Author: David T Croke ; Allen A Fienberg ; Noriaki Koshikawa ; Yasuyuki Makihara ; Rachel E Nally ; Hiroshi Yamamoto ; Anthony Kinsella ; Gerard J O'Sullivan ; Katsunori Tomiyama ; David K Grandy ; John L Waddington ; Orna Tighe ; David R Sibley

The role of D(1)-like [D(1), D(5)] and D(2)-like [D(2), D(3), D(4)] dopamine receptors and dopamine transduction via DARPP-32 in topographies of orofacial movement was assessed in restrained mice with congenic D(4) vs. D(5) receptor vs. DARPP-32 'knockout'. D(4) and DARPP-32 mutants evidenced no material phenotype; also, there were no alterations in topographical responsivity to either the selective D(2)-like agonist RU 24213 or the selective D(1)-like agonist SK and F 83959. In contrast, D(5) mutants evidenced an increase in spontaneous vertical jaw movements, which habituated more slowly than in wildtypes, and a decrease in horizontal jaw movements; topographical responsivity to SK and F 83959 and RU 24213 was unaltered. D(5) receptors regulate distinct topographies of vertical and horizontal jaw movement in an opposite manner. In assuming that the well-recognised role of the D(1)-like family in regulating orofacial movements involves primarily D(1) receptors, a role for their D(5) counterparts may have been overlooked.

01 Feb 2006·SynapseQ4 · MEDICINE

Ethological resolution of behavioral topography and D2-like vs. D1-like agonist responses in congenic D4 dopamine receptor “knockouts”: Identification of D4:D1-like interactions

Q4 · MEDICINE

Article

Author: Kinsella, Anthony ; Waddington, John L. ; Grandy, David K. ; O'Sullivan, Gerard J. ; Tighe, Orna ; Croke, David T.

To clarify the involvement of dopamine D4 receptors in behavioral regulation, the phenotypic ethogram of congenic D4 "knockout" mice was studied in terms of (i) course of exploration and habituation, and (ii) topographical responsiveness to the selective D2-like agonist RU 24213 and the selective D1-like agonists A 68930, SK&F 83959 and SK&F 83822. Congenic D4 knockouts were characterized by a small reduction in exploratory sniffing with delayed habituation of sifting. The magnitude and topographical specificity of these effects indicated that any functional role for D4 receptors in exploratory processes is subtle. Induction of stereotyped, ponderous locomotion by RU 24213 was reduced in D4-null mice consistent with an involvement of D4 receptors in the topographical expression of stereotypy. Induction of grooming and, at higher doses, seizures by A 68930, which stimulates both adenylyl cyclase (AC) and phospholipase C (PLC), were unaltered in congenic D4 knockouts. In contrast, induction of grooming by SK&F 83959, which stimulates PLC but not AC and fails to induce seizures, was reduced in D4-null mice; this indicates that D4 receptors interact with PLC-coupled D1-like receptors in regulating D1-like-mediated grooming. Conversely, induction of seizures by SK&F 83822, which stimulates AC but not PLC and fails to induce grooming, was reduced in congenic D4 knockouts; this indicates that D4 receptors interact with AC-coupled D1-like receptors in regulating D1-like-mediated seizures. These studies identify novel functional roles for the D4 receptor that are distinct from those of closely related D2-like family members and involve interactions with their D1-like counterparts.

15 Mar 2005·SynapseQ4 · MEDICINE

Ethological resolution of behavioural topography and D₁‐like versus D₂‐like agonist responses in congenic D₅ dopamine receptor mutants: Identification of D₅:D₂‐like interactions

Q4 · MEDICINE

Article

Author: John L. Waddington ; Gerard J. O'Sullivan ; David T. Croke ; David R. Sibley ; Anthony Kinsella ; Orna Tighe

AbstractThe phenotypic ethogram of congenic dopamine D5 receptor “knockout” mice was evaluated. Each individual topography of behaviour within the natural repertoire was assessed over the extended course of initial exploration of and subsequent habituation to the environment, and following challenge with a series of D1‐like agonists. Over initial exploration, D5‐null mice evidenced a modest reduction in locomotion and a modest increase in sifting. Subsequent habituation revealed additional phenotypic effects, primarily overall reduction in grooming and delayed habituation of rearing. Among D1‐like agonists, A 68930 stimulates both adenylyl cyclase and a putative D1‐like receptor coupled to stimulation of phospholipase C‐mediated phosphoinositide hydrolysis; conversely, SK&F 83959 stimulates phosphoinositide hydrolysis but not adenylyl cyclase while SK&F 83822 stimulates adenylyl cyclase but not phosphoinositide hydrolysis. Though programmed grooming syntax and episodic seizure activity induced by A 68930 and SK&F 83822 were unaltered, grooming induced by SK&F 83959 was reduced in D5 mutants. Stereotyped, ponderous locomotion induced by the D2‐like agonist RU 24213 was enhanced in D5 mutants. Phenotypic and pharmacological characterisation of congenic D5‐null mice at an ethological level identifies novel functional roles for the D5 receptor in mediating discrete topographies of behaviour relating to exploration, sequential motor coordination, and how these processes change over the course of interaction with and habituation to the environment. Additionally, they indicate the involvement of phosphoinositide hydrolysis and D5:D2‐like interactions in regulating these processes. Synapse 55:201–211, 2005. Published 2005 Wiley‐Liss, Inc.

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Psychotic Disorders	Discovery	DE	Aventis Pharma SARL	-

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