Investigating complex basal ganglia circuitry in the regulation of motor behaviour, with particular focus on orofacial movement.

Current concepts of basal ganglia function have evolved from the essentially motoric, to include a range of extramotoric functions that involve not only dopaminergic but also cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic mechanisms. We consider these mechanisms and their efferent systems, including spiralling, feed-forward striato-nigro-striatal circuitry, involving the dorsal and ventral striatum and the nucleus accumbens (NAc) core and shell. These processes are illustrated using three behavioural models: turning-pivoting, orofacial movements in rats and orofacial movements in genetically modified mice.

Constitutive and conditional mutant mouse models for understanding dopaminergic regulation of orofacial movements: emerging insights and challenges.

Among numerous mechanisms implicated in the regulation of orofacial movements, dopamine-containing neurons have received the most extensive study. Here we review the effects of a) constitutive knockout of D(1-5) dopamine receptors and b) conditional mutations with progressive ablation of D(1) receptor-expressing cells, on the topography of spontaneous and D(1)-like agonist-induced orofacial movements. In constitutive knockouts, D(1) and D(2) exert primary roles in regulating horizontal and vertical jaw movements, respectively, in opposite directions; in contrast, both D(1) and D(2) receptors regulate tongue protrusions and incisor chattering, in the same direction.

Regulation of orofacial movement: amino acid mechanisms and mutant models.

Generation and regulation of orofacial movements involve complex mechanisms that include primary roles not only for dopamine but also the amino acid neurotransmitters γ-aminobutyric acid (GABA) and glutamate. However, the roles of individual GABA and glutamate receptor subtypes, subunits and associated processes are unclear. Here we outline studies of motor function in mutant mice with "knockout" of GABA and glutamate receptor subtypes.

Regulation of orofacial movement: dopamine receptor mechanisms and mutant models.

Orofacial movements involve complex processes that include generators for down-stream patterns, with up-stream regulatory mechanisms. While the neurotransmitter dopamine plays a fundamental role, the role of individual dopamine receptor subtypes and their associated transduction mechanisms is unclear. Here we review systematic, comparative studies of orofacial function in mutant mice with "knockout" of D1, D2, D3, D4 or D5 receptors, or of their critical transduction component DARPP-32 at four levels: general orofacial behaviors within the mouse repertoire, as assessed naturalistically; individual components of orofacial movement, as assessed under non-naturalistic conditions; each of the above, as assessed also under challenge with a D1-like vs a D2-like agonist.

Phenotypic disruption to orofacial movement topography in conditional mutants with generalized CamKIIa/Cre D1Tox versus striatal-specific DARPP-32/Cre D1Tox ablation of D1 dopamine receptor-expressing cells.

Orofacial movements were quantified in (a) DARPP-32/Cre D1Tox mutants, having progressive loss of D1 dopamine receptor expressing striatal medium spiny neurons and (b) CamKIIa/Cre D1Tox mutants, having progressive, generalized loss of forebrain D1 receptor expressing cells. Horizontal jaw movements and tongue protrusions were reduced in DARPP-32/Cre but not in CamKIIa/Cre mutants; head and vibrissae movements were increased in DARPP-32/Cre but decreased in CamKIIa/Cre mutants. In drug challenge studies, tongue protrusions were increased in CamKIIa/Cre mutants following vehicle, suggesting a stress-related phenotype.

Orofacial movements in phospholipase C-related catalytically inactive protein-1/2 double knockout mice: Effect of the GABAergic agent diazepam and the D(1) dopamine receptor agonist SKF 83959.

Orofacial movements are regulated by D(1)-like dopamine receptors interacting with additional mechanisms. Phospholipase C-related catalytically inactive protein (PRIP) regulates cell surface expression of GABA(A) receptors containing a gamma2 subunit. Mutant mice with double knockout of PRIP-1 and PRIP-2 were used to investigate aspects of GABAergic regulation of orofacial movements and interactions with D(1) mechanisms.

Phenotype of spontaneous orofacial dyskinesia in neuregulin-1 'knockout' mice.

Studies in antipsychotic-naïve patients with schizophrenia indicate a baseline level of spontaneous involuntary movements, particularly orofacial dyskinesia. Neuregulin-1 is associated with risk for schizophrenia and its functional role can be studied in 'knockout' mice. We have shown previously that neuregulin-1 'knockouts' evidence disruption in social behaviour.

Differential involvement of cyclase- versus non-cyclase-coupled D1-like dopamine receptors in orofacial movement topography in mice: studies with SKF 83822.

Though orofacial movements are fundamental motor patterns that are known to be regulated critically by D1-like dopamine receptors, these processes remain poorly understood. This uncertainty is heightened by evidence for putative D1-like receptors that are linked not only to adenylyl cyclase (AC) but also to phospholipase C (PLC). Using a new method, we have characterised four topographies of orofacial movement in the mouse using the novel D1-like agonist SKF 83822, which stimulates AC but not PLC.

Disruption of orofacial movement topographies in congenic mutants with dopamine D5 but not D4 receptor or DARPP-32 transduction 'knockout'.

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'.

Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface.

Background: Mutants with targeted gene deletion ('knockout') or insertion (transgenic) of D1, D2, D3, D4 and D5 dopamine (DA) receptor subtypes are complemented by an increasing variety of double knockout and transgenic-'knockout' models, together with knockout of critical components of DA receptor signalling cascades such as G alpha(olf)[G gamma7], adenylyl cyclase type 5, PKA [RIIbeta] and DARPP-32. However, it is increasingly recognised that these molecular techniques have a number of inherent limitations. Furthermore, there are poorly understood methodological factors that contribute to inconsistent phenotypic findings between laboratories.

Topographical effects of D1-like dopamine receptor agonists on orofacial movements in mice and their differential regulation via oppositional versus synergistic D1-like: D2-like interactions: cautionary observations on SK&F 82958 as an anomalous agent.

Using a novel procedure, the regulation of individual topographies of orofacial movement in the mouse by oppositional versus cooperative/synergistic D1-like: D2-like dopamine receptor interactions was studied. The D1-like agonists SK&F 38393 and SK&F 83959 each induced vertical, but not horizontal, jaw movements, together with tongue protrusions and incisor chattering; however, SK&F 82958 induced a different profile which, consistent with other neurochemical and neurophysiological studies, suggests that this agent shows anomalous properties relative to other D1-like agonists. When given alone, the D2-like agonist quinpirole reduced horizontal jaw movements and incisor chattering.

D1-like dopamine receptor-mediated function in congenic mutants with D1 vs. D5 receptor "knockout".

Current understanding of the functional roles of individual dopamine D1-like [D1, D5] and D2-like [D2L/s, D3, D4] receptor subtypes remains incomplete. In particular, the lack of pharmacological agonists and antagonists able to distinguish between D1 and D5 receptors means that any differential roles in the regulation of behavior are poorly understood. Mutant mice with targeted gene deletion ("knockout") of individual dopamine receptor subtypes offer an important alternative approach to resolving these functional roles.

Comparative phenotypic resolution of spontaneous, D2-like and D1-like agonist-induced orofacial movement topographies in congenic mutants with dopamine D2 vs. D3 receptor "knockout".

Using a novel system, the role of D2-like dopamine receptors in distinct topographies of orofacial movement was assessed in mutant mice with congenic D2 vs. D3 receptor knockout, and compared with findings in D1A mutants. Under spontaneous conditions, D2 mutants evidenced increased vertical jaw movements and unaltered horizontal jaw movements, with reductions in tongue protrusions and incisor chattering; in D3 mutants, only incisor chattering was reduced.