Rodent 5-HT1R

Cross references: 
Serotonin Metabotropic Receptor
Rodent Hormone-Nerve Interaction  
Reverse Engineering Amphioxus Serotonin  
Comparing Amphioxus and Lamprey Serotonin 
Rodent 5-HT3R    Serotonin References   





FINAL SUMMARY
OF 13 REFERENCES
1994 - 2008


    "Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior."   
    Increased 5-HT at the autoreceptors in the DRN reduces the effect the serotonergic neurons have on their target neurons while increased 5-HT at the postsynaptic receptors, which are on the target neurons, increases the effect of the serotonergic neurons on their target neurons.


INITIAL SUMMARIES
OF THE REFERENCES



Following are initial summaries of the references.  The references are designated by the first words of their title and their year of publication.   

The references themselves follow this list of their initial summaries. 


Enhanced aggressive behavior ...  1994  
   
Lack of 5-HT1BR interferes with "the hyperlocomotor effect" but also potentiates attack.  I would have expected that hyperlocomotion would be an aspect of attack and that hyperlocomotion and attack would occur together.


5-HT1B receptor knock out-behavioral consequences.  1996  
   
This abstract is identical to the abstract for the preceding article.   


Serotonin receptor 1A knockout ... 1998     
   
"... mice without 5-HT1A receptors display decreased exploratory activity..."


Activation of hypothalamic serotonin receptors ... 1998  
    "... 5-HT(1B/2C) receptor agonists ... inhibited fat intake ..."


Altered emotional states in knockout mice ... 1999   
    "
While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types."


Sex differences in expression ... 1999   
   
Expression of 5-HT1AR mRNA differed by gender, but distribution of 5-HT1AR binding sites did not differ by gender.  Expression of 5-HT2AR mRNA did not differ by gender, but binding of 5-HT2AR did differ by gender. 


Somatodendritic 5-HT1A Autoreceptors...  2000 
   
This seems to imply that postsynaptic 5-HT1A receptors are associated with offensive aggression while 5-HT1A autoreceptors are associated with defensive aggression.   


Differential Occupancy of Somatodendritic ... 2001   
   
Increased 5-HT at the autoreceptors in the DRN reduces the effect the serotonergic neurons have on their target neurons while increased 5-HT at the postsynaptic receptors, which are on the target neurons, increases the effect of the serotonergic neurons on their target neurons.


Involvement of the 5-HT1A and 5-HT1B ... 2002 
    "The conclusion was made that the 5-HT1A subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT1B receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.


In Vivo Excitation of GABA ... 2004  
    "Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors."   


The roles of different types of serotonin ... 2004  
    "... mixed 5-HT1B/2C agonist ... blocked the increase in blood testosterone in males in response to presentation of females


5-HT1A and 5-HT1B receptor agonists ... 2005  
    "...
certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects ..."   


Social instigation and aggressive ... 2008   
    "Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior."   


THE REFERENCES


Enhanced aggressive behavior in mice lacking 5-HT1B receptors. 
(PubMed)  - 1994   
    Only abstract available online. 
from the abstract   
    "
Mutant mice lacking the 5-HT1B receptor were generated by homologous recombination. These mice did not exhibit any obvious developmental or behavioral defects. However, the hyperlocomotor effect of the 5-HT1A/1B agonist RU24969 was absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, mutant mice attacked the intruder faster and more intensely than did wild-type mice, suggesting the participation of 5-HT1B receptors in aggressive behavior."      
My comments
    1.  It seems to me that the two reported results contradict one another.  Lack of 5-HT1BR interferes with "
the hyperlocomotor effect" but also potentiates attack.  I would have expected that hyperlocomotion would be an aspect of attack and that hyperlocomotion and attack would occur together. 
    2.  This abstract is identical to the abstract for "
5-HT1B receptor knock out-behavioral consequences. - 1996   ", which follows.     


5-HT1B receptor knock out-behavioral consequences. - 1996   
    Only abstract available online. 
from the abstract   
    "
In an attempt to dissect the contribution of individual 5-HT receptor subtypes to behavior, we have generated by homologous recombination, mutant mice lacking the 5-HT1B receptor.
    These mice did not exhibit any obvious developmental or behavioral defect. However, the hyperlocomotor effect of the 5-HT1A/1B agonist, RU 24969 was completely absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, isolated mutant mice attacked the intruder faster and more intensely than wild-type mice, suggesting an involvement of 5-HT1B receptors in the modulation of aggressive behavior."  
     

My comments
    1.  It seems to me that the two reported results contradict one another.  Lack of 5-HT1BR interferes with "
the hyperlocomotor effect" but also potentiates attack.  I would have expected that hyperlocomotion would be an aspect of attack and that hyperlocomotion and attack would occur together. 
    2.  This abstract is identical to the abstract for the preceding article:   "
Enhanced aggressive behavior ...  - 1994 ".     
    3. 
Other related abstracts.   http://www.biopsychiatry.com/5ht1b-ko.htm   

   
Serotonin receptor 1A knockout: An animal model of anxiety-related disorder (Goog) - 1998     
Full length HTML and PDF available online for free. 
    "...
mice without 5-HT1A receptors display decreased exploratory activity
..." 
My comment
From a simplistic perspective, this is surprising since 5-HT1AR is inhibitory.  There's a lot more detail in the full article, but I found it confusing. 


Activation of hypothalamic serotonin receptors reduced intake of dietary fat and protein but not carbohydrate   (Goog)  - 1998   
Full length HTML and PDF available online for free. 
    "... 
5-HT(1B/2C) receptor agonists ... inhibited fat intake
..." 


Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B
receptors. - 1999     
   
PubMed Abstract.     
http://www.ncbi.nlm.nih.gov/pubmed/10432489       
   
Full length PDF available online for free.    
http://www.nature.com/npp/journal/v21/n1s/pdf/1395371a.pdf   
from the abstract   
    "
We have created mice that lack or express reduced levels of two serotonin receptors: 5-HT1A and 5-HT1B receptors.
    These receptors are localized both on serotonergic neurons where they act as autoreceptors and on non-serotonergic neurons. As a result, the 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic effects of serotonin. Agonists of these receptors are currently used in the treatment of migraine and anxiety disorders.
    Mice lacking these receptors develop, feed, and breed normally and do not display any obvious abnormalities. However, when analyzed in a number of behavioral paradigms, the 5-HT1A and 5-HT1B knockout mice display a number of contrasting phenotypes.
    While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types."  
   
   
 


Sex differences in expression of serotonin receptors (subtypes 1A and 2A) in rat brain: a possible role of testosterone (Goog) - 1999   
Only abstract available online.  I got the PDF through the library.   
    "
Expression of serotonin-1A receptor messenger RNA was greater in males in subregions of the hypothalamus and amygdala, and less in males in subregions of the hippocampus. No significant differences in the distribution of serotonin-1A receptor binding sites were found between the sexes.
    Serotonin-2A receptor messenger RNA expression was comparable in males and females in all brain regions except the ventromedial hypothalamic nuclei, where lower levels were seen in females. However, the binding of serotonin-2A receptor measured with [3H]ketanserin was significantly higher in females in all regions of the hippocampus.
 
   
In a separate study, gonadectomy in males significantly increased serotonin-1A messenger RNA content in the cortex, hypothalamus, hippocampus, amygdala and dorsal raphe, and decreased serotonin-2A messenger RNA in ventromedial hypothalamic nuclei only. Almost all gonadectomy-induced changes were reversed by concomitant administration of testosterone. Our data provide evidence for region-specific sex differences in serotonin receptor subtype 1A and 2A transcription and concentration in the rat brain, and further suggest a modulatory role of testosterone in serotonin (particularly subtype 1A) receptor expression.

My summary
    1. 
Expression of 5-HT1AR mRNA differed by gender, but distribution of 5-HT1AR binding sites did not differ by gender. 
    2.  Expression of 5-HT2AR mRNA did not differ by gender, but binding of 5-HT2AR did differ by gender. 

    3.  Testosterone influenced the expression of both 5-HT1AR and 5-HT2AR mRNAs.  
My assumption
    4.  When they use a phrase like "
serotonin-1A messenger RNA content", I guess they mean the total amount of mRNA that is transcribed in response to an agonist for 5-HT1AR without consideration of the identity of the protein for which that mRNA codes.   


Somatodendritic 5-HT1A Autoreceptors Mediate the Anti-Aggressive Actions of 5-HT1A Receptor Agonists in Rats (PubMed)  - 2000 
Full length HTML and PDF available online for free. 
    "
To elucidate the relative contribution of somatodendritic 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors in the specific anti-aggressive properties of 5-HT1A receptor agonists, the influence of the novel benzodioxopiperazine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT1A receptors and as an agonist at 5-HT1A autoreceptors, upon offensive and defensive aggression was investigated in wild-type rats using a resident-intruder paradigm.
    S-15535 exerted a potent dose-dependent decrease in offensive, but not defensive, aggressive behavior

    "
A resident-intruder agonistic paradigm was employed to monitor either offensive behavior (experimental resident) or defensive behavior (experimental intruder) which strongly resembles the natural patterns of wild rats to establish and defend their territory

    "... 
rats received a subcutaneous (s.c.) injection of one of the following
..." 
My comment
    1.  Testing for neuromodulation rather than neurotransmission, which is appropriate since 5-HT1Rs are metabotropic.  
    2.  This seems to imply that
postsynaptic 5-HT1A receptors are associated with offensive aggression while 5-HT1A autoreceptors are associated with defensive aggression.  


Differential Occupancy of Somatodendritic and Postsynaptic 5HT1A Receptors (Goog) - 2001     
http://www.nature.com/npp/journal/v24/n3/full/1395595a.html
Full length HTML & PDF online for free.  Research on humans, but some data on rodents.  Reference from "In Vivo ... (2004)".   
"...
somatodendritic 5-HT1A autoreceptors in the dorsal raphe nuclei (DRN), the major source of serotonin fibers to the forebrain (for review see Artigas et al. 1996). An acute increase of extracellular 5-HT in the DRN activates
the 5-HT1A autoreceptors and decreases the firing rate of the 5-HT neurons (Bel and Artigas 1992; Invernizzi et al. 1992)
"  "Preclinical studies also indicate that pindolol might be more potent at blocking the DRN 5-HT1A autoreceptors than the postsynaptic 5-HT1A receptors in cortical and limbic areas (Romero et al. 1996; Tada et al. 1999).
My comment
    Note that the 5-HT1A receptors are at both ends of the neuron.  If I understand correctly, the autoreceptors in the DRN inhibit the serotonergic neurons and thereby reduce the amount of 5-HT delivered to the postsynaptic receptors.  So the two different populations of receptors have opposing effects.  Increased 5-HT at the autoreceptors reduces the effect the serotonergic neurons have on their target neurons while increased 5-HT at the postsynaptic receptors, which are on the target neurons, increases the effect of the serotonergic neurons on their target neurons.    


Involvement of the 5-HT1A and 5-HT1B serotonergic receptor subtypes in sexual arousal in male mice (Goog) - 2002   
Only abstract available online.  I got the PDF through the library. 
    "The conclusion was made that the 5-HT1A subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT1B receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.


In Vivo Excitation of GABA Interneurons in the Medial Prefrontal Cortex through 5-HT3 Receptors - 2004     
http://cercor.oxfordjournals.org/cgi/content/full/14/12/1365 
Full length HTML and PDF available online for free. 
    Although this paper is focused primarily on the 5-HT3R, it also included many active links to other articles, some of which are cited and excerpted below. 
    For the portions of this article dealing with 5-HT3R, please see: 
Rodent 5-HT3R 
from the abstract   
    "
Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors."    
    "The present experiments were initiated in parallel to the study of the effect of DR/MnR stimulation on pyramidal neurons of mPFC mediated by 5-HT1A and 5-HT2A receptors (Puig et al., 2003, 2004; Amargós-Bosch et al., 2004)." 
My comments
    1.  According to the table in 
Serotonin Metabotropic Receptor  5-HT1AR is inhibitory while 5-HT2AR is stimulatory.   
    2.  The complexity of the results of this research reflects the complexity of the rodent nervous system.  I don't see any way of "reverse engineering" it in order to better understand the amphioxus or lamprey nervous systems. 


The roles of different types of serotonin receptors in activation of the hypophyseal-testicular complex induced in mice by the presence of a female.
(Goog) - 2004     
Only abstract available online. 
    "... 
the mixed 5-HT1B/2C agonist TFMPP (5.0 mg/kg) blocked the increase in blood testosterone in males in response to presentation of females

My comment
    I don't know how to interpret this.  I'm looking for a reference which tells me how testosterone interacts with the
5-HT1B/2C receptor, but this doesn't do that.  Instead, it tells me that the 5-HT1B/2C receptor controls the level of testosterone in the blood in response to the presence of a female.  The Abstract doesn't say how the TFMPP was administered.   
    The  hypothalamus also contains serotonin receptors, and these receptors appear to be 5-HT(1B/2C) [?].  
    Note:  I searched Google using "5-HT(1B/2C) receptor testosterone" and didn't find anything helpful in the first four pages of hits. 


5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis (PubMed) - 2005   
Only abstract available online.  I got the PDF through the library. 
    "
Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively.

My comments
    1.  Although it isn't mentioned, the use of "
systemic injections" implies that the 5-HT is functioning as a neuromodulator rather than a neurotransmitter. 
    2.  The article makes a distinction between: 
        a.  "
postsynaptic 5-HT(1A/1B) receptor sites" which influence the response to an unchanged release of 5-HT,  and 
        b.  "
somatodendritic and terminal autoreceptors" which influence how much 5-HT is released.  
    3.  The article also makes a distinction between: 
        a. 
5-HT1AR that are somatodendritic and
        b. 
5-HT1BR that are terminal autoreceptors 
    4. Although this article makes some instructive distinctions, their challenge of the "serotonin deficiency hypothesis" is incomplete.  Although 5-HT1A/B agonists may have an inhibitory influence at somatodendritic and terminal autoreceptors, they may also have an even greater inhibitory influence at postsynaptic receptor sites.   
     

Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex - 2008   
Only abstract available online.  I got the PDF from the library. 
    "
Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior.

    "
The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner.
"
My comments
    1.  Since the agonists were microinjected, they were acting as neuromodulators rather than neurotransmitters.  This is consistent with the fact that 5-HT1Rs are metabotropic rather than ionotropic.   
    2.  Since neither the amphioxus nor the lamprey has a VO PFC, the relevance of these findings to them is somewhat indirect.   






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