title: Differential roles of GABAB1 subunit isoforms on locomotor responses to acute and repeated administration of cocaine.
abstract: GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: laura.jacobson@florey.edu.au.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Fabian F
authors.initials: FF
authors.lastname: Sweeney
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland.
authors.forename: Olivia F
authors.initials: OF
authors.lastname: O'Leary
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D020033:Protein Isoforms; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D018765:Dopamine Uptake Inhibitors; C546266:Gabrb1 protein, mouse; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D003042:Cocaine
keywords: Dopamine; Drugs of abuse; GABA(B) receptors; Hyperlocomotion; Sensitization