Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine
Background and Purpose The endocannabinoids anandamide and 2‐arachidonoylglycerol (2‐AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagoni...
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| Veröffentlicht in: | British journal of pharmacology 2019-05, Vol.176 (10), p.1541-1551 |
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| creator | Gobira, Pedro H Oliveira, Ana C Gomes, Julia S Silveira, Vivian T Asth, Laila Bastos, Juliana R Batista, Edleusa M Issy, Ana C Okine, Bright N Oliveira, Antonio C Ribeiro, Fabiola M Del Bel, Elaine A Aguiar, Daniele C Finn, David P Moreira, Fabricio A |
| description | Background and Purpose
The endocannabinoids anandamide and 2‐arachidonoylglycerol (2‐AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine.
Experimental Approach
Male Swiss mice received i.p. injections of cannabinoid‐related drugs followed by cocaine, and were then tested for cocaine‐induced hyperlocomotion, c‐Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.
Key Results
The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine‐induced hyperlocomotion. The same results were obtained by combining sub‐effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine‐induced hyperlocomotion and c‐Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2‐AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine‐induced hyperlocomotion when given after a sub‐effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine‐induced conditioned place preference.
Conclusion and Implications
The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction‐related effects of cocaine.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc |
| doi_str_mv | 10.1111/bph.14473 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6487550</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2087997238</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3863-61677db4f6a36535b2a4fb481ea35c51e1ffa9feb2b83d17eac94a91b718e0883</originalsourceid><addsrcrecordid>eNpdkUFP3DAQha2qVVmgh_4DS1x6CXjiJHYulWBFSyUkeihny3bGrFHWTu2EFf8e74KQ2rnMSO_pmxk9Qr4CO4dSF2banEPTCP6BrKARXdVyCR_JijEmKgApj8hxzo-MFVG0n8kRZ1Bm6FcE76YpZh8eaIojZhodXV8B1WEovaZWh6CND9EPNKHFaY4pUx_ovEGaZ79dRh3mgz3hTqdhT0Ln0M4Hlo1W-4Cn5JPTY8Yvb_2E3P-4_rO-qW7vfv5aX95WlsuOVx10QgymcZ3mXctbU-vGmUYCat7aFhCc071DUxvJBxCobd_oHowAiUxKfkK-v3KnxWxxsBjmpEc1Jb_V6VlF7dW_SvAb9RCfVNdI0basAL69AVL8u2Ce1dZni2P5EuOSVc2k6HtR8_2us_-sj3FJobyn6rrvOEBf8-K6eHXt_IjP75cAU_vkVElOHZJTV79vDgN_Ac09jGA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2296311923</pqid></control><display><type>article</type><title>Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine</title><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Gobira, Pedro H ; Oliveira, Ana C ; Gomes, Julia S ; Silveira, Vivian T ; Asth, Laila ; Bastos, Juliana R ; Batista, Edleusa M ; Issy, Ana C ; Okine, Bright N ; Oliveira, Antonio C ; Ribeiro, Fabiola M ; Del Bel, Elaine A ; Aguiar, Daniele C ; Finn, David P ; Moreira, Fabricio A</creator><creatorcontrib>Gobira, Pedro H ; Oliveira, Ana C ; Gomes, Julia S ; Silveira, Vivian T ; Asth, Laila ; Bastos, Juliana R ; Batista, Edleusa M ; Issy, Ana C ; Okine, Bright N ; Oliveira, Antonio C ; Ribeiro, Fabiola M ; Del Bel, Elaine A ; Aguiar, Daniele C ; Finn, David P ; Moreira, Fabricio A</creatorcontrib><description>Background and Purpose
The endocannabinoids anandamide and 2‐arachidonoylglycerol (2‐AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine.
Experimental Approach
Male Swiss mice received i.p. injections of cannabinoid‐related drugs followed by cocaine, and were then tested for cocaine‐induced hyperlocomotion, c‐Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.
Key Results
The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine‐induced hyperlocomotion. The same results were obtained by combining sub‐effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine‐induced hyperlocomotion and c‐Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2‐AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine‐induced hyperlocomotion when given after a sub‐effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine‐induced conditioned place preference.
Conclusion and Implications
The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction‐related effects of cocaine.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.14473</identifier><identifier>PMID: 30101419</identifier><language>eng</language><publisher>London: Blackwell Publishing Ltd</publisher><subject>Activation ; Addictions ; Anandamide ; Animal behavior ; Brain ; Cannabinoid CB1 receptors ; Cannabinoid CB2 receptors ; Cannabinoid receptors ; Cocaine ; Conditioning ; Dopamine receptors ; Drug abuse ; Hypotheses ; Mesolimbic system ; Narcotics ; Nucleus accumbens ; Place preference conditioning ; Receptor mechanisms ; Research Paper ; Themed Section: Research Papers</subject><ispartof>British journal of pharmacology, 2019-05, Vol.176 (10), p.1541-1551</ispartof><rights>2018 The British Pharmacological Society</rights><rights>2019 The British Pharmacological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3863-61677db4f6a36535b2a4fb481ea35c51e1ffa9feb2b83d17eac94a91b718e0883</citedby><orcidid>0000-0001-6186-621X ; 0000-0002-3366-751X ; 0000-0002-0824-7302</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487550/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487550/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,1418,1434,27929,27930,45579,45580,46414,46838,53796,53798</link.rule.ids></links><search><creatorcontrib>Gobira, Pedro H</creatorcontrib><creatorcontrib>Oliveira, Ana C</creatorcontrib><creatorcontrib>Gomes, Julia S</creatorcontrib><creatorcontrib>Silveira, Vivian T</creatorcontrib><creatorcontrib>Asth, Laila</creatorcontrib><creatorcontrib>Bastos, Juliana R</creatorcontrib><creatorcontrib>Batista, Edleusa M</creatorcontrib><creatorcontrib>Issy, Ana C</creatorcontrib><creatorcontrib>Okine, Bright N</creatorcontrib><creatorcontrib>Oliveira, Antonio C</creatorcontrib><creatorcontrib>Ribeiro, Fabiola M</creatorcontrib><creatorcontrib>Del Bel, Elaine A</creatorcontrib><creatorcontrib>Aguiar, Daniele C</creatorcontrib><creatorcontrib>Finn, David P</creatorcontrib><creatorcontrib>Moreira, Fabricio A</creatorcontrib><title>Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine</title><title>British journal of pharmacology</title><description>Background and Purpose
The endocannabinoids anandamide and 2‐arachidonoylglycerol (2‐AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine.
Experimental Approach
Male Swiss mice received i.p. injections of cannabinoid‐related drugs followed by cocaine, and were then tested for cocaine‐induced hyperlocomotion, c‐Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.
Key Results
The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine‐induced hyperlocomotion. The same results were obtained by combining sub‐effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine‐induced hyperlocomotion and c‐Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2‐AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine‐induced hyperlocomotion when given after a sub‐effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine‐induced conditioned place preference.
Conclusion and Implications
The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction‐related effects of cocaine.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc</description><subject>Activation</subject><subject>Addictions</subject><subject>Anandamide</subject><subject>Animal behavior</subject><subject>Brain</subject><subject>Cannabinoid CB1 receptors</subject><subject>Cannabinoid CB2 receptors</subject><subject>Cannabinoid receptors</subject><subject>Cocaine</subject><subject>Conditioning</subject><subject>Dopamine receptors</subject><subject>Drug abuse</subject><subject>Hypotheses</subject><subject>Mesolimbic system</subject><subject>Narcotics</subject><subject>Nucleus accumbens</subject><subject>Place preference conditioning</subject><subject>Receptor mechanisms</subject><subject>Research Paper</subject><subject>Themed Section: Research Papers</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNpdkUFP3DAQha2qVVmgh_4DS1x6CXjiJHYulWBFSyUkeihny3bGrFHWTu2EFf8e74KQ2rnMSO_pmxk9Qr4CO4dSF2banEPTCP6BrKARXdVyCR_JijEmKgApj8hxzo-MFVG0n8kRZ1Bm6FcE76YpZh8eaIojZhodXV8B1WEovaZWh6CND9EPNKHFaY4pUx_ovEGaZ79dRh3mgz3hTqdhT0Ln0M4Hlo1W-4Cn5JPTY8Yvb_2E3P-4_rO-qW7vfv5aX95WlsuOVx10QgymcZ3mXctbU-vGmUYCat7aFhCc071DUxvJBxCobd_oHowAiUxKfkK-v3KnxWxxsBjmpEc1Jb_V6VlF7dW_SvAb9RCfVNdI0basAL69AVL8u2Ce1dZni2P5EuOSVc2k6HtR8_2us_-sj3FJobyn6rrvOEBf8-K6eHXt_IjP75cAU_vkVElOHZJTV79vDgN_Ac09jGA</recordid><startdate>201905</startdate><enddate>201905</enddate><creator>Gobira, Pedro H</creator><creator>Oliveira, Ana C</creator><creator>Gomes, Julia S</creator><creator>Silveira, Vivian T</creator><creator>Asth, Laila</creator><creator>Bastos, Juliana R</creator><creator>Batista, Edleusa M</creator><creator>Issy, Ana C</creator><creator>Okine, Bright N</creator><creator>Oliveira, Antonio C</creator><creator>Ribeiro, Fabiola M</creator><creator>Del Bel, Elaine A</creator><creator>Aguiar, Daniele C</creator><creator>Finn, David P</creator><creator>Moreira, Fabricio A</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6186-621X</orcidid><orcidid>https://orcid.org/0000-0002-3366-751X</orcidid><orcidid>https://orcid.org/0000-0002-0824-7302</orcidid></search><sort><creationdate>201905</creationdate><title>Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine</title><author>Gobira, Pedro H ; Oliveira, Ana C ; Gomes, Julia S ; Silveira, Vivian T ; Asth, Laila ; Bastos, Juliana R ; Batista, Edleusa M ; Issy, Ana C ; Okine, Bright N ; Oliveira, Antonio C ; Ribeiro, Fabiola M ; Del Bel, Elaine A ; Aguiar, Daniele C ; Finn, David P ; Moreira, Fabricio A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3863-61677db4f6a36535b2a4fb481ea35c51e1ffa9feb2b83d17eac94a91b718e0883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Activation</topic><topic>Addictions</topic><topic>Anandamide</topic><topic>Animal behavior</topic><topic>Brain</topic><topic>Cannabinoid CB1 receptors</topic><topic>Cannabinoid CB2 receptors</topic><topic>Cannabinoid receptors</topic><topic>Cocaine</topic><topic>Conditioning</topic><topic>Dopamine receptors</topic><topic>Drug abuse</topic><topic>Hypotheses</topic><topic>Mesolimbic system</topic><topic>Narcotics</topic><topic>Nucleus accumbens</topic><topic>Place preference conditioning</topic><topic>Receptor mechanisms</topic><topic>Research Paper</topic><topic>Themed Section: Research Papers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gobira, Pedro H</creatorcontrib><creatorcontrib>Oliveira, Ana C</creatorcontrib><creatorcontrib>Gomes, Julia S</creatorcontrib><creatorcontrib>Silveira, Vivian T</creatorcontrib><creatorcontrib>Asth, Laila</creatorcontrib><creatorcontrib>Bastos, Juliana R</creatorcontrib><creatorcontrib>Batista, Edleusa M</creatorcontrib><creatorcontrib>Issy, Ana C</creatorcontrib><creatorcontrib>Okine, Bright N</creatorcontrib><creatorcontrib>Oliveira, Antonio C</creatorcontrib><creatorcontrib>Ribeiro, Fabiola M</creatorcontrib><creatorcontrib>Del Bel, Elaine A</creatorcontrib><creatorcontrib>Aguiar, Daniele C</creatorcontrib><creatorcontrib>Finn, David P</creatorcontrib><creatorcontrib>Moreira, Fabricio A</creatorcontrib><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gobira, Pedro H</au><au>Oliveira, Ana C</au><au>Gomes, Julia S</au><au>Silveira, Vivian T</au><au>Asth, Laila</au><au>Bastos, Juliana R</au><au>Batista, Edleusa M</au><au>Issy, Ana C</au><au>Okine, Bright N</au><au>Oliveira, Antonio C</au><au>Ribeiro, Fabiola M</au><au>Del Bel, Elaine A</au><au>Aguiar, Daniele C</au><au>Finn, David P</au><au>Moreira, Fabricio A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine</atitle><jtitle>British journal of pharmacology</jtitle><date>2019-05</date><risdate>2019</risdate><volume>176</volume><issue>10</issue><spage>1541</spage><epage>1551</epage><pages>1541-1551</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Background and Purpose
The endocannabinoids anandamide and 2‐arachidonoylglycerol (2‐AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine.
Experimental Approach
Male Swiss mice received i.p. injections of cannabinoid‐related drugs followed by cocaine, and were then tested for cocaine‐induced hyperlocomotion, c‐Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.
Key Results
The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine‐induced hyperlocomotion. The same results were obtained by combining sub‐effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine‐induced hyperlocomotion and c‐Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2‐AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine‐induced hyperlocomotion when given after a sub‐effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine‐induced conditioned place preference.
Conclusion and Implications
The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction‐related effects of cocaine.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc</abstract><cop>London</cop><pub>Blackwell Publishing Ltd</pub><pmid>30101419</pmid><doi>10.1111/bph.14473</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6186-621X</orcidid><orcidid>https://orcid.org/0000-0002-3366-751X</orcidid><orcidid>https://orcid.org/0000-0002-0824-7302</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Addictions Anandamide Animal behavior Brain Cannabinoid CB1 receptors Cannabinoid CB2 receptors Cannabinoid receptors Cocaine Conditioning Dopamine receptors Drug abuse Hypotheses Mesolimbic system Narcotics Nucleus accumbens Place preference conditioning Receptor mechanisms Research Paper Themed Section: Research Papers |
| title | Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine |
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