Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
Can TAAR1 Drugs Blunt Psychosis Without Side Effects?

8 June 2012. In 2011, F. Hoffman-La Roche researchers in Basel, Switzerland, reported the first-ever selective agonist of the trace amine-associated receptor 1 (TAAR1). This was more than just another new drug ligand, as TAAR1 is a G-protein coupled receptor that modulates dopaminergic, serotonergic, and possibly glutamatergic systems, and so may be able to finetune the neurotransmitter signaling thought to be off-kilter in a number of psychiatric conditions, not the least of which is schizophrenia. Some evidence suggests that the endogenous ligands for TAAR1 receptors – the so-called trace amines found at very low concentrations in the brain – are present at abnormal levels in different psychiatric disorders (Berry 2007 ).

Last year's report highlighted the compound's anxiety-reducing effects in mice, with intruiging evidence for possible antipsychotic effects (see SRF news story ID 1675). Now the team, led by Marius Hoener, reports on two, more selective, agonists with particularly strong effects—one is tempted to call them antipsychotic-like—in rats. In their article published online 29 in Molecular Psychiatry, the team reports that the compounds also enhance cognition, exhibit antidepressant-like effects, and can mitigate motor and weight gain side effects of traditional antipsychotics.

Full or partial
First author Florent Revel and colleagues found that the two drugs potently activated TAAR1 receptors, as indicated by the ensuing G-protein induced cAMP production. One drug acted as a full agonist, reaching maximal levels of cAMP, whereas the other worked like a partial agonist, spurring only 59-85% of maximum. While both compounds altered firing rates of dopamine neurons and serotonin neurons recorded in mouse brain slices, they did not have these effects in transgenic mice lacking TAAR1.

As a proxy for the antipsychotic effects of these drugs, the researchers tested how well they could quell the hyperlocomotion induced by either overactive dopamine or glutamate signaling using cocaine or NMDA receptor agonists, respectively. Similar to antipsychotics, both drugs dose-dependently blocked this hyperlocomotion in mice, and could do so with doses as small as 0.003 mg/kg. Interestingly, each drug could augment proven antipsychotics to increase this inhibition: for example, while a subeffective dose of olanzapine halved the amount of cocaine-induced locomotion, adding in either one of the TAAR1 agonists blocked it completely. This raises the possibility that these TAAR1 agonists might work as therapeutic add-ons to current antipsychotic medications.

Beyond this one assay of antipsychotic action, the researchers noted that brain scans of rats on these drugs revealed brain activity patterns similar – but not identical -- to that of olanzapine. Magnetic resonance imaging detected increased activity in cortical and limbic regions, and decreased activity in subcortical areas like the ventral tegmental area for both study compounds and olanzapine. However differences arose in locus coeruleus, thalamus and nucleus accumbens, with olanzapine decreasing activity in these regions, but the TAAR1 agonists producing no change.

Downsizing side effects
Unlike olanzapine, the TAAR1 agonists were not associated with any weight gain. After two weeks of treatment with the partial agonist, rats weighed less than vehicle-treated controls, and did not show any significant change in their fat mass. Co-treatment of rats with olanzapine and the partial agonist seemed to neutralize the weight gain associated with olanzapine alone: when given at a dose that did not alter weight on its own, the TAAR1 partial agonist combined with olanzapine did not lead to a significant change in fat mass (nor a concomitant increase in feeding), whereas those given olanzapine alone increased their fat mass by 30%. Just how the TAAR1 agonists might mitigate the metabolic consequences of antipsychotics is unclear, but it may involve TAAR1 receptors residing in the insulin-making cells of the pancreas, the stomach and the intestine, as reported by this study and others.

The TAAR1 agonists limited the motor effects of older, typical antipsychotics, too. Though rats injected with haloperidol exhibited signs of catalepsy – as measured by the long time it took them to change their body position from one they were placed in by the researchers. Coinjecting the partial TAAR1 agonist partly prevented this; the full agonist, however, was not as effective. Neither TAAR1 agonist on its own produced signs of catalepsy.

These compounds might come with their own side effects, however. The researchers noted that that partial agonist promoted wakefulness, with the rats clocking nearly an hour more of awake time, at the expense of both REM and non-REM sleep.

Taking on cognitive and negative symptoms The researchers found that TAAR1 agonists also benefited cognition, as measured in monkeys performing an object retrieval task. Both TAAR1 agonists increased accuracy in the more difficult trials, getting 66% or 67% correct compared to about 50% in vehicle-treated controls. In rats, the researchers found that TAAR1 activation could reverse phencyclidine (PCP)-induced disruptions in cognitive flexibility, as measured by an attentional set-shifting test. This is similar to other cognitive enhancers, and suggests that TAAR1 agonists could have pro-cognitive effects.

Finally, the researchers report some antidepressant-like effects of the TAAR1 agonists. In a differential reinforcement of low-rate behavior paradigm, monkeys with TAAR1 agonists on board were able to withhold their responses to wait for the rewards that came few and far between better than vehicle-treated controls – an effect also shown for antidepressant drugs. In rats, treatment with the partial TAAR1 agonist during the forced-swim test reduced the amount of time spent immobile in the water compared to vehicle-treated controls by nearly a minute.

Future work will have to track how these drugs work in other assays for antipsychotic action, negative symptoms and cognition. The exact effects of TAAR1 agonists – particularly those of the partial agonist – may depend on the amount of trace amines in a particular system: when too little, the partial TAAR1 agonist will act more like an agonist, but when too much, it may function as a TAAR1 antagonist by outcompeting the endogenous trace amines. This complicates any immediate functional understanding of these compounds, but it might enable high-precision adjustments of neurotransmitter signaling in the brain.—Michele Solis.

Reference:
Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry. 2012 May 29.

 
Comments on Related Papers
Related Paper: A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Comment by:  Bryan Roth
Submitted 8 June 2012 Posted 8 June 2012

In this paper, a group from Roche Pharmaceuticals report on the properties of new trace amine associate receptor -1 (TAAR1) agonists. As previously reported by this group, these new compounds have antipsychotic drug like actions, at least after acute administration, in several models. It is interesting that they report only the effects on locomotor-based assays (inhibition of cocaine and PCP-induced locomotion). Presumably this group also examined the efficacies of these compounds in other models used to predict antipsychotic drug-like actions (e.g. normalization of disrupted pre-pulse inhibition; conditioned avoidance response test; inhibition of amphetamine-induced locomotion; inhibition of apomorphine-induced stereotypy, etc) and it will be interesting to see whether these compounds display a broad spectrum of actions at other models of antipsychotic drug actions.

This is important because, as has been reviewed previously (Conn and Roth, 2008), many potential atypical...  Read more


View all comments by Bryan Roth
Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
 
Enter the code as it is shown below:
This code helps prevent automated registrations.

Please note: A member needs to be both registered and logged in to submit a comment.

Comment:

(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright