Constitutive Hyperdopaminergia is Functionally Associated with Reduced Behavioral Lateralization

Abstract

According to the dopamine (DA) hypothesis of schizophrenia and the strong evidence for decreased cerebral lateralization in schizophrenic patients, we postulated that hyperactivity of the dopaminergic system could be associated with a reduced behavioral lateralization in mice. Mice lacking the dopamine transporter (DAT) gene were used as a genetic model of persistent hyperdopaminergia. The DAT null mutation was transferred on C57BL/6JOrl (B6) and DBA/2JOrl (D2) inbred backgrounds for more than 10 generations of backcrossing to derive three DAT strains, B6, D2, and B6 Â D2(F 1 ). Adult mutant mice of the three DAT strains and their littermates were tested for paw preference using Collins' protocol. Our results demonstrated that, whatever the genetic background, persistent hyperdopaminergia directly impairs the degree of lateralization without affecting the direction. Our results support the degree of lateralization as a good candidate phenotype to further improve genetic analysis of cerebral lateralization in normal and pathological conditions. Neuropsychopharmacology Keywords: schizophrenia; direction and degree of asymmetry; paw preference; knockout mice; cocaine INTRODUCTIONAnomalies in behavioral, neuroanatomical, and neurophysiological asymmetry have been widely documented in schizophrenic patients, supporting lateralization as a good candidate symptom that could contribute to clarifying schizophrenia heterogeneity (Leboyer et al, 1998). A metaanalysis of 19 studies on schizophrenia showed that the prevalence of non-right-handedness was significantly higher in patients than in healthy subjects (Sommer et al, 2001). Similarly, in the meta-analysis of three prospective followup studies, pre-schizophrenic subjects were significantly more often non-right-handed than the general population (Sommer et al, 2001). Furthermore, in vivo imaging studies of schizophrenia have provided evidence that the right-left asymmetry of the dopamine (DA) synthesis capacity and of the dopamine transporter (DAT) binding in the caudate are both lost in antipsychotic-naive patients (Hietala et al, 1999(Hietala et al, , 1995Hsiao et al, 2003;Laakso et al, 2000). In addition, neuroleptics are able to change the balance of hemispheric activity, thus improving left-hemispheric attentional processes (for a review, see Gruzelier, 1999), and a recent study demonstrated that haloperidol-induced downregulation of DA synthesis was significantly greater in the left than in the right striatum (Grunder et al, 2003). Finally, a highly significant correlation was reported between depressive symptoms in antipsychotic-naive schizophrenia and DA synthesis capacity in the left striatum (Hietala et al, 1999).Taken together, these data support the hypothesis of a potential link between cerebral lateralization and schizophrenia, and suggest that abnormal asymmetry of the dopaminergic transmission could be one of the key neurobiological substrates for this functional relationship. Based on the DA hypothesis of schizophrenia, which attributes the positive sc...

Reduced Laterality as a Trait Marker ofSchizophrenia—Evidence from Structural and Functional Neuroimaging

“…For example, Angrilli et al (2009) and Spironelli et al (2008) proposed a neuropsychological link between reduced language lateralization and the psychopathology of schizophrenia. Moreover, reduced laterality is a target for both twin (Niethammer et al, 2000) and molecular genetics (e.g., Leonard et al, 2006;Francks et al, 2007;Crow et al, 2009) studies and for animal models of schizophrenia (Morice et al, 2005).…”

Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knockout mice

“…As previously described (Morice et al 2004(Morice et al , 2005, we have maintained the DAT mutation simultaneously on two inbred genetic backgrounds: C57BL/6J (B6) and DBA/2 (D2). These two standard strains were chosen for their well-known stable and marked differences in most addiction-related phenotypes (Belknap et al 1993;Crabbe et al 1994Crabbe et al , 1999Cunningham et al 1992).…”

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

“…DAT KO mice show spontaneous hyperactivity and a paradoxical calming effect of psychostimulants, like methylphenidate used for ADHD therapy (Gainetdinov et al, 1999b;Spielewoy et al, 2001). These mice also exhibit a loss of lateralization, a deficit in pre-pulse inhibition of the startle reflex, as well as cognitive impairments, some of these being restored by antipsychotic agents (Gainetdinov et al, 1999a;Ralph et al, 2001;Morice et al, 2005;Morice et al, 2007). All these data suggest that DAT KO mice represent a pertinent model for some of the symptoms encountered in schizophrenia, ADHD, and drug abuse (Gainetdinov and Caron, 2000; for a review, see Gainetdinov et al, 2001).…”