Increased expression of 5-HT6 receptors in the nucleus accumbens blocks the rewarding but not psychomotor activating properties of cocaine.
BACKGROUND
Repeated exposure to cocaine produces enduring forms of drug experience-dependent behavioral plasticity, including conditioned place preference (CPP) and psychomotor sensitization, a progressive and persistent increase in cocaine's psychomotor activating effects. Although serotonin-6 receptors (5-HT6Rs) are abundantly expressed in the brain regions thought to underlie these phenomena, such as the nucleus accumbens (NAc), surprisingly little is known about the role of 5-HT6Rs in the rewarding and psychomotor activating effects of cocaine.


METHODS
Viral-mediated gene transfer was used to selectively increase 5-HT6R expression in the NAc of rats. The effects of 5-HT6R overexpression and the selective 5-HT6R antagonist Ro4368554 on CPP and psychomotor sensitization were examined.


RESULTS
Increased expression of 5-HT6Rs in the NAc blocks a CPP to cocaine but has no effect on either the acute locomotor response to cocaine or on the development of cocaine-induced locomotor sensitization. Furthermore, antagonism of 5-HT6Rs facilitates the acquisition of a CPP to cocaine but has no effect on cocaine-induced stereotypy.


CONCLUSIONS
These results demonstrate that 5-HT6Rs in the NAc can selectively modulate drug reward, possibly through facilitation of reward learning.
Ferguson
Susan M
SM
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Mitchell
Ellen S
ES
Neumaier
John F
JF
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012702:Serotonin Antagonists / Q000494:pharmacology; D018139:Simplexvirus / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D018765:Dopamine Uptake Inhibitors; D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; C507242:Ro4368554; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D049452:Green Fluorescent Proteins; D003042:Cocaine