Thursday, May 30, 2013

Serotonin 2 Receptor May Be A Key Cocaine Addiction Target

3-Dimensional Model of Cocaine Molecule
Cocaine dependence remains a significant public health problem in the U.S. and throughout the world.  

Relapse rates in cocaine dependence are high despite aggressive psychological interventions.  No evidence-based pharmacological treatments are currently available as adjunctive measures in cocaine dependence.

However, drug development in the treatment of cocaine dependence is an active area of research.  Although cocaine and other stimulants appear to target dopamine and the dopamine receptor, serotonin receptors also appear to be key in the biological mechanisms of initiation, maintenance and relapse.

Cunningham and colleagues recently published a paper in the journal ACS Chemical Neuroscience looking at serotonin receptor subtype synergism as a promising target for cocaine addiction.

The authors begin by noting that behavioral impulsivity and cue reactivity are key components to relapse.  These relapse behaviors appear to be regulated by serotonergic receptors and brain circuits affected by serotonin neurons.

In their experiment, they set out to conduct a proof-of-concept analysis to determine the effect of a combination of a serotonin 2A receptor antagonist (M100907) and a serotonin 2C receptor agonist (WAY 163909) on a rat model of markers for behavioral impulsivity and cue reactivity.

The key elements of the design of their study included a series of controlled experiments on male Sprague-Dawley rats.  Some of these experiments took place in rats that self-administered cocaine.

The primary findings from the study were that a combination of M100907 and WAY163909 synergistically produced in the rat model:

  • a reduction in cocaine-induced hyperactivity
  • a reduction in impulsive behaviors (inherent and cocaine-evoked)
  • a reduction in cocaine-seeking behavior in a a cue and cocaine-primed reinstatement task

Of note, neither of the experimental compounds alone produced similar behaviors underscoring the need for a synergistic serotinin 2A antagonist and 2C agonist combination for the desired effect.

The authors note that the mechanism for the synergism in these two serotonin receptors is unknown but that "the synergy between M100907 and WAY163909 suggests the potential for bifunctional ligands with therapeutic efficacy and limited side effects in cocaine dependence".

The potential for these types of compounds in other types of stimulant dependence, such as methamphetamine dependence is also promising.  

Readers with more interest in this topic can access the full text article for a limited type courtesy of the American Chemical Society by clicking HERE.

Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, Watson CS, Gilbertson SR, Rice KC, Rosenzweig-Lipson S, & Moeller FG (2013). Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS chemical neuroscience, 4 (1), 110-21 PMID: 23336050

Molecular model of cocaine is from the Wikipedia Commons file authored by Fuse809.
Readers with more interest can also view a 3 minute interview of Dr. Cunningham and a colleague discussing their research.


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