Effect of serotonergic agents on adenosine A2 receptor mediated catalepsy in mice

The effect of serotonergic agents was studied on the adenosine A₂ receptor agonist NECA-induced catalepsy in mice. The 5-HT releaser fenfluramine, the 5-HT_1A agonist 8-OH-DPAT, the 5-HT_2A/1C receptor agonist DOI and the 5-HT_2A/1C receptor antagonists ketanserin and mianserin reversed NECA-induced catalepsy. p-MPPI and ketanserin reversed the anticataleptic actions of 8-OH-DPAT and DOI, respectively. Further, the 5-HT reuptake inhibitor fluoxetine, the 5-HT_1B/1C receptor agonist TFMPP, the 5-HT synthesis inhibitor p-CPA, the selective 5-HT_1A receptor antagonist p-MPPI, the 5-HT_1A/1B receptor antagonist pindolol and the 5-HT₃ receptor antagonist LY 278, 584 had no effect on NECA-induced catalepsy. The anticataleptic action of fenfluramine was not affected by pretreatment with p-CPA. In p-CPA treated rats, ketanserin did not affect the anticataleptic effect of fenfluramine, whereas p-MPPI partially reversed this effect. It is concluded that modulation of serotonergic neurotransmission at 5-HT_1A and 5-HT_2A/1C receptors affects the cataleptic action of experimental antipsychotic agents with adenosine A₂ receptor agonistic activity. Received: 5 May 1997/Final version: 2 September 1997     

Possible neuronal mechanisms involved in neurotensin-induced catalepsy in mice

The neuronal mechanisms of neurotensin (NT)-induced catalepsy were investigated in mice. NT administered intracerebroventricularly (ICV 0.5, 1.0 and 2.0 g) produced catalepsy in a dose-dependent fashion. A significant effect was observed at 2.0 g and a maximal effect 2–3 h after injection. The NT-induced catalepsy was inhibited by pretreatment with atropine, trihexyphenidyl or biperiden (each drug, 0.8–5.0 mg/kg, IP), anticholinergic drugs, and L-DOPA (100, 200 mg/kg, IP). However, the catalepsy was not significantly antagonized by p-chlorphenylalanine (300 mg/kg×3 days, IP) or methysergide (5, 10 mg/kg, IP), antiserotonergic drugs, and was not potentiated by the GABAergic drugs, aminooxyacetic acid (25 mg/kg, IP) or muscimol (1 mg/kg, IP). In addition, the NT-induced catalepsy was dose-dependently reduced by antihistamines, such as diphenhydramine (0.8–10 mg/kg, IP) and tripelennamine (0.4–5.0 mg/kg, IP) and was potentiated after treatment with histidine (250, 500 mg/kg, IP), a precursor of brain histamine. NT-induced catalepsy was also reduced by ICV pretreatment with diphenhydramine (1–5 g/rat), a H₁ antagonist, but not by cimetidine (5, 20 g/rat), a H₂ antagonist. These findings suggest that the catalepsy induced by NT may involve not only central cholinergic and dopaminergic mechanisms but also a histaminergic mechanism mediated via H₁-histamine receptors, and seems to differ from the catalepsy induced by neuroleptics.     

Effect of metergoline,fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine

Summary The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT_1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s. c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT_1A receptor mediated events in both types of catalepsy. Send offprint requests to C. L. E. Broekkamp at the above address     

The role of amphetamine metabolism in the alpha-methyl-p-tyrosine-d-amphetamine catalepsy

Administration of amphetamine to rats pretreated with the tyrosine hydroxylase inhibitor α-methyl p-tyrosine methylester HCl (α-MpT) leads to a cataleptic state, the d-isomer being more active than the 1-isomer. Inhibition of either aromatic hydroxylation of d-amphetamine or β-hydroxylation of the metabolic product p-hydroxyamphetamine failed to prevent development of the cataleptic state. Changes in the time of onset of catalepsy can be attributed to the higher tissue levels of amphetamine prevailing after blockade of its metabolic pathway. Differences in the degree of catalypsy induced by d- and 1-amphetamine in α-MpT-pretreated animals cannot be attributed to differences in metabolism of the two isomers.     

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP

Rationale: Current treatment of Parkinson’s disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A_2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. Objectives: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A_2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro-1H-purine-2,6-dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson’s disease. Methods: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A_2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. Results: The ED₅₀s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED₅₀ of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and l-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A_2A receptor antagonist KW-6002 and dopaminergic agents. Conclusions: To our knowledge, KW-6002 is the most potent and orally active adenosine A_2A receptor antagonist in experimental models of Parkinson’s disease, and may offer a new therapeutic approach to the treatment of Parkinson’s disease. Received: 22 March 1999 / Final version: 25 May 1999     

The role of dopamine in pilocarpine-induced catalepsy

Summary The cataleptic effect of the cholinomimetic compound, pilocarpine, was compared to the pilocarpine-induced changes in striatal dopamine metabolism in rats.Pilocarpine induced catalepsy, the intensity of which increased with increasing dosage, but it did not make rats maximally cataleptic in the doses studied here. Doses higher than 200 mg/kg i.p. could not be studied because of toxicity. Pilocarpine increased the striatal homovanillic acid (HVA) content up to three times the original concentration. The greatest increase was found 2 h after 50 mg/kg of pilocarpine. Atropine (50 mg/kg) antagonized both the catalepsy and HVA increase produced by pilocarpine (200 mg/kg). Apomorphine (10 mg/kg) lowered the striatal HVA content by about 85%. This decrease had disappeared after 4 h. Apomorphine antagonized the HVA increase caused by 50 mg/kg of pilocarpine, but after an initial decrease apomorphine potentiated the HVA increase produced by 200 mg/kg of pilocarpine. Apomorphine did not modify the slight cataleptic effect of 50 mg/kg of pilocarpine but potentiated and prolonged the catalepsy produced by 200 mg/kg of pilocarpine. Pilocarpine-catalepsy was potentiated by -methyl-p-tyrosine (MPT 250 mg/kg) and pilocarpine accelerated the dopamine decrease caused by MPT. Pilocarpine alone in doses up to 200 mg/kg did not statistically significantly change the brain dopamine concentration.These results show that when the striatal cholinergic mechanisms are disturbed changes are induced in striatal dopamine metabolism. The striatal cholinergic and dopaminergic systems are antagonistic but the dopaminergic system can compensate for the overactivity of the striatal cholinergic system only to a certain extent.This study was supported by the National Research Council for Medical Sciences Finland, and the Finnish Medical Society, Duodecim.     

Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy

Pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective serotonin neuronal uptake blocker, was found to potentiate the cataleptic effect of haloperidol in a dose-dependent manner in rats. Pretreatment with methysergide, a serotonin antagonist, reduced the cataleptic effect of haloperidol. The results indicate that the cataleptic effect of neuroleptics depends on the balance between the dopaminergic and serotonergic systems, and that the serotonergic system exerts an inhibitory influence on the dopaminergic system.     

Mirtazapine enhances the effect of haloperidol on apomorphine-induced climbing behaviour in mice and attenuates haloperidol-induced catalepsy in rats

 Activation of 5-HT_1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT_1A receptor stimulating properties as well as antagonist properties at α₂-adrenoceptors and 5-HT₂ receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2–22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT_1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/ kg) was attenuated by mirtazapine (2.2–22 mg/kg). The strongest effect was seen at 90 min after haloperidol treament. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window. Received: 6 May 1997/Final version: 10 August 1997     

The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats

Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01-1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, d-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties.     

Postnatal development of a cholinergic influence on neuroleptic-induced catalepsy

The development of cholinergic influence on neuroleptic-induced catalepsy was investigated in 10-, 15- and 20-day-old rat pups. It was found that the antimuscarinic atropine was ineffective in decreasing the catalepsy produced by spiroperidol treatment at 10 and 15 days. By day 20, however, atropine attenuated cataleptic behavior in a dose-dependent manner. Atropine alone was shown paradoxically to elicit mild to moderate cataleptic responses in 10- and 15-day-olds, but not at day 20. Clozapine by itself produced the same age dependent pattern of catalepsy response as the spiroperidol and atropine combination treatment. These results suggest that cholinergic mechanisms which interact antagonistically with the dopamine systems underlying cataleptic behavior are not functionally mature until after day 15 in the rat.     

Evidence for an A2 adenosine receptor in guinea pig lung

Summary Adenosine receptors in guinea pig lung were characterized by measurement of cyclic AMP formation and radioligand binding. 5-N-Ethylcarboxamidoadenosine (NECA) increased cyclic AMP levels in lung slices about 4-fold over basal values with an EC₅₀ of 0.32 mol/l. N⁶-R-(–)-Phenylisopropyladenosine (R-PIA) was 5-fold less potent than NECA. 5-N-Methylcarboxamidoadenosine (MECA) and 2-chloroadenosine had EC₅₀-values of 0.29 and 2.6 mol/l, whereas adenosine and inosine had no effect. The adenosine receptors in guinea pig lung can therefore be classified as A₂ receptors. Several xanthine derivatives antagonized the NECA-induced increase in cyclic AMP levels. 1,3-Diethyl-8-phenylxanthine (DPX; K _i 0.14 mol/l) was the most potent analogue, followed by 8-phenyltheophylline (K _i 0.55 mol/l), 3-isobutyl-1-methylxanthine (IBMX; K _i 2.9 mol/l) and theophylline (K _i 8.1 mol/l). In contrast, enprofylline (1 mmol/l) enhanced basal and NECA-stimulated cyclic AMP formation. In addition, we attempted to characterize these receptors in binding studies with [³H]NECA. The K _D for [³H]NECA was 0.25 mol/l and the maximal number of binding sites was 12 pmol/mg protein. In competition experiments MECA (K _i 0.14 mol/l) was the most potent inhibitor of [³H]NECA binding, followed by NECA (K _i 0.19 mol/l) and 2-chloroadenosine (K _i 1.4 mol/l). These results correlate well with the EC₅₀-values for cyclic AMP formation in lung slices. However, the K _i-values of R-PIA and theophylline were 240 and 270 mol/l, and DPX and 8-phenyltheophylline did not compete for [³H]NECA binding sites. Therefore, a complete characterization of A₂ adenosine receptors by [³H]NECA binding was not achieved. In conclusion, our results show the presence of adenylate cyclase-coupled A₂ adenosine receptors in lung tissue which are antagonized by several xanthines.     

Suppressive effect of cholecystokinin and its related peptides on beta-endorphin-induced catalepsy in rats

The effects of the C-terminal octapeptide of cholecystokinin (CCK-8) and its related peptides on the onset and duration of beta-endorphin-induced catalepsy on injection of the peptides into the lateral ventricle were investigated in male rats. The onset of catalepsy was delayed to some extent by nonsulfated CCK-8 and CCK-7 but CCK-8 and caerulein were ineffective. Naltrexone and caerulein significantly shortened the duration of catalepsy, but CCKs were less effective to shorten it. Pentagastrin had no effect on either parameter.     

Comparative effects of estradiol stereoisomers on pimozide-induced catalepsy, locomotor activity and body-weight in the rat

The effects of 17-alpha and 17-beta estradiol were compared at three dose levels on locomotor activity, pimozide-induced catalepsy, and changes in body weight. At 10 micrograms/kg/day they increased locomotor activity to a similar degree but at 5 and 1 microgram/kg/day the beta form was mor effective. However the alpha isomer failed to potentiate catalepsy, or reduce body weight, even at the highest dose whereas 17-beta estradiol did both. From these and other results it is suggested that estradiol might act on intracellular receptors and not by changing catecholamine metabolism.     

Effects of dopaminergic and cholinergic drugs,naloxone and l-prolyl-leucyl-glycinamide on LSD-induced catalepsy

Summary In an attempt to elucidate the mechanism of d-lysergic acid diethylamide (LSD) induced catalepsy, the effects of cholinergic and dopaminergic agents, naloxone and l-propyl-leucyl-glycinamide (PLG) were studied in rats. The dose-dependent (50–500 g kg^–1 s.c.) and time-related cataleptic response elecited by LSD was preceded by a phase of hyperexcitability. The non-hallucinogenic analogue, 2-bromo-LSD (BOL), was without effect. Both apomorphine, the dopamine agonist, and l-DOPA antagonized LSD-induced catalepsy whereas the dopamine depleting agent -methyl-p-tyrosine (-MPT) slightly prolonged the cataleptic effect. Cholinergic muscarinic receptor stimulation with pilocarpine antagonized LSD-induced catalepsy. The muscarinic antagonists, atropine and scopolamine, intensified the hyperexcitable phase and potentiated the cataleptic effects of LSD. Nicotine slightly potentiated LSD action but mecamylamine antagonized it. While pre-treatment with naloxone, the narcotic antagonist and PLG prolonged the cataleptic response, post-treatment with naloxone effectively attenuated LSD-induced catalepsy. The behavioural data are interpreted to suggest that LSD-induced catalepsy may be mediated through diminished dopaminergic and cholinergic neuronal activity and under enkephalinergic modulation. The neuroanatomical foci and exact mechanism of action remain to be delineated.     

Subsensitivity to muscimol-induced catalepsy after long-term administration of phenytoin in rats

Male albino rats were injected with 25 mg/kg of phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 or 2 mg/kg of muscimol, a GABA receptor agonist. Rats treated with PHT showed a decreased responsiveness to muscimol-induced catalepsy (2 mg/kg) on day 21 but not on day 28. Acutely administered PHT, on the contrary, had a tendency to potentiate muscimol-induced catalepsy. Muscimol-induced catalepsy was not antagonized by acute treatment with bicuculline (0.5–2.0 mg/kg). It is proposed that withdrawal after long-term administration of PHT reduces the sensitivity of a GABA receptor site not sensitive to bicuculline.     

Evaluation of amphetamine-induced hyperlocomotion and catalepsy following long-acting risperidone administration in rats

It has been proposed that long-acting risperidone could provide a constant antipsychotic efficacy associated with a reduced liability to induce extra-pyramidal symptoms. To ascertain this hypothesis, antagonism of amphetamine-induced hyperlocomotion and catalepsy were analyzed in rats for a period of 1–6 weeks following long-acting risperidone (20–60 mg/kg) injection. Long-acting risperidone reduced amphetamine-induced hyperlocomotion after 2–5 weeks from drug injection, without producing significant extra-pyramidal symptoms. Following the administration of long-acting risperidone a constant ability to antagonize amphetamine-induced hyperlocomotion was observed during the day, but not when the antipsychotic was chronically administered using a short-acting formulation. The pre-clinical results confirmed that long-acting risperidone may represent an advance in antipsychotic therapy.     

Sub-chronic inhibition of nitric-oxide synthesis modifies haloperidol-induced catalepsy and the number of NADPH-diaphorase neurons in mice

Rationale: N ^G-nitro-l-arginine (l-NOARG), an inhibitor of nitric-oxide synthase (NOS), induces catalepsy in mice. This effect undergoes rapid tolerance, showing a significant decrease after 2 days of sub-chronic l-NOARG treatment. Nitric oxide (NO) has been shown to influence dopaminergic neurotransmission in the striatum. Neuroleptic drugs such as haloperidol, which block dopamine receptors, also cause catalepsy in rodents. Objectives: To investigate the effects of sub-chronic l-NOARG treatment in haloperidol-induced catalepsy and the number of NOS neurons in areas related to motor control. Methods: Male albino Swiss mice were treated sub-chronically (twice a day for 4 days) with l-NOARG (40 mg/kg i.p.) or haloperidol (1 mg/kg i.p.). Catalepsy was evaluated at the beginning and the end of the treatments. Reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was also employed to visualize NOS as an index of enzyme expression in mice brain regions related to motor control. Results: l-NOARG sub-chronic administration produced tolerance of l-NOARG and of haloperidol- induced catalepsy. It also induced an increase in the number of NADPH-d-positive cells in the dorsal part of the caudate and accumbens nuclei compared with haloperidol and in the pedunculopontine tegmental nucleus compared with saline. In contrast, there was a decrease in NADPH-d neuron number in the substantia nigra, pars compacta in both haloperidol-treated and l-NOARG-treated animals. Conclusions: The results give further support to the hypothesis that NO plays a role in motor behavior control and suggest that it may take part in the synaptic changes produced by antipsychotic treatment. Received: 23 February 1999 / Final version: 28 July 1999     

The effect of amantadine on motor activity and catalepsy in rats

The effect of amantadine on motor activity was investigated in rats. The compound was used at doses which antagonized the catalepsy induced by spiroperidol, triperidol, chlorpromazine and reserpine. These doses moderately stimulated motor activity in normal rats; their activity was effectively antagonized by spiroperidol, chlorpromazine, phenoxybenzamine but only slightly, if at all, by -methyltyrosine, dimethyldithiocarbamate and reserpine. The behavioral effects of amantadine in normal and reserpinized rats were potentiated by l-DOPA, nialamide, desipramine and, in particular, by cocaine. The cocaine-induced potentiation of the amantadine effect was prevented by spiroperidol. -Methyltyrosine did not influence the antagonism of amantadine towards spiroperidol-induced catalepsy. Noradrenaline and dopamine levels in the whole brain and dopamine levels in the corpus striatum were unaltered by amantadine. The main mechanism of action of amantadine appears to be the activation of central dopamine receptors.     

Small doses of apomorphine induced catalepsy and antagonize methamphetamine stereotypy in rats

Small doses of apomorphine (AP, 31.25–125 g/kg IP) induced dose-dependent catalepsy in rats. However. unlike the stereotyped behavior induced by high doses of AP which has a rapid onset and is short-lasting, the cataleptic effect induced by small doses of AP was evident 30 min after AP injection and was unusually long-lasting. Further, AP (31.25–125 g/kg) administered 60 min before methamphetamine was found to significantly antagonize the methamphetamine-induced stereotyped behavior. Pretreatment with molindone (0.45 and 0.8 mg/kg IP), in doses reported to selectively block the presynaptic DA receptors, not only decreased the cataleptic effect of AP but also reversed the AP antagonism of methamphetamine stereotypy. The results suggest that small doses of AP induce catalepsy and antagonize methamphetamine stereotypy probably by an action at presynaptic DA receptor sites.     

Effects of naloxone on methamphetamine and apomorphine stereotypy and on haloperidol catalepsy in rats

Pretreatment with the opiate antagonist naloxone, at 1.25–5 mg/kg, increased the intensity of methamphetamine stereotypy, had no effect (over a range of 0.3125–5 mg/kg) on apomorphine stereotypy, and antagonized haloperidol catalepsy in rats at 1.25–5 mg/kg. It is suggested that naloxone, by blocking the opiate receptors located on the nigro-striatal and mesolimbic dopamine (DA) nerve terminals, releases the DA systems from endogenous inhibition, presumably caused by endogenous opiate systems, and thereby potentiates methamphetamine stereotypy and antagonizes haloperidol catalepsy. However, the possibility that naloxone might have affected methamphetamine stereotypy and haloperidol catalepsy by modulating the activity of the central noradrenergic and GABAergic systems, which are reported to influence dopaminergically mediated behaviours, also needs to be considered.