Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.
A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
B
B
Boury-Jamot
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
A
A
Carrard
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
J L
JL
Martin
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
O
O
Halfon
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.|King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.|Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
P J
PJ
Magistretti
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.|Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
B
B
Boutrel
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001089:Arabinose; D001253:Astrocytes / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D003214:Conditioning, Classical / Q000187:drug effects; D003213:Conditioning, Psychological; D003463:Cues; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050113:Imino Furanoses; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013402:Sugar Alcohols
D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; C400751:Cuzd1 protein, rat; D050113:Imino Furanoses; D008565:Membrane Proteins; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D019344:Lactic Acid; D001089:Arabinose; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine