The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade.

Dopamine D2 and adenosine A(2A) receptors interact to regulate aspects of motor and motivational function, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of parkinsonism and depression. The present experiments were performed to characterize the effects of Lu AA47070, which is a phosphonooxymethylene prodrug of a potent and selective adenosine A(2A) receptor antagonist, for its ability to reverse the motor and motivational effects of D2 antagonism. In the first group of studies, Lu AA47070 (3.75-30 mg/kg IP) was assessed for its ability to reverse the effects of the D2 receptor antagonist pimozide (1.0 mg/kg IP) using several measures of motor impairment, including catalepsy, locomotion, and tremulous jaw movements, which is a rodent model of parkinsonian tremor. Lu AA47070 produced a significant reversal of the effects of pimozide on all three measures of parkinsonian motor impairment. In addition, Lu AA47070 was able to reverse the effects of a low dose of the D2 antagonist haloperidol on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. The ability of Lu AA47070 to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression.

Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.

Dietary n-3 and n-6 fatty acids are equipotent in stimulating volume regulation in Ehrlich ascites tumor cells.

This investigation addresses whether enriching cellular phospholipids with n-3 or n-6 fatty acids affects the process of regulatory volume decrease (RVD) in murine Ehrlich ascites tumor cells. Two weeks of dietary n-3-rich fish oil (7.5%, wt/wt) increased the ratio of eicosapentaenoic acid to arachidonic acid in cellular phospholipids compared with an olive oil control diet. Cells grown in mice fed on fish oil had an accelerated RVD response after hypotonic exposure, indicating that the volume-induced K+ conductance was increased. The fish oil diet furthermore resulted in an increased Cl- conductance during RVD, demonstrated as an increased initial rate of cell shrinkage after addition of K+ ionophore to the swollen cells. The initial rate of volume recovery correlated positively with the sum of eicosanoid precursors (arachidonic acid plus eicosapentaenoic acid) (P = 0.007). Diet supplemented with n-6 fatty acids resulted in an enhanced RVD response as well. RVD was inhibited by anti-calmodulin drugs, and exogenous leukotriene D5 and leukotriene D4 were equipotent in attenuating this inhibition. We conclude that dietary polyunsaturated fatty acids result in a more effective RVD response because of an increase in the volume-induced Cl- and K+ conductances. We propose that this is caused by an enhanced volume-induced leukotriene synthesis due to an increase in eicosanoid precursor availability.

[Effect of amantadine on intracranial self-stimulation behavior and cerebral glucose utilization in rats].

Effect of amantadine, an adamantane derivative, was investigated on intracranial self-stimulation behavior and cerebral glucose utilization (CGU) in rats. The experiments were performed on Wistar strain male rats. The low rate responses induced by low current brain stimulation on lateral hypothalamic self-stimulation behavior in a Skinner box were increased by p.o. administration of amantadine at doses of 5 and 10 mg/kg, but were decreased at doses of over 50 mg/kg. Amantadine at doses of 5 and 10 mg/kg, p.o., increased the running speed in run-way performance of animals rewarded with electric stimulation of the medial forebrain bundle in the lateral hypothalamus. On a "conflict" situation induced by combining the hypothalamic self-stimulation with midbrain dorsal central gray stimulation in a Skinner box, amantadine at doses of 5 and 10 mg/kg, p.o. caused an increase of lever pressing in the unpunished period without affecting the punished responses. The CGU measured by [14C] 2-deoxyglucose autoradiography was increased by i.p. administration of 5 mg/kg. In addition, amantadine at a dose of 5 mg/kg, i.p., decreased the high optic density in bilateral habenulae induced by pimozide at 0.75 mg/kg, i.p. These results indicate that amantadine facilitates the intracranial self-stimulation behavior related to a dopaminergic mechanism at low doses, and inhibits the high local CGU of bilateral habenulae induced by pimozide.

Opposite action of m-chlorophenylpiperazine on avoidance depression induced by trazodone and pimozide in CD-1 mice.

m-Chlorophenylpiperazine (CPP) given in doses up to 2 mg/kg did not affect conditioned avoidance responses (CAR) of CD-1 mice pre-trained in a shuttle box. It reversed the inhibitory action of trazodone (10 mg/kg) on CAR, but dose-dependently potentiated the inhibitory effect of pimozide (0.2 and 0.5 mg/kg). Apparently, dopaminergic transmission is important for the attenuating effect of CPP on CAR inhibition.

Restoration of self-stimulation inhibited by neuroleptics.

Pimozide-induced inhibition of lever-pressing for brain stimulation in the lateral hypothalamic area was differentially restored by the centrally acting anticholinergic, dexetimide and by different dopaminergic drugs. In addition, a differential antagonism towards chlorpromazine-induced inhibition of self-stimulation was shown. The results indicate that anticholinergis (non-competitive antagonism) or drugs which enhance endogenous neuro-transmission by increased release or by uptake blockade (competitive antagonism) are able to reserve the neuroleptic-induced inhibition of self-stimulation more effectively than are receptor agonists.

The effects of dexetimide on pimozide-, haloperidol- and pipamperone-induced inhibition of brain self-stimulation in rats.

Pimozide (0.04, 0.16, 0.63 and 2.50 mg/kg), haloperidol (0.01, 0.04, 0.16 and 0.63 mg/kg) and pipamperone (2.50, 10.0, 40.0 and 160 mg/kg) were given subcutaneously to rats, pressing a lever for brain-stimulation through electrodes implanted in the lateral hypothalamic region of the medial forebrain bundle. The lowest dose of each neuroleptic did not affect self-stimulation; the second dose inhibited the response rate by approximately 50%, whereas the two highest doses completely suppressed self-stimulation behaviour. The centrally acting anticholinergic dexetimide (0.63 mg/kg, s.c.) completly antagonized the pimozide-induced inhibition; the haloperidol-induced inhibition was also completely antagonized except at its highest doses, whereas the effects of the sedative neuroleptic pipamperone were not antagonized. These data are consistent with a presumed dopaminergic cholinergic striatal interaction and show brain self-stimulation to be an effective measure of neuroleptic-anticholinergic interaction.

Cholinergic-dopaminergic interaction in the striatum: the effect of 6-hydroxydopamine or pimozide treatment on the increased striatal acetylcholine levels induced by apomorphine, piribedil and d-amphetamine.

Apomorphine (1 and 2 mg/kg), piribedil (15 and 60 mg/kg) and d-amphetamine (5 and 10 mg/kg) increased rat striatal acetylcholine levels without affecting choline. Pretreatment with pimozide (0.5 mg/kg) completely antagonized the effect of apomorphine and piribedil and by itself markedly decreased striatal acetylcholine levels. d-Amphetamine signigicantly antagonized the effect of pimozide. Nine days after pretreatment with 6-hydroxydopamine plus pargyline, striatal dopamine was decreased by 78% while acetylcholine and choline levels remained unaltered. Under these conditions, the effect of d-amphetamine was completely abolished while apomorphine and piribedil were just as active as in the vehicle-treated group. The results suggest that d-amphetamine acted indirectly to increase striatal acetylcholine levels probably through the release of dopamine and/or noradrenaline, while apomorphine and piribedil acted directly at dopamine receptor sites.

Antagonistic effect of cyproheptadine on neuroleptic-induced catalepsy.

The influence of cyproheptadine on the neuroleptic-catalepsy in rats was studied. Cyproheptadine antagonized dose-dependently the catalepsy induced by spiroperidol, pimozide, fluphenazine and reserpine. The anticataleptic effect of two antiparkinsonian drugs, L-DOPA or amantadine was potentiated by cyproheptadine.