Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableThe effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear(OXFORD UNIV PRESS, 2014-09)The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.
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ItemKnockdown of CRF1 Receptors in the Ventral Tegmental Area Attenuates Cue- and Acute Food Deprivation Stress-Induced Cocaine Seeking in Mice(SOC NEUROSCIENCE, 2014-08-27)Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.
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ItemNetrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine(SPRINGER, 2013-12)RATIONALE: The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant methamphetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established. OBJECTIVES: Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice. RESULTS: While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice. CONCLUSIONS: Impaired METH-induced hyperactivity and dose-related responding in adult dcc het mice suggest that reduced DCC alters METH-related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH-consumption and seeking following abstinence.
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ItemThe Metabotropic Glutamate 5 Receptor Modulates Extinction and Reinstatement of Methamphetamine-Seeking in Mice(PUBLIC LIBRARY SCIENCE, 2013-07-04)Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.