Abstract
Background
Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine
intake in both humans and rats. We tested the hypothesis that median raphe nucleus
(MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate
these phenotypes.
Methods
We used virally mediated RNA interference to locally downregulate SERT expression
and compared the results with those of constitutive SERT knockout. Rats were allowed
either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration
to model moderate versus compulsive-like cocaine taking.
Results
SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions
and, like ShA cocaine self-administration, reduced corticotropin-releasing factor
(CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast,
SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions
and, like LgA cocaine self-administration, reduced CRF immunodensity in the central
nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior,
as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT
knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific
SERT knockdown.
Conclusions
Our results highlight a differential role of serotonergic projections arising from
the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced
shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven
serotonergic control of CRF levels in the amygdala may contribute to the transition
from moderate to compulsive intake of cocaine.
Keywords
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Article info
Publication history
Published online: November 20, 2017
Accepted:
October 18,
2017
Received in revised form:
October 12,
2017
Received:
May 18,
2017
Identification
Copyright
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