title: Enhancing glutamatergic transmission during adolescence reverses early-life stress-induced deficits in the rewarding effects of cocaine in rats.
abstract: Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological processes, including reward function, and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25-46) animals were treated with the glutamate transporter activator, riluzole, or the NMDA receptor antagonist, memantine. Adult reward function was assessed using voluntary cocaine intake measured via intravenous self-administration. We found that early-life stress in the form of maternal-separation impaired reward function, reducing the number of successful cocaine-infusions achieved during the intravenous self-administration procedure as well impairing drug-induced reinstatement of cocaine-taking behaviour. Interestingly, riluzole and memantine treatment reversed this stress-induced impairment. These data suggest that reducing glutamatergic signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing SUDs including certain adolescent populations, particularly those which may have experienced trauma during early-life.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.affiliation: APC Microbiome Institute, University College Cork, Ireland.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Moloney
authors.affiliation: Department of Cognitive Neuroscience, Radbound University Medical Centre, The Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Glennon
authors.affiliation: School of Nursing and Human Sciences, Faculty of Science and Health, Dublin City University, Ireland.
authors.forename: Styliani
authors.initials: S
authors.lastname: Vlachou
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D061605:Administration, Intravenous; D000375:Aging / Q000187:drug effects / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid; D008297:Male; D008426:Maternal Deprivation; D008559:Memantine / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012201:Reward; D019782:Riluzole / Q000494:pharmacology; D012646:Self Administration; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019782:Riluzole; D003042:Cocaine; D008559:Memantine
keywords: Addiction; Glutamate; Stress