Diverse Psychotomimetics Act Through a Common Signaling Pathway

Svenningsson, Per; Tzavara, Eleni T.; Carruthers, Robert; Rachleff, Ilan; Wattler, Sigrid; Nehls, Michael; McKinzie, David L.; Fienberg, Allen A.; Nomikos, George G.; Greengard, Paul

doi:10.1126/science.1089681

Cited by 296 publications

(258 citation statements)

References 20 publications

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“…Given the large number of manipulations that are capable of altering sensorimotor gating (cf., Geyer et al, 2001Geyer et al, , 2002Swerdlow et al, 2001a), it is clear that the molecular and neural circuits regulating this automatic neural process are quite complex. Our work, and those of others measuring region-specific effects (eg Svenningsson et al, 2003), suggests another layer of complexity in the regulation of sensorimotor gating in that each brain region may have a unique molecular signature.…”

Section: Discussionsupporting

confidence: 55%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gas (Gas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

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Section: Discussionsupporting

confidence: 55%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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“…DARPP-32 + / + Â DARPP-32 + / + and DARPP-32 -/-Â DARPP-32 -/-mating was performed separately for no more than two generations. Mice bearing a mutation in which Thr34 or Thr75 were replaced by a nonphosphorylatable Ala (T34A and T75A mutant mice, respectively) (Svenningsson et al, 2003) were obtained from heterozygous animals generated from C57BL/6 Â 129SV hybrids bred for one generation on a C57BL/6 background. Mice were age matched, and both female and male offspring were used.…”

Section: Animalsmentioning

confidence: 99%

Activation of the cAMP/PKA/DARPP-32 Signaling Pathway is Required for Morphine Psychomotor Stimulation but not for Morphine Reward

Borgkvist

Usiello

Greengard

et al. 2007

Neuropsychopharmacol

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Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.

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“…Indeed, several reports have shown that GSK-3b levels or its phosphorylation state (Ser-9-GSK3b), are altered among schizophrenic individuals (Kozlovsky et al, 2000(Kozlovsky et al, , 2001Beasley et al, 2001;Emamian et al, 2004). Moreover, GSK-3b has been shown to be a target of the action mood-stabilizers such as lithium and VPA ( Klein and Melton, 1996;Chen et al, 1999;Hall et al, 2002), antipsychotics drugs, as clozapine, haloperidol and risperidone (Alimohamad et al, 2005a, b) and psychotomimetics drugs, which induce an schizophreniclike state in humans and animal models (Svenningsson et al, 2003;Ahn et al, 2005).…”

Section: Schizophrenia and Polymorphisms In Frizzled 3 And Gsk3bmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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Diverse Psychotomimetics Act Through a Common Signaling Pathway

Cited by 296 publications

References 20 publications

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Activation of the cAMP/PKA/DARPP-32 Signaling Pathway is Required for Morphine Psychomotor Stimulation but not for Morphine Reward

The ups and downs of Wnt signaling in prevalent neurological disorders

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