Mu and Delta Opioid Receptors Oppositely Regulate Motor Impulsivity in the Signaled Nose Poke Task

Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1) or delta- (Oprd1) opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6) or a hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB) background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue) and motor impulsivity (premature responses). Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders

Synaptic Zinc: An Emerging Player in Parkinson’s Disease

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Synaptic Zinc, A Novel Player In The Pathophysiology Of Parkinson’s Disease

International audienceExcessive glutamatergic transmission in the striatum is recognized as a key pathophysiological mechanism contributing to Parkinson's disease (PD). Subset of glutamatergic cortical-striatal projections uses ionic zinc (Zn 2+) as a co-transmitter, but its role in PD remains unexplored. Here we used pharmacological and genetic tools in combination with neurotoxic murine models of PD to investigate the pathophysiological role of synaptic zinc in PD. We first studied the behavioural effects of central injections of zinc in C57BL/6J mice. Bilateral infusions of zinc chloride (ZnCl 2) into dorsal striatum produced a dose-dependent locomotor hyperactivity. When injected unilaterally, ZnCl 2 restored motor impairments (forelimb asymmetry and reduced rearing activity) caused by the complete unilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. The beneficial effect of ZnCl 2 was detected with a behaviourally silent dose in sham control mice, suggesting that reduced striatal synaptic zinc signalling contributes to the expression of the motor deficits. We next used synaptic zinc transporter-3 knockout (ZnT3-KO) mice and a partial unilateral 6-OHDA lesion that produces mild impairment of motor function to examine whether ablation of synaptic zinc could exacerbate the motor deficits. Lesioned wildtype mice displayed a locomotor impairment and a slight forelimb asymmetry. Unexpectedly, a significant improvement was detected in lesioned ZnT3-KO mice, pointing to a deleterious role of synaptic zinc during early stages of PD. Together, our findings show that synaptic zinc is an important player in PD. Ongoing studies seek to elucidate how synaptic zinc exerts its beneficial and deleterious actions during different stages of the disease

Synaptic zinc contributes to motor and cognitive deficits in 6- hydroxydopamine mouse models of Parkinson's disease

International audienceHyperactivity of glutamatergic corticostrial pathways is recognized as a key pathophysiological mechanism contributing to development of PD symptoms and dopaminergic neurotoxicity. Subset of corticostriatal projection neurons uses Zn 2+ as a co-transmitter alongside glutamate, but the role of synaptically released Zn 2+ in PD remains unexplored. We used genetically modified mice and pharmacological tools in combination with 6-hydroxydopamine (6-OHDA) lesion models of PD to investigate the contribution of synaptic zinc to disease associated behavioral deficits and neurodegeneration. Vesicular zinc transporter-3 (ZnT3) knockout mice lacking releasable Zn 2+ were more resistant to locomotor deficit and memory impairment of nigrostriatal dopamine (DA) denervation compared to wildtype littermates. The loss of striatal dopaminergic fibers was comparable between genotypes, indicating that synaptically released Zn 2+ contributes to behavioral deficits but not neu-rotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn 2+ actions, we used the extracellular Zn 2+ chelator CaEDTA and knock-in mice lacking the high affinity Zn 2+ inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn 2+ in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn 2+ suppresses locomotor behavior. Disruption of the Zn 2+-GluN2A interaction had, on the other hand, no impact on locomotor deficit or neurotoxic effect of 6-OHDA. Collectively, these findings provide clear evidence for the implication of striatal synaptic Zn 2+ in the pathophysiology of PD. They unveil that synaptic Zn 2+ plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms.

International audienceThe present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5mg/kg) and MK-801 (0.05mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1mg/kg and 0.1mg/kg, respectively) or concomitantly at sub-effective doses (0.5mg/kg and 0.05mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands

<i>Oprd1</i>^−/− and <i>Oprd1</i>^+/+ mice are impaired by ethanol in the signaled nose poke task.

<p>A: Ethanol produced a dose-dependent decrease in efficiency ratios (rewards/nosepokes) in all groups of animals, with knockout mice displaying lower efficiency ratios throughout testing. B: Ethanol increased nose pokes that occurred during the 1–8 s pre-CS period and during the inter-trial interval (ITI) (C). Both wild-type and knockout mice on a BL6 background exhibited higher rates of responding than HYB mice during the ITI but this effect did not interact with dose or with group. D: Ethanol altered conditioned responses in both <i>Oprd1 </i>^+/+ and <i>Oprd1 </i>^−/− mice, although only the highest dose (1.75 g/kg) produced an effect. <i>Oprd1^+/+</i> HYB, <i>n = </i>9<i>; Oprd1^+/+</i> BL6, <i>n</i> = 12; <i>Oprd1 ^−/−</i> HYB, <i>n = </i>8<i>; Oprd1 ^−/−</i> BL6, <i>n = </i>10.</p

Training on the signaled nose poke task.

<p>The first two columns display the proportion (±SEM) of magazine entries that occurred during elevation of the sucrose dipper across two sessions of magazine training. The last three columns display the days to criterion measure for Phases 1–3 during task training. With fixed ratio (FR) responding in Phases 1 and 2, the criterion to progress to the next phase was 25 reinforcers earned per 40-min session. With the introduction of the inter-trial interval (ITI) in Phase 3, this was reduced to 10 reinforcers per session. There were no significance differences between knockout and wild-type animals on any measure.</p><p>wild-type HYB, <i>n</i> = 20; <i>Oprm1</i>^−/− HYB, <i>n</i> = 10; <i>Oprd1 ^−/−</i> HYB, <i>n = </i>8<i>;</i></p><p>wild-type BL6, <i>n</i> = 24; <i>Oprm1</i>^−/− BL6, <i>n</i> = 11; <i>Oprd1 ^−/−</i> BL6, <i>n = </i>10</p

<i>Oprm1</i>^−/− mice perform better in the signaled nose poke task.

<p>Performance on Phase 4 of the signaled nose poke task for mu-opioid receptor knockout mice and their wild-type controls on a HYB (A–D) and BL6 (E–H) backgrounds. A and E: Efficiency ratios (rewards/nose pokes) increased across sessions with <i>Oprm1 ^−/−</i> mice on both genetic backgrounds performing significantly better than wild-type controls. Mice lacking the <i>Oprm1</i> gene exhibited lower levels of responding throughout Phase 4 testing; this phenotypic difference was most apparent during the pre-CS period (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004410#pone-0004410-g002" target="_blank">Fig. 2B and 2F</a>), when animals must learn to inhibit responding in order to maximize the number of rewards earned. C and G: Responses on the rewarded side during the 20-s inter-trial interval (ITI) decreased across sessions with lower overall responses in the <i>Oprm1^−/−</i> groups and in the HYB strain. D and H: Conditioned responding (rewards/signals) increased across sessions with no genotype or background differences. <i>Oprm1</i>^+/+ HYB, <i>n</i> = 11; <i>Oprm1</i>^+/+ BL6, <i>n</i> = 12; <i>Oprm1 </i>^−/− HYB, <i>n</i> = 10; <i>Oprm1 </i>^−/− BL6, <i>n</i> = 11.</p

GPR88 in A2A receptor-expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating

The orphan receptor, GPR88, is emerging as a key player in the pathophysiology of several neuropsychiatric diseases, including psychotic disorders. Knockout (KO) mice lacking GPR88 throughout the brain exhibit many abnormalities relevant to schizophrenia including locomotor hyperactivity, behavioural hypersensitivity to dopaminergic psychostimulants and deficient sensorimotor gating. Here, we used conditional knockout (cKO) mice lacking GPR88 selectively in striatal medium spiny neurons expressing A2A receptor to determine neuronal circuits underlying these phenotypes. We first studied locomotor responses of A2A R-Gpr88 KO mice and their control littermates to psychotomimetic, amphetamine, and to selective D1 and D2 receptor agonists, SKF-81297 and quinpirole, respectively. To assess sensorimotor gating performance, mice were submitted to acoustic and visual prepulse inhibition (PPI) paradigms. Total knockout GPR88 mice were also studied for comparison. Like total GPR88 KO mice, A2A R-Gpr88 KO mice displayed a heightened sensitivity to locomotor stimulant effects of amphetamine and SKF-81297. They also exhibited enhanced locomotor activity to quinpirole, which tended to suppress locomotion in control mice. By contrast, they had normal acoustic and visual PPI, unlike total GPR88 KO mice that show impairments across different sensory modalities. Finally, none of the genetic manipulations altered central auditory temporal processing assessed by gap-PPI. Together, these findings support the role of GPR88 in the pathophysiology of schizophrenia and show that GPR88 in A2A receptor-expressing neurons modulates psychomotor behaviour but not sensorimotor gating