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S.08.02 Cocaine increases synaptic efficacy at excitatory inputs onto lateral habenula neurons
S.08. Cocaine and glutamatergic plasticity
S.08. Cocaine and glutamatergic plasticity S.08.01 Drug-evoked synaptic plasticity causing addiction behaviour C. L¨uscher1 ° 1 Geneva University, Department of Basic Neurosciences, Geneva, Switzerland Current models of addiction build on the hypothesis that aberrant function and remodeling of neural circuits cause the pathological behaviors. Drug exposure, through excessive activation of the mesolimbic dopamine system would trigger specific forms of synaptic plasticity, which in susceptible subjects will become persistent and lead to compulsive consumtion of the drug. I will review the arguments in favor of abnormal neuronal plasticity underlying pathological behavior and argue that research must start with a comprehensive description of the relevant functional anatomy. This will allow to resolve of molecular mechanisms that underlie the induction and expression of addiction relevant plasticity in identified afferent of defined neurons. To establish causality, I will describe experiments where reversal of cocaine-evoked plasticity reduces cue-associated cocaine seeking. After withdrawal from self-administration, glutamatergic transmission is selectively affected in NAc D1 receptor expressing medium spiny neurons (D1R-MSNs) of the nucleus accumbens. Within these neurons, afferents from the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHippo) express contrasting forms of drug-evoked synaptic plasticity. Specific stimulation protocols allow for selective reversal on one or both pathways with distinct effects on behavior. We conclude that mPFC inputs code for action outcome, while vHippo inputs convey the vigor with which the animals is seeking to obtain the drug. Beyond strengthening the causal relationship between drug-evoked synaptic plasticity and relapse behavior, the present work may have translational implications, such as inspiring novel protocols for deep brain stimulation. S.08.02 Cocaine increases synaptic efficacy at excitatory inputs onto lateral habenula neurons M. Mameli1 ° France
1 INSERM
U839, Institut du Fer a` Moulin, Paris,
The lateral habenula (LHb) has been implicated in a variety of negative emotional states and pathologies including depression and addiction. Recent studies show that synaptic adaptations in the LHb may arise upon drug exposure. The cellular processes underlying cocaine evoked plasticity in the LHb remain however unknown. Using patch clamp recordings in freshly prepared brain slices, we find that cocaine experience increases excitatory synaptic transmission onto LHb neurons that project their axons to the rostromedial tegmental nucleus (RMTg). We mapped RMTgprojecting neurons by employing a modified herpes simplex virus, stereotactically injected in the RMTg two weeks prior treating the animals. When recording from retrogradely labeled neurons, we find that the amplitude of mEPSCs, recorded in voltageclamp mode and in presence of tetrodotoxin, increases 24 hours after a two-days exposure protocol. Cocaine-evoked plasticity in LHb depends on D2 receptors activation as it is prevented
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by pre-treatment with eticlopride. We further investigated the mechanisms of expression and identified that AMPA receptors trafficking is a requirement for cocaine-evoked plasticity. Indeed, we used a viral-based strategy that allows to prevent activity dependent incorporation of AMPAR at synapses with spatial and temporal precision. We find that impairing the AMPAR trafficking expressing the C-tail dominant negative of GluA1 prevent the expression of cocaine-evoked plasticity in the LHb. These results are in line with a projection-specific cocaine-evoked synaptic plasticity, which requires activation of dopamine D2 receptors and trafficking of AMPARs as induction and expression mechanisms. Altogether, our results suggest that a neural circuit mediating negative emotional responses plays a role in the behavioral effects of drugs of abuse. S.08.03 Repeated cocaine exposure during adolescence alters stress-induced glutamate signaling in rat prefrontal cortex F. Fumagalli1 ° , L. Caffino1 , G. Giannotti1 , G. Racagni1 1 University of Milan, Department of Pharmacological and Biomolecular Sciences and Collaborative Center of Dept. of Antidrug Policies Presidency of the Council of Ministers Rome Italy, Milan, Italy The brain is still maturing during adolescence and interfering with its correct development may lead to short or long lasting neuroadaptations [1]. The aim of our study was to investigate the effects of repeated administration of cocaine during brain development [from postnatal day (PND) 28 to PND 42] on the glutamate system and to investigate whether the rapid coping response of the glutamatergic synapse to an acute stress (5 minutes of swim stress and killing 15 min later) was influenced by the previous cocaine history. Critical determinants of glutamatergic homeostasis were measured in medial prefrontal cortex, by means of Real Time PCR and Western blots. Circulating corticosterone levels were analyzed by ELISA. The developmental exposure to cocaine and stress caused increased responsiveness of the presynaptic terminal measured as increased expression of the vesicular glutamate transporter, an effect that was coupled with increased activation of the postsynaptic terminal as evidenced by enhanced NMDA receptor phosphorylation. We also observed a reduction of the glial glutamate transporters (GLAST and GLT-1), further corroborating the hyperreactivity of the glutamate synapse. No changes were observed in corticosterone plasma levels in cocaine-treated rats whereas a significant increase was observed in stressed animals, independent from previous cocaine history. Also, adolescent cocaine-treated rats showed higher immobility (during the swim stress) indicating a depressive-like state. Our results suggest a coordinated mechanism that might contribute to explain the increased reactivity of abstinent cocaine addicts to adverse events and the negative emotional state observed during the initial phase of cocaine withdrawal. References [1] Wong WC, Ford KA, Pagels NE, McCutcheon JE, Marinelli M. 2013 Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence. J Neurosci. 33(11): 4913−22.
S.08. Cocaine and glutamatergic plasticity S.08.01 Drug-evoked synaptic plasticity causing addiction behaviour C. L¨uscher1 ° 1 Geneva University, Department of Basic Neurosciences, Geneva, Switzerland Current models of addiction build on the hypothesis that aberrant function and remodeling of neural circuits cause the pathological behaviors. Drug exposure, through excessive activation of the mesolimbic dopamine system would trigger specific forms of synaptic plasticity, which in susceptible subjects will become persistent and lead to compulsive consumtion of the drug. I will review the arguments in favor of abnormal neuronal plasticity underlying pathological behavior and argue that research must start with a comprehensive description of the relevant functional anatomy. This will allow to resolve of molecular mechanisms that underlie the induction and expression of addiction relevant plasticity in identified afferent of defined neurons. To establish causality, I will describe experiments where reversal of cocaine-evoked plasticity reduces cue-associated cocaine seeking. After withdrawal from self-administration, glutamatergic transmission is selectively affected in NAc D1 receptor expressing medium spiny neurons (D1R-MSNs) of the nucleus accumbens. Within these neurons, afferents from the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHippo) express contrasting forms of drug-evoked synaptic plasticity. Specific stimulation protocols allow for selective reversal on one or both pathways with distinct effects on behavior. We conclude that mPFC inputs code for action outcome, while vHippo inputs convey the vigor with which the animals is seeking to obtain the drug. Beyond strengthening the causal relationship between drug-evoked synaptic plasticity and relapse behavior, the present work may have translational implications, such as inspiring novel protocols for deep brain stimulation. S.08.02 Cocaine increases synaptic efficacy at excitatory inputs onto lateral habenula neurons M. Mameli1 ° France
1 INSERM
U839, Institut du Fer a` Moulin, Paris,
The lateral habenula (LHb) has been implicated in a variety of negative emotional states and pathologies including depression and addiction. Recent studies show that synaptic adaptations in the LHb may arise upon drug exposure. The cellular processes underlying cocaine evoked plasticity in the LHb remain however unknown. Using patch clamp recordings in freshly prepared brain slices, we find that cocaine experience increases excitatory synaptic transmission onto LHb neurons that project their axons to the rostromedial tegmental nucleus (RMTg). We mapped RMTgprojecting neurons by employing a modified herpes simplex virus, stereotactically injected in the RMTg two weeks prior treating the animals. When recording from retrogradely labeled neurons, we find that the amplitude of mEPSCs, recorded in voltageclamp mode and in presence of tetrodotoxin, increases 24 hours after a two-days exposure protocol. Cocaine-evoked plasticity in LHb depends on D2 receptors activation as it is prevented
S121
by pre-treatment with eticlopride. We further investigated the mechanisms of expression and identified that AMPA receptors trafficking is a requirement for cocaine-evoked plasticity. Indeed, we used a viral-based strategy that allows to prevent activity dependent incorporation of AMPAR at synapses with spatial and temporal precision. We find that impairing the AMPAR trafficking expressing the C-tail dominant negative of GluA1 prevent the expression of cocaine-evoked plasticity in the LHb. These results are in line with a projection-specific cocaine-evoked synaptic plasticity, which requires activation of dopamine D2 receptors and trafficking of AMPARs as induction and expression mechanisms. Altogether, our results suggest that a neural circuit mediating negative emotional responses plays a role in the behavioral effects of drugs of abuse. S.08.03 Repeated cocaine exposure during adolescence alters stress-induced glutamate signaling in rat prefrontal cortex F. Fumagalli1 ° , L. Caffino1 , G. Giannotti1 , G. Racagni1 1 University of Milan, Department of Pharmacological and Biomolecular Sciences and Collaborative Center of Dept. of Antidrug Policies Presidency of the Council of Ministers Rome Italy, Milan, Italy The brain is still maturing during adolescence and interfering with its correct development may lead to short or long lasting neuroadaptations [1]. The aim of our study was to investigate the effects of repeated administration of cocaine during brain development [from postnatal day (PND) 28 to PND 42] on the glutamate system and to investigate whether the rapid coping response of the glutamatergic synapse to an acute stress (5 minutes of swim stress and killing 15 min later) was influenced by the previous cocaine history. Critical determinants of glutamatergic homeostasis were measured in medial prefrontal cortex, by means of Real Time PCR and Western blots. Circulating corticosterone levels were analyzed by ELISA. The developmental exposure to cocaine and stress caused increased responsiveness of the presynaptic terminal measured as increased expression of the vesicular glutamate transporter, an effect that was coupled with increased activation of the postsynaptic terminal as evidenced by enhanced NMDA receptor phosphorylation. We also observed a reduction of the glial glutamate transporters (GLAST and GLT-1), further corroborating the hyperreactivity of the glutamate synapse. No changes were observed in corticosterone plasma levels in cocaine-treated rats whereas a significant increase was observed in stressed animals, independent from previous cocaine history. Also, adolescent cocaine-treated rats showed higher immobility (during the swim stress) indicating a depressive-like state. Our results suggest a coordinated mechanism that might contribute to explain the increased reactivity of abstinent cocaine addicts to adverse events and the negative emotional state observed during the initial phase of cocaine withdrawal. References [1] Wong WC, Ford KA, Pagels NE, McCutcheon JE, Marinelli M. 2013 Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence. J Neurosci. 33(11): 4913−22.