic knowledge I think I have got from my research so far. Note that this is only the most basic understanding and I can’t guarantee it’s accurate, so please correct me if I say anything wrong.

First of all, dopamine does directly contribute to pleasure, but is much more important in encoding the pursuit of pleasure and facilitating motivation, cognitive changes and motor activity to assist in the pursuit of that pleasure or any other salient goal.

D1 receptors through the PKA/DARPP32 pathway amongst many others, stimulate memory formation and retention. they are also involved in the immediate experience of natural and drug-related reward as well as reward related learning, habit learning, facilitation of effort exertion and problem-solving ability. D1 receptors achieve this effect, predominantly by stimulating long-term potentiation (LTP) as the PKA pathway they stimulate causes insertion of new NMDA and AMPA receptors into the postsynaptic membranes. D1 receptors are believed to play The biggest role in psychostimulant related cognitive improvement in both ADHD and healthy humans as well as the immediate rewarding/euphoric affects of these substances.

D2 receptors on the other hand are more strongly associated with alerting/wakefulness promotion/Maintaining of wakefulness, stimulation of motor activity, facilitation of impulsive/reward seeking behaviour, perhaps heightening of any contextual emotional States, facilitation of divergent/creative thinking and last, but not least, unfortunately, in states of excessive activation, the promotion of psychotic states or disorders. D2 receptors have many downstream pathways, but one of their most important is the inhibition of the PKA pathway and induction of long-term depression (LTD). this is in effect, the complete opposite of D1 receptor function. D2 receptors are supposedly more involved in the stimulation of motor activity, impulsivity, anxiety altered thought patterns etc associated with psychostimulant use. They are also largely responsible for the sensitised responses, in which the behaviours I have just mentioned intensify with repeated psychostimulant use.

Of course, this is at the most basic level of understanding. dopamine receptors can actually form heterodimers and other complexes with those in their own class, as well as other dopamine receptors from different classes and their downstream pathways and pharmacology are completely unique. This ads a whole new layer of complexity so I think it’s best to stick to individual receptors for now. also, it should be noted that dopamine receptors may have different effects, depending on which areas of the brain they are activated in and often they work together. For example, stimulation of D2 receptors in the indirect pathway of the striatum causes stimulation by decrease of GABA output, and this can have similar, but not identical effects to stimulation of D1 receptors and enhanced glutamatergic function in the direct pathway.
In terms of drug abuse, especially psychostimulants, I think the main problem arises when an imbalance between the function of these two dopamine receptors occurs. for example, initial/early stages of cocaine use are associated with strong euphoria, stimulation and acquisition of a conditioned place/drug preference. these effects are predominantly mediated by the D1 receptors, which are only activated at much higher concentrations of dopamine. however, D1 receptors quickly desensitise to regular cocaine use and D2 receptor signalling then predominates.
This apparently explains the change from euphoria/ reward and cognition enhancement to more generalised psycho motor stimulation, impulsivity, and drug seeking that occurs with regular psychostimulant administration.
Does anyone who has used psychostimulants have experience of this phenomena? on Reddit i’ve come across many reports/anecdotes of stimulant sensitisation in which chronic use of psychostimulants like amphetamine or methylphenidate results in increasingly stimulatory and uncomfortable effects with aspects of paranoid or manic behaviour. these people say they had to discontinue stimulants altogether despite initially really enjoying them. This is unusual given the highly addictive nature of this class of drugs, but from what they describe, I assume excessive D2 signalling and diminished D1 receptor signalling is involved.
Actually, I recently came across a study, which suggested that D1 receptor selective agonists could reverse established amphetamine sensitisation in animals. this apparently occurred through reversing D2 receptor supersensitivity that often occurs with repeated stimulant use or antipsychotic withdrawal.

 

[t_xeplionhell]

okay, here’s the basic knowledge I think I have got from my research so far. Note that this is only the most basic understanding and I can’t guarantee it’s accurate, so please correct me if I say anything wrong.

First of all, dopamine does directly contribute to pleasure, but is much more important in encoding the pursuit of pleasure and facilitating motivation, cognitive changes and motor activity to assist in the pursuit of that pleasure or any other salient goal.

D1 receptors through the PKA/DARPP32 pathway amongst many others, stimulate memory formation and retention. they are also involved in the immediate experience of natural and drug-related reward as well as reward related learning, habit learning, facilitation of effort exertion and problem-solving ability. D1 receptors achieve this effect, predominantly by stimulating long-term potentiation (LTP) as the PKA pathway they stimulate causes insertion of new NMDA and AMPA receptors into the postsynaptic membranes. D1 receptors are believed to play The biggest role in psychostimulant related cognitive improvement in both ADHD and healthy humans as well as the immediate rewarding/euphoric affects of these substances.

D2 receptors on the other hand are more strongly associated with alerting/wakefulness promotion/Maintaining of wakefulness, stimulation of motor activity, facilitation of impulsive/reward seeking behaviour, perhaps heightening of any contextual emotional States, facilitation of divergent/creative thinking and last, but not least, unfortunately, in states of excessive activation, the promotion of psychotic states or disorders. D2 receptors have many downstream pathways, but one of their most important is the inhibition of the PKA pathway and induction of long-term depression (LTD). this is in effect, the complete opposite of D1 receptor function. D2 receptors are supposedly more involved in the stimulation of motor activity, impulsivity, anxiety altered thought patterns etc associated with psychostimulant use. They are also largely responsible for the sensitised responses, in which the behaviours I have just mentioned intensify with repeated psychostimulant use.

Of course, this is at the most basic level of understanding. dopamine receptors can actually form heterodimers and other complexes with those in their own class, as well as other dopamine receptors from different classes and their downstream pathways and pharmacology are completely unique. This ads a whole new layer of complexity so I think it’s best to stick to individual receptors for now. also, it should be noted that dopamine receptors may have different effects, depending on which areas of the brain they are activated in and often they work together. For example, stimulation of D2 receptors in the indirect pathway of the striatum causes stimulation by decrease of GABA output, and this can have similar, but not identical effects to stimulation of D1 receptors and enhanced glutamatergic function in the direct pathway.
In terms of drug abuse, especially psychostimulants, I think the main problem arises when an imbalance between the function of these two dopamine receptors occurs. for example, initial/early stages of cocaine use are associated with strong euphoria, stimulation and acquisition of a conditioned place/drug preference. these effects are predominantly mediated by the D1 receptors, which are only activated at much higher concentrations of dopamine. however, D1 receptors quickly desensitise to regular cocaine use and D2 receptor signalling then predominates.
This apparently explains the change from euphoria/ reward and cognition enhancement to more generalised psycho motor stimulation, impulsivity, and drug seeking that occurs with regular psychostimulant administration.
Does anyone who has used psychostimulants have experience of this phenomena? on Reddit i’ve come across many reports/anecdotes of stimulant sensitisation in which chronic use of psychostimulants like amphetamine or methylphenidate results in increasingly stimulatory and uncomfortable effects with aspects of paranoid or manic behaviour. these people say they had to discontinue stimulants altogether despite initially really enjoying them. This is unusual given the highly addictive nature of this class of drugs, but from what they describe, I assume excessive D2 signalling and diminished D1 receptor signalling is involved.
Actually, I recently came across a study, which suggested that D1 receptor selective agonists could reverse established amphetamine sensitisation in animals. this apparently occurred through reversing D2 receptor supersensitivity that often occurs with repeated stimulant use or antipsychotic withdrawal.

point of blocking D2 is to prevent interest of individual in their(his/her) delusions and thus they let-go of them or temporally forget about them because they arent important to them anymore.

 

[t_xeplionhell]

point of blocking D2 is to prevent interest of individual in their(his/her) delusions and thus they let-go of them or temporally forget about them because they arent important to them anymore.

but that is very lazy way of doing it because it does more harm than good to the person. It would be better for the person to be put in jail and assigned a proper therapist.

 

[t_xeplionhell]

all delusions are mental construct and have core which can be resolved with talk theraphy and can never be truly resolved with playing god with antagonizing chemical receptors in brain.
antagonizing can have terrible consequences which are unimaginable to one who didn't experience it.
paliperidone(strong AP) caused me ton of severe side-effects which I listed in my posts in invega thread.

 

[ecstacylover]

okay, here’s the basic knowledge I think I have got from my research so far. Note that this is only the most basic understanding and I can’t guarantee it’s accurate, so please correct me if I say anything wrong.

First of all, dopamine does directly contribute to pleasure, but is much more important in encoding the pursuit of pleasure and facilitating motivation, cognitive changes and motor activity to assist in the pursuit of that pleasure or any other salient goal.

D1 receptors through the PKA/DARPP32 pathway amongst many others, stimulate memory formation and retention. they are also involved in the immediate experience of natural and drug-related reward as well as reward related learning, habit learning, facilitation of effort exertion and problem-solving ability. D1 receptors achieve this effect, predominantly by stimulating long-term potentiation (LTP) as the PKA pathway they stimulate causes insertion of new NMDA and AMPA receptors into the postsynaptic membranes. D1 receptors are believed to play The biggest role in psychostimulant related cognitive improvement in both ADHD and healthy humans as well as the immediate rewarding/euphoric affects of these substances.

D2 receptors on the other hand are more strongly associated with alerting/wakefulness promotion/Maintaining of wakefulness, stimulation of motor activity, facilitation of impulsive/reward seeking behaviour, perhaps heightening of any contextual emotional States, facilitation of divergent/creative thinking and last, but not least, unfortunately, in states of excessive activation, the promotion of psychotic states or disorders. D2 receptors have many downstream pathways, but one of their most important is the inhibition of the PKA pathway and induction of long-term depression (LTD). this is in effect, the complete opposite of D1 receptor function. D2 receptors are supposedly more involved in the stimulation of motor activity, impulsivity, anxiety altered thought patterns etc associated with psychostimulant use. They are also largely responsible for the sensitised responses, in which the behaviours I have just mentioned intensify with repeated psychostimulant use.

Thanks for posting that, I've been wondering for awhile whether it was D1 or D2 which promotes motor activity.

Also, dopamine depletion in rodents has zero effect on how much they like (i.e. find pleasurable) a particular stimulus, whereas MOR signaling plays a significant role. But of course wanting/pursuing a stimulus is a different story, and dopamine does play a significant role in that context.

 

[Neuroprotection]

Very interesting replies so far. I’ve noticed a few of you mentioned the horrifying effects of antipsychotics. yes, those are due to blockade of D2 receptors. Their are two serious issues that arise when blocking these receptors. firstly, there is the obvious suppression of motivation and interest in all life activities, which manifests as anhedonia, along with severe depression and anxiety in many cases. The second issue is enhanced LTP and glutamate signalling/toxicity in certain areas of the brain. D2 receptors play a powerful neuroprotective role by inducing LTD via removing AMPA receptors from the postsynaptic membrane especially decreasing the availability of the GLUR1 AMPA subunits. D2 receptor agonists are under investigation for depression treatment, especially to deal with the anhedonia and lack of motivation in this disorder, symptoms, which so many antidepressants have failed to treat and so many psychiatrists have ignored.

Speaking of antipsychotics, the dopamine hypothesis of schizophrenia is coming under more scrutiny and according to some studies I’ve read, it is likely that dopamine is necessary, but not sufficient to induce psychosis in schizophrenia. furthermore, it’s very interesting to note that the powerful dopamine agonist apomorphine, given at High doses to schizophrenics, did not precipitate or worsen psychosis despite being a powerful agonist of the D2 receptor.

Hopefully, a better understanding of schizophrenia pathophysiology will see antipsychotics Limited to the pages of history books and extinct from medical practice.

 

[Neuroprotection]

point of blocking D2 is to prevent interest of individual in their(his/her) delusions and thus they let-go of them or temporally forget about them because they arent important to them anymore.

Thanks for that. Probably why antipsychotics often zap the joy out of patients lives. often, being interested or obsessed with something, even if it’s a delusion, is in its self a major pleasure. this is just my personal theory but please let me know what you think. I believe that the want/drive produced by dopamine keeps us happy and going bye causing us to fix onto something and then pursue that without feeling that we have to put any conscious effort in. Basically, it kind of does the thinking for us. furthermore, when you’re fixed on trying to pursue a reward or goal, emotions like anxiety and stress are either suppressed or cast aside. I recently read that D2 receptors, by virtue of their induction of LTD can directly suppress anxiety in certain brain areas.

 

[Serhat]

Dopamine indeed plays a crucial role in a variety of physiological and behavioral processes, and understanding its signaling pathways and receptor functions is critical for elucidating its role in various disorders, including addiction and schizophrenia.

1. D1 and D2 receptors are two major subtypes of dopamine receptors, and they have distinct roles in modulating behavior and the effects of psychostimulant drugs. D1 receptors are generally associated with excitatory effects, whereas D2 receptors are associated with inhibitory effects. Activation of D1 receptors often enhances motivation and reward-related behaviors, whereas activation of D2 receptors can have the opposite effect. Psychostimulant drugs, such as cocaine and amphetamines, increase dopamine levels in the brain and can lead to increased activation of both D1 and D2 receptors, which may contribute to their reinforcing and addictive properties.
2. The downstream pathways of dopamine receptors are complex and involve multiple signaling molecules and effector proteins. Activation of D1 receptors typically leads to activation of the adenylate cyclase-cAMP-PKA pathway, which can modulate the function of various ion channels and proteins involved in synaptic transmission. Activation of D2 receptors, on the other hand, inhibits adenylate cyclase activity and can lead to modulation of potassium and calcium channels. These signaling pathways can influence synaptic strength and the function of glutamate receptors, which are critical for synaptic plasticity and learning and memory.
3. The role of dopamine receptors in stimulant-induced and schizophrenia-related psychosis is still not fully understood, and it is likely that multiple receptor subtypes and signaling pathways are involved. Both D1 and D2 receptors have been implicated in the pathophysiology of schizophrenia, and antipsychotic drugs often target D2 receptors to reduce positive symptoms of schizophrenia, such as hallucinations and delusions. However, the exact mechanisms by which dopamine receptor signaling contributes to psychosis and how antipsychotic drugs reverse these changes are still areas of active research.

It's great that you are planning to contribute further to this discussion and share some links. Please don’t worry about any grammatical errors or messy links; your effort to participate and share knowledge is highly appreciated. Looking forward to your next post.

 

[Neuroprotection]

Here’s a nice review that I think summarises dopamine affects on ion channels and neuronal plasticity.

Modulation of the glutamatergic transmission by Dopamine: a focus on Parkinson, Huntington and Addiction diseases

Dopamine (DA) plays a major role in motor and cognitive functions as well as in reward processing by regulating glutamatergic inputs. In particular in the striatum the release of DA rapidly influences synaptic transmission modulating both AMPA and NMDA ...

www.ncbi.nlm.nih.gov

Here’s an article on dopamine and motivation, not read this yet, but I will do soon hopefully.

Dopamine in motivational control: rewarding, aversive, and alerting

Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but non-rewarding ...

www.ncbi.nlm.nih.gov

 

[Neuroprotection]

Dopamine indeed plays a crucial role in a variety of physiological and behavioral processes, and understanding its signaling pathways and receptor functions is critical for elucidating its role in various disorders, including addiction and schizophrenia.

1. D1 and D2 receptors are two major subtypes of dopamine receptors, and they have distinct roles in modulating behavior and the effects of psychostimulant drugs. D1 receptors are generally associated with excitatory effects, whereas D2 receptors are associated with inhibitory effects. Activation of D1 receptors often enhances motivation and reward-related behaviors, whereas activation of D2 receptors can have the opposite effect. Psychostimulant drugs, such as cocaine and amphetamines, increase dopamine levels in the brain and can lead to increased activation of both D1 and D2 receptors, which may contribute to their reinforcing and addictive properties.
2. The downstream pathways of dopamine receptors are complex and involve multiple signaling molecules and effector proteins. Activation of D1 receptors typically leads to activation of the adenylate cyclase-cAMP-PKA pathway, which can modulate the function of various ion channels and proteins involved in synaptic transmission. Activation of D2 receptors, on the other hand, inhibits adenylate cyclase activity and can lead to modulation of potassium and calcium channels. These signaling pathways can influence synaptic strength and the function of glutamate receptors, which are critical for synaptic plasticity and learning and memory.
3. The role of dopamine receptors in stimulant-induced and schizophrenia-related psychosis is still not fully understood, and it is likely that multiple receptor subtypes and signaling pathways are involved. Both D1 and D2 receptors have been implicated in the pathophysiology of schizophrenia, and antipsychotic drugs often target D2 receptors to reduce positive symptoms of schizophrenia, such as hallucinations and delusions. However, the exact mechanisms by which dopamine receptor signaling contributes to psychosis and how antipsychotic drugs reverse these changes are still areas of active research.

It's great that you are planning to contribute further to this discussion and share some links. Please don’t worry about any grammatical errors or messy links; your effort to participate and share knowledge is highly appreciated. Looking forward to your next post.

Thanks for your encouragement.

Just posted some links, i’ll start with two as they are very detailed. unfortunately, I can’t find the Study for this, but I’ve read that dopamine D1 receptors can have some paradoxical effects in the nucleus accumbens, for example decreasing neuronal activity which directly generates a rewarding response. this is at odds with the D1 mediated enhancement of LTP/Insertion of GLUR1 AMPA receptors into the membrane. my favourite transcription factor DELTA FOSB works to enhance the effect of dopamine in the nucleus accumbens via up-regulation of GLUR2 subunit of the AMPA receptor. AMPA receptors containing GLUR2 subunits are generally impermeable to calcium and have lower overall conductance. this magnifies the inhibition of nucleus accumbens reactivity thus greatly magnifying reward sensitivity and inducing resilience to stress. basically, I believe that DELTA FOSB mediated over expression of GLUR2 could encourage dopamine D1 receptors in the nucleus accumbens to paradoxically act in an inhibitory manner more often and with greater efficiency. again, in reference to paradoxes with D1 receptors, this study shows that activation of these receptors using a selective agonist is highly rewarding in morphine dependent animals but is not so in those that are opioid naive.

Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats

Chronic opiate administration induces neuro-adaptations within the nucleus accumbens (NAc) and ventral tegmental area (VTA) that can contribute to dependence. We have shown that morphine dependence shifts the behavioral consequences of D1 dopamine (DA) ...

www.ncbi.nlm.nih.gov

 

[Serhat]

Thanks for your encouragement.

Just posted some links, i’ll start with two as they are very detailed. unfortunately, I can’t find the Study for this, but I’ve read that dopamine D1 receptors can have some paradoxical effects in the nucleus accumbens, for example decreasing neuronal activity which directly generates a rewarding response. this is at odds with the D1 mediated enhancement of LTP/Insertion of GLUR1 AMPA receptors into the membrane. my favourite transcription factor DELTA FOSB works to enhance the effect of dopamine in the nucleus accumbens via up-regulation of GLUR2 subunit of the AMPA receptor. AMPA receptors containing GLUR2 subunits are generally impermeable to calcium and have lower overall conductance. this magnifies the inhibition of nucleus accumbens reactivity thus greatly magnifying reward sensitivity and inducing resilience to stress. basically, I believe that DELTA FOSB mediated over expression of GLUR2 could encourage dopamine D1 receptors in the nucleus accumbens to paradoxically act in an inhibitory manner more often and with greater efficiency. again, in reference to paradoxes with D1 receptors, this study shows that activation of these receptors using a selective agonist is highly rewarding in morphine dependent animals but is not so in those that are opioid naive.

Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats

Chronic opiate administration induces neuro-adaptations within the nucleus accumbens (NAc) and ventral tegmental area (VTA) that can contribute to dependence. We have shown that morphine dependence shifts the behavioral consequences of D1 dopamine (DA) ...

www.ncbi.nlm.nih.gov

It sounds like you're touching on a lot of complex and nuanced topics in neuroscience, particularly the role of dopamine D1 receptors in the nucleus accumbens, their relation to long-term potentiation (LTP), the role of FosB as a transcription factor, and the effects of specific AMPA receptor subunits like GluR2 on neuronal activity and behavior.

First, it's important to note that dopamine's role in the brain is multifaceted and context-dependent. Even within a single region like the nucleus accumbens, dopamine can have a variety of effects depending on the receptor subtype it binds to (D1 or D2), the specific neural circuits it is acting within, and other neurotransmitters and factors that are present.

Second, FosB is a fascinating transcription factor because of its long-lasting effects, and it has been implicated in the regulation of several genes that could affect dopamine signaling and synaptic plasticity. Its role in upregulating GluR2 subunits is particularly interesting. As you pointed out, AMPA receptors containing GluR2 are calcium-impermeable and have lower overall conductance, which could have a range of effects on excitability and synaptic plasticity. It is conceivable that ΔFosB-mediated changes could influence how D1 receptors function, but this is a speculative point that would require empirical support.

The paper you mention about the paradoxical effects of D1 receptor activation in morphine-dependent animals vs. opioid-naive animals adds another layer of complexity. It's not uncommon in neuroscience to find that the same receptor or signaling pathway has different effects depending on the 'state' of the system such as whether an animal is drug-naive or drug-dependent.

To bring these threads together: it would be fascinating to explore whether FosB-mediated changes in GluR2 expression could 'tilt the balance' in how D1 receptors in the nucleus accumbens function, perhaps making them more prone to exert inhibitory rather than excitatory effects under specific conditions. This would likely depend on a host of factors, including the specific neural circuits that are active, the presence of other neurotransmitters, and even the behavioral state of the animal.

Given the complexity and dynamism of these systems, definitive answers would likely require a combination of techniques including molecular biology, electrophysiology, and behavioral assays, possibly in animal models that allow for genetic or pharmacological manipulation of these specific pathways.

 

[Neuroprotection]

Aside from the direct neurophysiological effects of dopamine, anyone have any thoughts on my theory of dopamine and its associated behaviours acting as a protective distraction that prevents us from overthinking. I developed this idea after my own experience of temporary anhedonia which I’ve posted about elsewhere on this site. won’t go too much into it, but during that time I completely lacked the motivation to pursue any pleasure and didn’t look forward to anything. I also dreaded any sort of work but especially cognitive tasks as even the smallest task felt like a chore. interestingly, during that time, I began to constantly overthink everything and that thinking was extremely draining. As I recovered from this, and my motivation came back, I began to wonder whether the pursuit of pleasure, rather than pleasure itself is the tool we need to cope with the hardships of life. I can think of many examples of this in my own life. For example, the excitement and joy I would feel on the night before a school trip would be immensely more pleasurable than actually going on the trip itself. likewise, I generally prefer and feel much happier on Friday rather than on the weekend as the anticipation of having no work to do gives me more pleasure than the occasion itself. this actually helps me to perform better in tasks requiring brain power towards the end of the week. this isn’t because I feel any smarter, but rather, I find it easier to filter out distractions being guided by the ultimate goal of having no more work to do. finally, when I was at school, being told that a girl I found attractive liked me, would temporarily transform me from a lazy apathetic student Who slept through lessons and couldn’t concentrate on anything, into a laser focused and highly determined Star of the class. I strongly believe a huge dopamine release was involved in these phenomena.

 

[Serhat]

Aside from the direct neurophysiological effects of dopamine, anyone have any thoughts on my theory of dopamine and its associated behaviours acting as a protective distraction that prevents us from overthinking. I developed this idea after my own experience of temporary anhedonia which I’ve posted about elsewhere on this site. won’t go too much into it, but during that time I completely lacked the motivation to pursue any pleasure and didn’t look forward to anything. I also dreaded any sort of work but especially cognitive tasks as even the smallest task felt like a chore. interestingly, during that time, I began to constantly overthink everything and that thinking was extremely draining. As I recovered from this, and my motivation came back, I began to wonder whether the pursuit of pleasure, rather than pleasure itself is the tool we need to cope with the hardships of life. I can think of many examples of this in my own life. For example, the excitement and joy I would feel on the night before a school trip would be immensely more pleasurable than actually going on the trip itself. likewise, I generally prefer and feel much happier on Friday rather than on the weekend as the anticipation of having no work to do gives me more pleasure than the occasion itself. this actually helps me to perform better in tasks requiring brain power towards the end of the week. this isn’t because I feel any smarter, but rather, I find it easier to filter out distractions being guided by the ultimate goal of having no more work to do. finally, when I was at school, being told that a girl I found attractive liked me, would temporarily transform me from a lazy apathetic student Who slept through lessons and couldn’t concentrate on anything, into a laser focused and highly determined Star of the class. I strongly believe a huge dopamine release was involved in these phenomena.

Your observation about the anticipatory effects of dopamine is intriguing and aligns with some of the existing scientific understanding of dopamine's role in behavior and cognition. Dopamine is often associated with pleasure, but more recent theories suggest that it actually plays a key role in motivation and the pursuit of goals. Neuroscientists often refer to this as the "wanting" versus the "liking" system. In this framework, "wanting" is the anticipatory pleasure or motivation driven by dopamine, whereas "liking" is the actual enjoyment of the experience, which may involve different neurotransmitters like endorphins.

The experience you describe of feeling more motivated, focused, and pleasurable in anticipation of an event rather than during the event itself could indeed be related to the release of dopamine as you anticipate a rewarding experience. The dopamine system is complex and interacts with other neurotransmitters and hormones, but one of its main functions is to help us predict rewards and then take action to achieve those rewards. In essence, it helps guide behavior toward outcomes that are expected to be beneficial.

Your theory about dopamine acting as a "protective distraction" to prevent overthinking is an interesting take. While dopamine's role in preventing overthinking is not widely discussed in scientific literature, it's plausible that a balanced dopamine system might help modulate or temper excessive rumination or obsessive thoughts by focusing your mental resources on goal-directed tasks or positive anticipatory experiences. The lack of dopamine, as you experienced during your period of anhedonia, could theoretically contribute to a state of cognitive overload or obsessive thought patterns, although this is largely speculative.

The effects you describe, like increased focus and productivity when motivated by a reward (e.g., the weekend, or knowing someone you're attracted to is interested in you), align well with what is known about dopamine's role in enhancing motivation and goal-directed behavior.

That said, it's important to remember that the neuroscience of behavior is complex and not fully understood. Dopamine interacts with a variety of other neurotransmitters and exists within a complex network of neural circuits that collectively influence behavior and cognition. So while dopamine likely plays a significant role in the phenomena you describe, it's not the whole story.

 

[Neuroprotection]

Thank you so much for this. I found your post and interest in my questions very encouraging.

Thanks again.

 

[Serhat]

Thank you so much for this. I found your post and interest in my questions very encouraging.

Thanks again.

You're very welcome! I'm glad you found my response encouraging.

 

[Neuroprotection]

Your observation about the anticipatory effects of dopamine is intriguing and aligns with some of the existing scientific understanding of dopamine's role in behavior and cognition. Dopamine is often associated with pleasure, but more recent theories suggest that it actually plays a key role in motivation and the pursuit of goals. Neuroscientists often refer to this as the "wanting" versus the "liking" system. In this framework, "wanting" is the anticipatory pleasure or motivation driven by dopamine, whereas "liking" is the actual enjoyment of the experience, which may involve different neurotransmitters like endorphins.

The experience you describe of feeling more motivated, focused, and pleasurable in anticipation of an event rather than during the event itself could indeed be related to the release of dopamine as you anticipate a rewarding experience. The dopamine system is complex and interacts with other neurotransmitters and hormones, but one of its main functions is to help us predict rewards and then take action to achieve those rewards. In essence, it helps guide behavior toward outcomes that are expected to be beneficial.

Your theory about dopamine acting as a "protective distraction" to prevent overthinking is an interesting take. While dopamine's role in preventing overthinking is not widely discussed in scientific literature, it's plausible that a balanced dopamine system might help modulate or temper excessive rumination or obsessive thoughts by focusing your mental resources on goal-directed tasks or positive anticipatory experiences. The lack of dopamine, as you experienced during your period of anhedonia, could theoretically contribute to a state of cognitive overload or obsessive thought patterns, although this is largely speculative.

The effects you describe, like increased focus and productivity when motivated by a reward (e.g., the weekend, or knowing someone you're attracted to is interested in you), align well with what is known about dopamine's role in enhancing motivation and goal-directed behavior.

That said, it's important to remember that the neuroscience of behavior is complex and not fully understood. Dopamine interacts with a variety of other neurotransmitters and exists within a complex network of neural circuits that collectively influence behavior and cognition. So while dopamine likely plays a significant role in the phenomena you describe, it's not the whole story.

I’m hoping to do more research on this in the coming days and I am very hopeful we can eventually cure anhedonia especially in those with chronic depression. This probably won’t address depression fully, but it will no doubt make it easier for depressed people to live life, and maybe even get out of their depression by changing their mental state and circumstances.

 

[Neuroprotection]

in regards to dopamine and addiction, apparently, low baseline dopamine levels maintain the highly reinforcing value of drugs like cocaine as there is a larger difference in increase once the addictive drug is administered. an interesting proposal which is under investigation, is the use of dopamine beta-hydroxylase inhibitors in recovering cocaine or other psychostimulant addicts. DBH inhibitors prevent the hydroxylation of dopamine to norepinephrine thus increasing available dopamine whilst decreasing available norepinephrine. there are two ways in which this approach can be beneficial. Firstly, by increasing dopamine availability, negative symptoms of drug withdrawal, especially anhedonia May be reduced or eliminated. however, increase dopamine is also linked to another benefit. this is that the effects of dopaminergic stimulants are intensely magnified to the point where they become aversive. this has been demonstrated in many animal studies. Secondly, norepinephrine depletion or rather reduction of synthesis can decrease or eliminate the negative arousal which often occurs in withdrawal. actually, whilst norepinephrine is important in fighting against depression, it’s also an important part of the stress response and facilitates emotional learning. this is why administration of the drug yohimbine, which dramatically increases norepinephrine levels can precipitate relapse to addictive drugs ranging from alcohol to cocaine in animals.

 

[t_xeplionhell]

in regards to dopamine and addiction, apparently, low baseline dopamine levels maintain the highly reinforcing value of drugs like cocaine as there is a larger difference in increase once the addictive drug is administered. an interesting proposal which is under investigation, is the use of dopamine beta-hydroxylase inhibitors in recovering cocaine or other psychostimulant addicts. DBH inhibitors prevent the hydroxylation of dopamine to norepinephrine thus increasing available dopamine whilst decreasing available norepinephrine. there are two ways in which this approach can be beneficial. Firstly, by increasing dopamine availability, negative symptoms of drug withdrawal, especially anhedonia May be reduced or eliminated. however, increase dopamine is also linked to another benefit. this is that the effects of dopaminergic stimulants are intensely magnified to the point where they become aversive. this has been demonstrated in many animal studies. Secondly, norepinephrine depletion or rather reduction of synthesis can decrease or eliminate the negative arousal which often occurs in withdrawal. actually, whilst norepinephrine is important in fighting against depression, it’s also an important part of the stress response and facilitates emotional learning. this is why administration of the drug yohimbine, which dramatically increases norepinephrine levels can precipitate relapse to addictive drugs ranging from alcohol to cocaine in animals.

Strong antipsychotics and neuroleptics drops the baseline more than x100.

When saying 100% is an average baseline, then decreasing it more than 90% would be what invega sustenna does.

One of key roles of dopamine is rewarding pursuit of goal and rewarding the goal when it happens, but if your expectation of that goal changes at the moment of achieving the goal then reward also gets a bit decreased and that's a one reason why for most people pursuit of goal is more likeable.

While dopamine system rewards the pursuit, it also de-focuses you from other things like pain, anxiety and suffering.
Also adding: when you are in suffering or doing something you don't want, that moment will seem much longer depending on potential of suffering/unwantness (no its not a word, but I couldn't find better one),
Invega sustenna makes one day seem like years at the beginning of recovery, and that gradually goes away (it still didn't completely go away for me).

It disables serotonin system too, so invega will likely remove or decrease satisfaction when you accomplish goals, especially long term goals, also makes mood non-existent and blunts or completely removes feelings of emotions which will also confuse you. Often gives insomnia. Decreases ability to cope with stress. Also memory impairment and many more issues it will cause....

 

[AlsoTapered]

Neuroleptics are so DIRTY. At least I can see some rational design in the atypical ones,

When I first studied them in 1992 my advisor pointed out that schizophrenia is considered to be as disabling as quadriplegia and so it was acceptable because it's treating a life-threatening illness. But their remain 4 different pharmacological models for the disease, a disease which is difficult to model in animal studies and the criteria are very broad. In essence, beyond using drugs to estimate schizophrenia, it's really only human studies that provide the bulk of the information. But if a candidate ligand reaches human trials, vast amounts of money have already been spent and so the pressure to produce a medication that can receive MA is very high indeed,

I have seen start-ups that essentially HAD to succeed with their first medicine to survive and so I suspect the researchers are very conservative.

I used to know a psychiatric nurse and he was able to convince the management of the RSU to allow me a tour. I have to say it WAS scary to interact with people who shared so few frames of reference, Almost all posed a risk to themselves rather than to anyone else but the distress was very clear to see. The paranoia wasn't 'senseless' from the perspective of the patient as the way they experienced the world was in conflict with what they were told.

Also interesting to note that roughly ⅓ of the patients seemed unusual BUT shared many frames of reference. About ⅓rd vacillated between shared and unshared reality but the final ⅓rd were some of the most interesting. After medication they would seem to be fine but as the hours passed, they displayed many of the more classic things like echolalia and word salad (I forget the correct term for this ) do apologize.

But it DID appear that for the MOST disturbed, the medication wasn't correctly applied or quite possibly was inappropriate, To find people who had been on haloperidol for 30+ years and what it had done to them seemed criminal. But I suppose at some point it was prescribed... and in 30 years no reassessment had ever been undertaken.

Asenapine has a fascinating structure with a chiral 2-alkoxy-5-chloro PEA molecules buried in it. 5HT2a (slightly selective) but all over the place on affinity to dopamine receptor subtypes.

BTW Neuroprotection - excellent work in explaining WHY certain targets are selected. I'm sure you know that the cerebrospinal fluid of schizophrenics has either elevated levels of DOPAC (dopamine metabolite suggesting too much dopamine in the brain) and/or too little NMDA. Clozapine was hailed as an amazing treatment for refractive patents because it appears to increase NMDA levels as well as being a D2 antagonist. But of course, being so dirty meant unexpected toxicity. Also, trials of drugs that JUST increased NMDA levels were amazingly successful for the minority (circa 10%) of patients who had normal dopamine levels, just too little NMDA were total success BUT a drug that only benefits (vastly improves life quality) of just 10% of patients wasn't considered viable... so now they are orphen drugs.