Differential effects of treatment with typical and atypical antipsychotic drugs on adenylyl cyclase and G proteins

Kaplan, Gary B.; Leite‐Morris, Kimberly A.; Keith, Dove J.

doi:10.1016/s0304-3940(99)00610-2

Cited by 16 publications

(15 citation statements)

References 16 publications

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“…In contrast, Kaplan et al (1999) reported no change in the striatum but a decrease in G s ␣ levels in the cortex. No change in these two subunits after HAL (See et al, 1993;Meller and Bohmaker, 1996) or olanzapine (Kaplan et al, 1999) treatment has also been reported. In light of these observations, it is quite possible that the mechanism of action of typical and atypical antipsychotic drugs may lie in their ability to differentially regulate adenylyl cyclase-cAMP pathway at the level of functional response.…”

mentioning

confidence: 86%

“…Other significant observations are that whereas HAL decreases G i and G s ␣ in rat striatum, CLOZ increases them (Gupta and Mishra, 1992;Shin et al, 1995). In contrast, Kaplan et al (1999) reported no change in the striatum but a decrease in G s ␣ levels in the cortex. No change in these two subunits after HAL (See et al, 1993;Meller and Bohmaker, 1996) or olanzapine (Kaplan et al, 1999) treatment has also been reported.…”

mentioning

confidence: 96%

“…More recent studies suggest that CLOZ decreases 5HT 1A -mediated (Assie et al, 1997) and muscarinic M 4 -mediated (Zeng et al, 1997) cAMP formation. On the other hand, Kaplan et al (1999) showed that whereas HAL increases GTP␥-S-stimulated adenylyl cyclase activity in rat cortex, olanzapine decreases it. But in the striatum, olanzapine produces effects opposite those of the cortex, and HAL has no effects on GTP␥-S-stimulated adenylyl cyclase activity.…”

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confidence: 98%

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Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Dwivedi

Rizavi²,

Pandey³

2002

J Pharmacol Exp Ther

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The present study was undertaken to examine whether the mechanism of action of typical and atypical antipsychotics is related in their ability to regulate key phosphorylating enzyme of adenylyl cyclase-cAMP pathway, i.e., protein kinase A (PKA). For this purpose, regulatory (R) and catalytic (Cat) activities of PKA and expression of various isoforms of regulatory and catalytic subunits were examined in rat brain after single or chronic (21-day) treatment with haloperidol (HAL, 1 mg/kg) or clozapine (CLOZ, 20 mg/kg). It was observed that chronic but not acute treatment of CLOZ significantly decreased [ 3 H]cAMP binding to the regulatory subunit of PKA as well as catalytic activity of PKA in particulate and cytosol fractions of the rat cortex, hippocampus, and striatum. In these fractions, CLOZ significantly decreased protein levels of selective RII␣-, RII␤-, and Cat␤-subunit isoforms of PKA. These decreases were accompanied by decreases in their respective mRNA expression. In contrast, chronic but not acute treatment of HAL significantly increased [3 H]cAMP binding and the catalytic activity of PKA in particulate and cytosol fractions of only the striatum brain area. In addition, chronic treatment of HAL significantly increased mRNA and protein levels of RII␣-and RII␤-subunit isoforms in the striatum. None of the antipsychotics caused any change in the expression of the Cat␣-, RI␣-, or RI␤-subunit isoform. These results, thus, suggest that HAL and CLOZ differentially regulate PKA catalytic and regulatory activities and the expression of selective catalytic and regulatory subunit isoforms of PKA, which may be associated with their mechanisms of action.

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confidence: 86%

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confidence: 96%

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confidence: 98%

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Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Dwivedi

Rizavi²,

Pandey³

2002

J Pharmacol Exp Ther

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“…Previous studies have displayed the stability of haloperidol and olanzapine in micro-osmotic pumps over at least 14 days (Andersen and Pouzet, 2001;Frey, 1983;Gysling and Beinfeld, 1984;Kaplan et al, 1999;McMillen, 1985;Tarazi et al, 2002). There were eight mice in each treatment group except for olanzapine 2.5 which had seven mice.…”

Section: Treatment Groupsmentioning

confidence: 96%

Effects of Chronic Olanzapine and Haloperidol Differ on the Mouse N1 Auditory Evoked Potential

Maxwell

Liang

Weightman

et al. 2004

Neuropsychopharmacol

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Auditory evoked potentials have been used in a variety of animal models to assess information-processing impairments in schizophrenia. Previous mouse models have primarily employed a paired click paradigm to assess the transient measures of auditory gating. The current study uses stimulus trains at varied interstimulus intervals (ISI) between 0.25 and 8 s in mice to assess the effects of chronic olanzapine and haloperidol on auditory processing. Data indicate that olanzapine increases the amplitude of the N40, P80, and P20/N40 components of the auditory evoked potential, whereas haloperidol had no such effect. The ISI paradigm also allowed for an evaluation of several components of the mouse evoked potential to assess those that display response properties similar to the human P50 and N100. Data suggest that the mouse N40 displays an ISI response relationship that shares characteristics with the human N100, whereas the P20 appears more consistent with the human P50 across the ISI range evaluated in this task. This study suggests that olanzapine may help improve N100 impairments seen in schizophrenia, while haloperidol does not.

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“…Amphetamine, an indirect dopaminergic agonist, decreases PPI via dopamine D2 receptors (Ralph-Williams et al, 2002) that inhibit AC activity (Neves et al, 2002). Conversely, haloperidol, a typical antipsychotic that blocks D2 receptors (cf., Miyamoto et al, 2005) and increases cAMP signaling in forebrain structures (Berndt and Schwabe, 1973;Kaneko et al, 1992;Kaplan et al, 1999;Dwivedi et al, 2002; but see Kebabian et al, 1972;Carenzi et al, 1975), increases PPI (Ouagazzal et al, 2001). Thus, there appears to be a relationship between cAMP and PPI levels.…”

Section: Introductionmentioning

confidence: 96%

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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Differential effects of treatment with typical and atypical antipsychotic drugs on adenylyl cyclase and G proteins

Cited by 16 publications

References 16 publications

Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Effects of Chronic Olanzapine and Haloperidol Differ on the Mouse N1 Auditory Evoked Potential

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

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Differential effects of treatment with typical and atypical antipsychotic drugs on adenylyl cyclase and G proteins

Cited by 16 publications

References 16 publications

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Effects of Chronic Olanzapine and Haloperidol Differ on the Mouse N1 Auditory Evoked Potential

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

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Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Differential Effects of Haloperidol and Clozapine on [³H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain