Limits...
Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

Jerlhag E, Egecioglu E, Dickson SL, Engel JA - Psychopharmacology (Berl.) (2010)

Bottom Line: As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist.Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

View Article: PubMed Central - PubMed

Affiliation: Section for Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden. elisabet.jerlhag@pharm.gu.se

ABSTRACT

Introduction: Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.

Results: We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist.

Conclusions: Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

Show MeSH

Related in: MedlinePlus

Suppressed ghrelin signaling by ghrelin receptor (GHS-R1A) antagonist (JMV2959) attenuates amphetamine, and cocaine-induced locomotor stimulation and accumbal dopamine release. a Amphetamine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group; ***P < 0.001, #P = n.s for Veh-Veh vs JMV-Amph). b The amphetamine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square), Veh-Amph (filled triangle), and JMV-Veh (triangle) groups and n = 9 in JMV-Amph (circle) group). This difference was evident at time interval 60 min (**P < 0.01, Bonferroni post-hoc test). Even though JMV2959 does not completely block the amphetamine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. c Cocaine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group). (**P < 0.01, ***P < 0.001, ###P < 0.001 for Veh-Veh vs JMV-Coc). d The cocaine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square) and JMV-Veh (triangle) groups, n = 9 in Veh-Coc (filled triangle) and n = 10 in JMV-Coc groups (circle). This difference was evident at time intervals 20–180 min (**P < 0.01, ***P < 0.001). Even though JMV2959 does not completely block the cocaine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2908453&req=5

Fig1: Suppressed ghrelin signaling by ghrelin receptor (GHS-R1A) antagonist (JMV2959) attenuates amphetamine, and cocaine-induced locomotor stimulation and accumbal dopamine release. a Amphetamine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group; ***P < 0.001, #P = n.s for Veh-Veh vs JMV-Amph). b The amphetamine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square), Veh-Amph (filled triangle), and JMV-Veh (triangle) groups and n = 9 in JMV-Amph (circle) group). This difference was evident at time interval 60 min (**P < 0.01, Bonferroni post-hoc test). Even though JMV2959 does not completely block the amphetamine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. c Cocaine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group). (**P < 0.01, ***P < 0.001, ###P < 0.001 for Veh-Veh vs JMV-Coc). d The cocaine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square) and JMV-Veh (triangle) groups, n = 9 in Veh-Coc (filled triangle) and n = 10 in JMV-Coc groups (circle). This difference was evident at time intervals 20–180 min (**P < 0.01, ***P < 0.001). Even though JMV2959 does not completely block the cocaine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment

Mentions: As expected, amphetamine increased locomotor activity, accumbal dopamine release, and induced a CPP. All of these effects of amphetamine were attenuated by peripheral administration of JMV2959 (Figs. 1a, b and 2a). Amphetamine-induced locomotor stimulation (P < 0.001) was blocked by a single injection of JMV2959 (P < 0.001) in mice (F(3,28) = 14.57, P = 0.001). Amphetamine increased accumbal dopamine release relative to vehicle treatment (P = 0.001), and this effect was attenuated by pre-treatment with JMV2959 (P = 0.01) (treatment F(3,29) = 13.31, P = 0.001; time F(12,348) = 15.98, P = 0.001; treatment × time interaction F(12,348) = 7.03, P = 0.001). This difference was evident at time interval of 60 min (P < 0.01). Even though JMV2959 does not completely block the amphetamine-induced dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. The amphetamine-induced CPP was attenuated by an acute single injection of JMV2959 (F(1,14) = 6.82, P = 0.02).Fig. 1


Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

Jerlhag E, Egecioglu E, Dickson SL, Engel JA - Psychopharmacology (Berl.) (2010)

Suppressed ghrelin signaling by ghrelin receptor (GHS-R1A) antagonist (JMV2959) attenuates amphetamine, and cocaine-induced locomotor stimulation and accumbal dopamine release. a Amphetamine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group; ***P < 0.001, #P = n.s for Veh-Veh vs JMV-Amph). b The amphetamine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square), Veh-Amph (filled triangle), and JMV-Veh (triangle) groups and n = 9 in JMV-Amph (circle) group). This difference was evident at time interval 60 min (**P < 0.01, Bonferroni post-hoc test). Even though JMV2959 does not completely block the amphetamine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. c Cocaine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group). (**P < 0.01, ***P < 0.001, ###P < 0.001 for Veh-Veh vs JMV-Coc). d The cocaine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square) and JMV-Veh (triangle) groups, n = 9 in Veh-Coc (filled triangle) and n = 10 in JMV-Coc groups (circle). This difference was evident at time intervals 20–180 min (**P < 0.01, ***P < 0.001). Even though JMV2959 does not completely block the cocaine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908453&req=5

Fig1: Suppressed ghrelin signaling by ghrelin receptor (GHS-R1A) antagonist (JMV2959) attenuates amphetamine, and cocaine-induced locomotor stimulation and accumbal dopamine release. a Amphetamine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group; ***P < 0.001, #P = n.s for Veh-Veh vs JMV-Amph). b The amphetamine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square), Veh-Amph (filled triangle), and JMV-Veh (triangle) groups and n = 9 in JMV-Amph (circle) group). This difference was evident at time interval 60 min (**P < 0.01, Bonferroni post-hoc test). Even though JMV2959 does not completely block the amphetamine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. c Cocaine-induced locomotor stimulation was attenuated by a single i.p. injection of JMV2959, but not by vehicle injection in mice (n = 8 in each group). (**P < 0.01, ***P < 0.001, ###P < 0.001 for Veh-Veh vs JMV-Coc). d The cocaine-induced increase in accumbal dopamine release was absent in GHS-R1A antagonist (JMV2959, i.p.), but not in vehicle-treated mice (n = 8 in Veh-Veh (square) and JMV-Veh (triangle) groups, n = 9 in Veh-Coc (filled triangle) and n = 10 in JMV-Coc groups (circle). This difference was evident at time intervals 20–180 min (**P < 0.01, ***P < 0.001). Even though JMV2959 does not completely block the cocaine-induced accumbal dopamine release, this increase fails to reach statistical significance compared to vehicle treatment
Mentions: As expected, amphetamine increased locomotor activity, accumbal dopamine release, and induced a CPP. All of these effects of amphetamine were attenuated by peripheral administration of JMV2959 (Figs. 1a, b and 2a). Amphetamine-induced locomotor stimulation (P < 0.001) was blocked by a single injection of JMV2959 (P < 0.001) in mice (F(3,28) = 14.57, P = 0.001). Amphetamine increased accumbal dopamine release relative to vehicle treatment (P = 0.001), and this effect was attenuated by pre-treatment with JMV2959 (P = 0.01) (treatment F(3,29) = 13.31, P = 0.001; time F(12,348) = 15.98, P = 0.001; treatment × time interaction F(12,348) = 7.03, P = 0.001). This difference was evident at time interval of 60 min (P < 0.01). Even though JMV2959 does not completely block the amphetamine-induced dopamine release, this increase fails to reach statistical significance compared to vehicle treatment. The amphetamine-induced CPP was attenuated by an acute single injection of JMV2959 (F(1,14) = 6.82, P = 0.02).Fig. 1

Bottom Line: As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist.Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

View Article: PubMed Central - PubMed

Affiliation: Section for Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden. elisabet.jerlhag@pharm.gu.se

ABSTRACT

Introduction: Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.

Results: We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist.

Conclusions: Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

Show MeSH
Related in: MedlinePlus