Effect of Dopamine Uptake Inhibition on Brain Catecholamine Levels and Locomotion in Catechol-O-methyltransferase-Disrupted Mice

Abstract

Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake 1 , followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake 2 , followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy-]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wildtype mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.The dopamine transporter (DAT) and monoamine oxidase (MAO) play key roles in dopamine elimination and are expected to have pleiotropic effects on susceptibility to a wide range of behavioral/psychiatric disorders and symptoms associated with dysregulation of dopamine transmission. Due the extraneuronal location in the brain (astrocytes, capillary walls, and postsynaptic dendritic spines; Karhunen et al., 1995), the significance of catechol-O-methyltransferase (COMT) on dopamine metabolism remains secondary under normal conditions.

Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

“…In outline, 10 mice (Fig. 1) The exploratory phenotype of COMT deletion was not characterized by any generic change in 'activity', as noted previously [8,10,14]. Rather, the present behavioural approach revealed reduction in rearing free and increases in sifting and chewing.…”

“…Phenotypic studies in COMT knockouts have involved behavioural paradigms which include general motor activity, anxiety, aggression and sensorimotor gating [8,10,14]. Additionally, low COMT activity may fail to buffer the effect of related 22q11 mutations that also effect DA turnover in the PFC [26].…”

The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring

“…In addition to the direct impact COMT might thus have on prefrontal functioning, different mechanisms have been pro- posed for a relationship between COMT activity and dopamine release in the basal ganglia: extrasynaptic COMT in the basal ganglia might directly influence local tonic dopaminergic activity (Huotari et al, 2002) or, alternatively, prefrontal COMT level might drive striatal dopamine levels via a regulation of glutamatergic projections from PFC to the basal ganglia (Bilder et al, 2004;Meyer-Lindenberg et al, 2006). More specifically, lower COMT level will increase firing of pyramidal neurons in the PFC and increase corticostriatal glutamate transmission, resulting finally in increased glutamatestimulated tonic dopamine release in the striatum and suppression of phasic dopamine release (Bilder et al, 2004).…”

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…Further studies in the COMT knockout mice, using cocaine, GBR 12909 (a dopamine transporter inhibitor), levodopa, or amphetamine, showed that some but not all neurochemical and behavioral responses to these pharmacological challenges are sex specific (Huotari et al, 2002a(Huotari et al, , b, 2004see also O'Tuathaigh et al, 2007). For example, d-amphetamine administration affected dopamine metabolism equally in male and female knockout mice (Huotari et al, 2004), whereas hyperactivity in response to GBR 12909 was attenuated only in male mice (Huotari et al, 2002b).…”