No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats

Abstract

Catechol-O-methyltransferase inhibitors have been newly introduced as adjunct drugs to the levodopa/dopa decarboxylase inhibitor therapy in Parkinson's disease. When given alone, catechol-O-methyltransferase inhibitors seem to affect behaviour. We wanted to determine whether the concentrations of free amine would be increased by catechol-O-methyltransferase inhibition with tolcapone and underpin the positive behavioural effects. To this end, dopamine and noradrenaline levels were analyzed in the microdialysis perfusion fluid collected from several brain regions in chloral hydrate anaesthetized rats. We also analyzed the turnover rate of catecholamines in the brain after single doses of tolcapone and entacapone using the α-methyl-p-tyrosine method. On their own, tolcapone (at 10 or 30 mg/kg) did not elevate dopamine or noradrenaline levels in any brain region studied although the formation of catechol-O-methyltransferase-dependent metabolites was strongly reduced. Neither tolcapone nor entacapone (at 30 mg/kg) affected the turnover rate of catecholamines. It seems that catechol-O-methyltransferase inhibitors do not alter behaviour by elevating extracellular levels of free catecholamines levels but other explanations are needed.

Introduction

Catechol-O-methyltransferase inhibitors have been newly introduced as adjunct drugs to the levodopa/dopa decarboxylase inhibitor therapy used in Parkinson's disease. Catechol-O-methyltransferase-inhibition improves the bioavailability of l-dopa and its transport into the brain and subsequently enhances dopamine synthesis in the brain (Kaakkola et al., 1994; Männistö et al., 1992b). There are two such drugs available. Tolcapone inhibits brain catechol-O-methyltransferase activity at moderate doses (3–10 mg/kg) suppressing homovanillic acid (HVA) levels and increasing dihydroxyphenyl acetic acid (DOPAC) levels in the striatum and in the microdialysis fluid (Männistö et al., 1992a; Zürcher et al., 1990). In contrast, entacapone at doses of 30 mg/kg and higher only temporarily suppresses striatal catechol-O-methyltransferase activity (Nissinen et al., 1992). Doses up to 100 mg/kg have been needed in in vivo microdialysis studies to significantly decrease the striatal HVA efflux and to increase DOPAC efflux (Kaakkola and Wurtman, 1992).

Generally, when given alone, catechol-O-methyltransferase inhibitors have virtually no effect on the motoric behaviour of rodents (Männistö, 1998; Männistö et al., 1992b; Maj et al., 1990). However, a compound which interferes with adrenergic transmission would be predicted to have important cognition enhancing effects via improved attention and motivation or by regulation of cholinergic functions (Kelland et al., 1993; Levin et al., 1990). In fact, we have found that catechol-O-methyltransferase inhibitors affect several phases of learning in a simple passive avoidance paradigm (Khromova et al., 1997). In more sophisticated studies, spatial working memory (radial-arm maze) of intact rats was facilitated following pretraining i.p. administration of tolcapone (10 mg/kg). Similarly, tolcapone improved the performance of senescent poor performers in the spatial memory task (linear arm maze). However, tolcapone was not able to counteract the performance deficits in rats in which the memory had been impaired by scopolamine or bilateral lesions in the nucleus basalis magnocellularis (Liljequist et al., 1997). In a special brain stimulation model, tolcapone given alone has shown antidepressant activity (Moreau et al., 1994). In our studies, however, also levodopa was needed to reveal the antidepressant-like effect of tolcapone in two other rat models of depression (Männistö et al., 1995).

It is documented that the new catechol-O-methyltransferase inhibitors, when combined with levodopa and dopa decarboxylase inhibitors, lead to an increase in brain (Männistö et al., 1992a; Zürcher et al., 1990) and extracellular l-dopa and dopamine levels (Acquas et al., 1992; Kaakkola and Wurtman, 1993; Törnwall et al., 1994). Similar neurochemical studies with catechol-O-methyltransferase inhibitors given alone are rather rare. However, we (Törnwall et al., 1994) and others (Acquas et al., 1992; Kaakkola and Wurtman, 1992) have found that tolcapone alone does not alter striatal extracellular dopamine levels.

In the present study, noradrenaline levels were analyzed in the microdialysis fluid collected from the frontal cortex, nucleus accumbens and dentate gyrus and dopamine levels collected from the striatum and nucleus accumbens in chloral hydrate anaesthetized rats to determine whether the concentrations of free amine would be increased by catechol-O-methyltransferase inhibition with tolcapone in some of the brain regions involved in learning and memory. We also analyzed turnover rate of catecholamines in the brain after single doses of tolcapone and entacapone. The latter drug was used as a negative control reflecting mainly peripheral catechol-O-methyltransferase inhibition.