Omega-3 Decreases D1 And D2 Receptors Expression In The Prefrontal Cortex - PUBMED 2019

Lokzo

Member
Forum Supporter
Joined
Mar 26, 2016
Messages
2,123
Location
Melbourne
Abstract
Amphetamine (AMPH) abuse is a serious public health problem due to the high addictive potential of this drug, whose use is related to severe brain neurotoxicity and memory impairments. So far, therapies for psychostimulant addiction have had limited efficacy. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have shown beneficial influences on the prevention and treatment of several diseases that affect the central nervous system. Here, we assessed the influence of fish oil (FO), which is rich in n-3 PUFA, on withdrawal and relapse symptoms following re-exposure to AMPH. Male Wistar rats received d,l-AMPH or vehicle in the conditioned place preference (CPP) paradigm for 14 days. Then, half of each experimental group was treated with FO (3 g/kg, p.o.) for 14 days. Subsequently, animals were re-exposed to AMPH-CPP for three additional days, in order to assess relapse behavior. Our findings have evidenced that FO prevented relapse induced by AMPH reconditioning. While FO prevented AMPH-induced oxidative damages in the prefrontal cortex, molecular assays allowed us to observe that it was also able to modulate dopaminergic cascade markers (DAT, TH, VMAT-2, D1R and D2R) in the same brain area, thus preventing AMPHinduced molecular changes. To the most of our knowledge, this is the first study to show a natural alternative tool which is able to prevent psychostimulant relapse following drug withdrawal. This non-invasive and healthy nutraceutical may be considered as an adjuvant treatment in detoxification clinics.


Sci-Hub | | 10.1016/j.jnutbio.2019.02.007
 

Frankdee20

Member
Joined
Jul 13, 2017
Messages
3,772
Location
Sun Coast, USA
I wonder why supplementing with Fish Oil or even Flax Oil (which I do not do ever) always gives me anxiety, and terrible insomnia. I cannot tolerate it for more than a day or 2.
 

Dave Clark

Member
Joined
Jun 2, 2017
Messages
1,978
Well, referring to one of the recent posts by Haidut, are any benefits the result of the C:15 fatty acids that are also found in fish oil? Like was talked about, maybe these supposed benefits from n-3 oils are not from the PUFA, but from the pentadecanoic and heptadecanoic acids.
 

frankmp0

Member
Joined
Jul 19, 2023
Messages
139
Location
Chicago
Well, referring to one of the recent posts by Haidut, are any benefits the result of the C:15 fatty acids that are also found in fish oil? Like was talked about, maybe these supposed benefits from n-3 oils are not from the PUFA, but from the pentadecanoic and heptadecanoic acids.
I think a lot of the benefits are shown with strictly extracted DHA and EPA.
 

frankmp0

Member
Joined
Jul 19, 2023
Messages
139
Location
Chicago
How could this possibly be a good thing?

I still don't understand D2 like receptors.

They're supposed to be inhibitory. Meaning that they have "anti-dopamine" effects when agonized directly, at least in brain areas where the function of dopamine is excitatory, meaning D1 like receptors outnumber D2.

Many D2 antagonists are used as antipsychotics, and are shown to reduce hedonic response.

How is this possible? Lol.
 

Time&energy

Member
Joined
Aug 21, 2018
Messages
28
I still don't understand D2 like receptors.

They're supposed to be inhibitory. Meaning that they have "anti-dopamine" effects when agonized directly, at least in brain areas where the function of dopamine is excitatory, meaning D1 like receptors outnumber D2.

Many D2 antagonists are used as antipsychotics, and are shown to reduce hedonic response.

How is this possible? Lol.
Prostaglandin E2 acts on EP1 receptor and amplifies both dopamine D1 and D2 receptor signaling in the striatum - PubMed its because omega 3 displaces PGE2 and reduces dopamine agonist binding.
 

frankmp0

Member
Joined
Jul 19, 2023
Messages
139
Location
Chicago
Prostaglandins increase DR signaling? What's the mechanism of this?

Could this really be the reason? The study shows lower signaling(I have not read the study yet), but Lucas's study shows decreased expression of the receptors.

My question was about the function of D2 receptors specifically. It seems like in many cases, agonizing them increases signaling of the neuron, and antagonizing them decreases signaling of the neuron, which makes no sense since the receptor activates inhibitory processes within the cell.
 

Time&energy

Member
Joined
Aug 21, 2018
Messages
28
Prostaglandins increase DR signaling? What's the mechanism of this?

Could this really be the reason? The study shows lower signaling(I have not read the study yet), but Lucas's study shows decreased expression of the receptors.

My question was about the function of D2 receptors specifically. It seems like in many cases, agonizing them increases signaling of the neuron, and antagonizing them decreases signaling of the neuron, which makes no sense since the receptor activates inhibitory processes within the cell.
Dopamine D2 can be inhibitory based on a personal physiology, for instance if someone has ADHD they can become calm when administered stimulants. I think the consensus is they have low dopamine D2r availability, leading to increased novelty seeking behaviours. It can reduce the activation of adenylate cyclase, which is conversely active in dopamine D1/CREB dominance in the PFC.

Prostaglandins alter the conformation of the cell via CB1 signalling, allowing a permissive environment for stimulation by dopamine agonists such as methamphetamine. Omega 3 offers another substrate for utilisation by phospholipases, for example changing LTB4 to LTb5 signalling. It can reduce the activation of the cannabinoid receptors as such, lowering the potential for agonist stimulation of dopamine.
 

frankmp0

Member
Joined
Jul 19, 2023
Messages
139
Location
Chicago
Dopamine D2 can be inhibitory based on a personal physiology, for instance if someone has ADHD they can become calm when administered stimulants. I think the consensus is they have low dopamine D2r availability, leading to increased novelty seeking behaviours. It can reduce the activation of adenylate cyclase, which is conversely active in dopamine D1/CREB dominance in the PFC.

Prostaglandins alter the conformation of the cell via CB1 signalling, allowing a permissive environment for stimulation by dopamine agonists such as methamphetamine. Omega 3 offers another substrate for utilisation by phospholipases, for example changing LTB4 to LTb5 signalling. It can reduce the activation of the cannabinoid receptors as such, lowering the potential for agonist stimulation of dopamine.
The second explanation is highly intriguing and I hadn't thought any of that. Several new concepts introduced to me.

I'm going to disagree with the first one, though. The(established) reason for novelty seeking behavior is usually low dopaminergic neuron activity in executive systems, primarily the PFC.

If an individual with a high ratio of D1 to D2 was administered stimulants, the response would be even more excitatory than in an individual with more balance. The paradox is that actual stimulation of certain areas can have inhibitory effects on behavior because of increased executive function. I would attribute the difference in response to stimulants in ADHDers vs non-ADHDers to the U-affect of catecholamines in ADHD. Low catecholamines cause ADHD-like behaviors, medium catecholamines normalize it, and highly elevated catecholamines with stimulants leads back to inattention and hyperactivity.

You said that there might be a consensus that ADHDers have low D2r availability, where have you seen that? I have not heard that before.

My confusion about the D2 receptor is that antagonizing it with antipsychotics causes anhedonia, when antagonizing an inhibitory receptor should actually cause increased hedonic response. It seems like the D2 receptor is often referred to or maybe even behaves as an excitatory receptor, which confuses me.
 

Time&energy

Member
Joined
Aug 21, 2018
Messages
28
The second explanation is highly intriguing and I hadn't thought any of that. Several new concepts introduced to me.

I'm going to disagree with the first one, though. The(established) reason for novelty seeking behavior is usually low dopaminergic neuron activity in executive systems, primarily the PFC.

If an individual with a high ratio of D1 to D2 was administered stimulants, the response would be even more excitatory than in an individual with more balance. The paradox is that actual stimulation of certain areas can have inhibitory effects on behavior because of increased executive function. I would attribute the difference in response to stimulants in ADHDers vs non-ADHDers to the U-affect of catecholamines in ADHD. Low catecholamines cause ADHD-like behaviors, medium catecholamines normalize it, and highly elevated catecholamines with stimulants leads back to inattention and hyperactivity.

You said that there might be a consensus that ADHDers have low D2r availability, where have you seen that? I have not heard that before.

My confusion about the D2 receptor is that antagonizing it with antipsychotics causes anhedonia, when antagonizing an inhibitory receptor should actually cause increased hedonic response. It seems like the D2 receptor is often referred to or maybe even behaves as an excitatory recep

The second explanation is highly intriguing and I hadn't thought any of that. Several new concepts introduced to me.

I'm going to disagree with the first one, though. The(established) reason for novelty seeking behavior is usually low dopaminergic neuron activity in executive systems, primarily the PFC.

If an individual with a high ratio of D1 to D2 was administered stimulants, the response would be even more excitatory than in an individual with more balance. The paradox is that actual stimulation of certain areas can have inhibitory effects on behavior because of increased executive function. I would attribute the difference in response to stimulants in ADHDers vs non-ADHDers to the U-affect of catecholamines in ADHD. Low catecholamines cause ADHD-like behaviors, medium catecholamines normalize it, and highly elevated catecholamines with stimulants leads back to inattention and hyperactivity.

You said that there might be a consensus that ADHDers have low D2r availability, where have you seen that? I have not heard that before.

My confusion about the D2 receptor is that antagonizing it with antipsychotics causes anhedonia, when antagonizing an inhibitory receptor should actually cause increased hedonic response. It seems like the D2 receptor is often referred to or maybe even behaves as an excitatory receptor, which confuses me.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237589/I'm definitely no expert but I think dopamine D1 by facilitating memory processes through NMDA/CREB can cause drug reinforcement cues via it's excitatory effect. D2 blocks cyclic amp so can in theory reduce catecholamines, but obviously different drugs can bind to multiple receptors and makes it difficult to attribute effects to one thing.

https://www.ncbi.nlm.nih.gov/pmc/ar... receptors are,Beaulieu and Gainetdinov, 2011).from this:
"Dopamine receptors (D1–D5) are members of the large, rhodopsin-like (Class A), seven transmembrane superfamily of G-protein coupled receptors (GPCRs). The five mammalian receptor subtypes are divided into two major groups that form the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. Members of the D1-family are located on non-dopamine neurons and stimulate neuronal signaling via Gαs/olf to activate adenylyl cyclase (AC) and increase cAMP levels. In axon terminal regions, the activation of D1-receptors leads to increases in excitability and promotes transitions to the up-state via increases in NMDA receptor, L-type calcium channel and sodium channel currents (Surmeier et al., 2010).

Dopamine D2-like receptors are inhibitory. These receptors couple to Gαi/o to inhibit AC and calcium channels, and activate inhibitory G-protein activated inwardly rectifying potassium channels (GIRK) (Neve et al., 2004, Beaulieu and Gainetdinov, 2011)."

https://www.ncbi.nlm.nih.gov/pmc/ar... receptors are,Beaulieu and Gainetdinov, 2011).

"Dopamine D2 receptor gene (DRD2)​

The first molecular genetic studies of ADHD were reported in 1991 by Comings et al following the discovery by Blum and associates linking DRD2 A1 allele to severe alcoholism (Blum et al 1990). They examined the prevalence of the Taq A1 allele of the DRD2 gene in impulsive, compulsive, addictive behaviors. These results suggested that genetic variants at the DRD2 locus played a role in a range of impulsive, compulsive, addictive disorders, including ADHD."
 

frankmp0

Member
Joined
Jul 19, 2023
Messages
139
Location
Chicago
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237589/I'm definitely no expert but I think dopamine D1 by facilitating memory processes through NMDA/CREB can cause drug reinforcement cues via it's excitatory effect. D2 blocks cyclic amp so can in theory reduce catecholamines, but obviously different drugs can bind to multiple receptors and makes it difficult to attribute effects to one thing.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108583/#:~:text=Dopamine D2-like receptors are,Beaulieu and Gainetdinov, 2011).from this:
"Dopamine receptors (D1–D5) are members of the large, rhodopsin-like (Class A), seven transmembrane superfamily of G-protein coupled receptors (GPCRs). The five mammalian receptor subtypes are divided into two major groups that form the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. Members of the D1-family are located on non-dopamine neurons and stimulate neuronal signaling via Gαs/olf to activate adenylyl cyclase (AC) and increase cAMP levels. In axon terminal regions, the activation of D1-receptors leads to increases in excitability and promotes transitions to the up-state via increases in NMDA receptor, L-type calcium channel and sodium channel currents (Surmeier et al., 2010).

Dopamine D2-like receptors are inhibitory. These receptors couple to Gαi/o to inhibit AC and calcium channels, and activate inhibitory G-protein activated inwardly rectifying potassium channels (GIRK) (Neve et al., 2004, Beaulieu and Gainetdinov, 2011)."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108583/#:~:text=Dopamine D2-like receptors are,Beaulieu and Gainetdinov, 2011).

"Dopamine D2 receptor gene (DRD2)​

The first molecular genetic studies of ADHD were reported in 1991 by Comings et al following the discovery by Blum and associates linking DRD2 A1 allele to severe alcoholism (Blum et al 1990). They examined the prevalence of the Taq A1 allele of the DRD2 gene in impulsive, compulsive, addictive behaviors. These results suggested that genetic variants at the DRD2 locus played a role in a range of impulsive, compulsive, addictive disorders, including ADHD."
From my understanding, the current highest candidate gene for ADHD is DRD4.7.

In a group of 500 people with ADHD, 50% of them have the gene. In 500 people who don't, 20-25% of them still have it. Meaning that if you did this with DRD2 it would be even more drastic.

Also, even selective d2r antagonists with no activity at d1 still reduce hedonic reponse
 

Time&energy

Member
Joined
Aug 21, 2018
Messages
28
From my understanding, the current highest candidate gene for ADHD is DRD4.7.

In a group of 500 people with ADHD, 50% of them have the gene. In 500 people who don't, 20-25% of them still have it. Meaning that if you did this with DRD2 it would be even more drastic.

Also, even selective d2r antagonists with no activity at d1 still reduce hedonic reponse
https://www.sciencedirect.com/science/article/abs/pii/S0006899308016727 Not too sure about DRD4 but according to wiki it has a reducing effect on cAMP similar to 2. I think cAMP may be why FAO induces endorphin and opioid release.
 
Back
Top Bottom