Abstract
Rationale Several studies suggest a role for neuropeptide Y
(NPY) in addiction to drugs of abuse, including cocaine.
However, the NPY receptors mediating addiction-related
effects remain to be determined. Objectives To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.
Methods The Y5 antagonist L-152,804 and Y5-knockout
(Y5-KO) mice were tested in two models of cocaine
addiction-related behaviour: acute self-administration
and cocaine-induced hyperactivity. We also studied
effects of Y5 receptor antagonism on cocaine-induced
c-fos expression and extracellular dopamine with microdialysis
as well as dopamine transporter-mediated uptake
of dopamine in vitro. Immunocytochemistry was used to
determine whether dopamine neurons express Y5-like
immunoreactivity.
Results In self-administration, L-152,804 prominently decreased
nose-poking for the peak dose of cocaine and
shifted the dose–response curve for cocaine downward.
Y5-KO mice also showed modestly attenuated selfadministration.
Cocaine-induced hyperactivity was attenuated
by L-152,804 and in Y5-KO mice. Cocaine failed to
increase c-fos expression in the nucleus accumbens and
striatum of L-152,804-treated mice, indicating that the Y5
antagonist could act by influencing neural activity in these
regions. Accordingly, the cocaine-induced increase in
accumbal extracellular dopamine was attenuated by L-
152,804 and in Y5-KO mice, suggesting that Y5 antagonism
influences cocaine-induced behaviour by regulating
dopamine. Consistent with this concept, dopamine neurons
in the ventral tegmental area appeared to contain Y5 receptors.
In contrast, neither L-152,804 nor NPY influenced
dopamine transporter-mediated dopamine uptake.
Conclusions The present data indicate that Y5 antagonism
may attenuate cocaine-induced behavioural effects, suggesting
that Y5 receptors could be a potential therapeutic target
in cocaine addiction.
(NPY) in addiction to drugs of abuse, including cocaine.
However, the NPY receptors mediating addiction-related
effects remain to be determined. Objectives To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.
Methods The Y5 antagonist L-152,804 and Y5-knockout
(Y5-KO) mice were tested in two models of cocaine
addiction-related behaviour: acute self-administration
and cocaine-induced hyperactivity. We also studied
effects of Y5 receptor antagonism on cocaine-induced
c-fos expression and extracellular dopamine with microdialysis
as well as dopamine transporter-mediated uptake
of dopamine in vitro. Immunocytochemistry was used to
determine whether dopamine neurons express Y5-like
immunoreactivity.
Results In self-administration, L-152,804 prominently decreased
nose-poking for the peak dose of cocaine and
shifted the dose–response curve for cocaine downward.
Y5-KO mice also showed modestly attenuated selfadministration.
Cocaine-induced hyperactivity was attenuated
by L-152,804 and in Y5-KO mice. Cocaine failed to
increase c-fos expression in the nucleus accumbens and
striatum of L-152,804-treated mice, indicating that the Y5
antagonist could act by influencing neural activity in these
regions. Accordingly, the cocaine-induced increase in
accumbal extracellular dopamine was attenuated by L-
152,804 and in Y5-KO mice, suggesting that Y5 antagonism
influences cocaine-induced behaviour by regulating
dopamine. Consistent with this concept, dopamine neurons
in the ventral tegmental area appeared to contain Y5 receptors.
In contrast, neither L-152,804 nor NPY influenced
dopamine transporter-mediated dopamine uptake.
Conclusions The present data indicate that Y5 antagonism
may attenuate cocaine-induced behavioural effects, suggesting
that Y5 receptors could be a potential therapeutic target
in cocaine addiction.
| Original language | English |
|---|---|
| Journal | Psychopharmacology |
| Volume | 222 |
| Pages (from-to) | 565-577 |
| Number of pages | 13 |
| ISSN | 0033-3158 |
| DOIs | |
| Publication status | Published - Aug 2012 |