Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS

Abstract

In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.

Glucocorticoids attenuate haloperidol-induced catalepsy through adrenal catecholamines

“…After this stressful procedure, the catalepsy was significantly reduced in sham-ADX but not in ADX rats. These observations are in agreement with recent reports that the release of catecholamines from adrenals induced by stress reduce catalepsy whereas adrenalectomy prevents the response to stress (Verhagen-Kamerbeek et al, 1993;Yntema and Korf, 1987). During stress, not only NA but also corticosteroids are secreted into blood (Vetrugno et al, 1993).…”

“…Similar observations have been made by others (Yntema and Korf, 1987;Verhagen-Kamerbeek, 1993). In contrast to this, administration of glucocorticoids (s.c.) at maximum catalepsy score attenuated the catalepsy in sham-ADX but failed to do so in ADX rats.…”

“…NS not significant It has been reported that some forms of akinesia, axial apraxia and freezing of gait and speech failed to respond to L-DOPA or anticholinergics (Verhagen-Kamerbeek et al, 1993) but were improved by 3 weeks glucocorticoid treatment (Nagao et al, 1991). These symptoms have been attributed at least in part to a deficiency of NA in the brain of patients with advanced stages of PD (Narabayashi, 1984).…”

“…However, recently it has been reported that some symptoms of PD were not improved by several month's treatment with L-DOPA but were improved by 3 weeks administration of glucocorticoids (Nagao et al, 1991). Such symptoms, which do not respond to L-DOPA or anticholinergics (Verhagen-Kamerbeek et al, 1993), have been attributed to noradrenaline deficiency in brain (Narabayashi, 1984).…”

Clozapine reversal of the deficits in coordinated movement induced by D2 receptor blockade does not depend upon antagonism of α2 adrenoceptors

“…Indeed, there is evidence that noradrenergic mechanisms are involved in specific Parkinson's disease symptoms: the administration of the noradrenaline precursor L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) ameliorates symptoms such as freezing of gait which are unresponsive to levodopa and carbidopa treatment in late stage Parkinson's disease (Tohgi et al 1990). L-threo-DOPS reduces haloperidol-induced catalepsy in rats (Verhagen-Kamerbeek et al 1993). Interestingly, it has been hypothesised that this may be due to an enhancement of peripheral noradrenaline: the i.v.…”