Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

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Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where selfstimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue-and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.T he shell of the nucleus accumbens (NAcSh) is known to be an important center for reward and motivation. It is a major terminal area of the mesolimbic dopamingergic system, which projects from the ventral tegmental area (VTA) (1). The NAcSh neurons express both dopamine D1 and D2 receptors, which have opposite effects on cAMP-dependent signaling; however, motivated behaviors require concomitant D1 and D2 receptor signaling in the NAcSh (2). The NAcSh receives inputs from different brain areas, in particular, from the lateral hypothalamus (LH) (3). The importance of the LH in reward and motivation has been shown by Olds (4), who discovered that electrical activation of the LH induced an extraordinarily intense self-stimulation response in rats. However, the transmitter(s) responsible for this action have not been established definitively. We now know of 2 neuropeptides that are uniquely synthesized in the LH: the orexins/hypocretins (5), and melanin-concentrating hormone (MCH) (6-8). The orexin/ hypocretin neurons do not project prominently to the NAcSh, whereas the MCH neurons do (9). This data suggested to us that the MCH system may regulate the activities of the NAcSh neurons to influence reward.MCH is a cyclic, 19-amino acid peptide originally isolated from salmon pituitary as a melanophore-concentrating factor (10). It is also present in rats and humans (11,12), where it is viewed as important in regulating nutritional homeostasis (8, 13). In mammals, MCH is expressed predominantly centrally, and occurs only in 2 nuclei: the perikarya of the LH area (LHA), and the zona incerta (ZI). However, MCH fibers project in many areas throughout the CNS (6, 9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14-18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels. Indeed, the ...

Section: Discussionmentioning

confidence: 99%

The melanin-concentrating hormone system modulates cocaine reward

Chung

Hopf

Nagasaki

et al. 2009

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140

“…S2 A and B). Secondly, chronic amphetamine-induced locomotor sensitization was examined as described previously (21) in D2GSK3β −/− and D1GSK3β −/− mice. Similar to the acute locomotor effects of amphetamine, D2GSK3β −/− (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Locomotor sensitization was performed as described previously (21) and locomotor activity measured as described above. Details are described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)-and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA-or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1-or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β −/− ) but not D1 (D1GSK3β −/− ) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β −/− or D1GSK3β −/− mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β −/− or D1GSK3β −/− mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2-and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.functional selectivity | schizophrenia | bipolar disorder | striatum | frontal cortex

“…We tested the development of AMPH sensitization in these animals by monitoring their locomotion in activity chambers after AMPH (2.5 mg/kg) administration for 5 consecutive days. This dose is in the range used in AMPH sensitization paradigms in mice (21)(22)(23), and was chosen because it resulted in a robust acute locomotor response (4.4-fold increase compared with saline) across all control groups, as well as profound locomotor sensitization (4.8-fold increase in locomotion on AMPH treatment day 5 versus day 1) among all control groups. The long-term maintenance of a sensitized response was tested by challenge injections at 3 d of withdrawal (3 DW) and 21 DW (Fig.…”

Section: Nmdar Signaling In Dopamine Neuronsmentioning

confidence: 99%

Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

Beutler

Wanat

Quintana

et al. 2011

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1R MSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.