Alma J. Gower

α2-ADRENOCEPTORS MEDIATE CLONIDINE-INDUCED SEDATION IN THE RAT

1 The central α‐adrenoceptors responsible for mediating clonidine‐induced sedation in rats have been characterized according to their sensitivity to α‐adrenoceptor agonists and antagonists. 2 Clonidine, injected intraperitoneally or intracerebroventricularly, caused dose‐dependent sedation, both in terms of a reduction in the time that rats could remain on an accelerating rotarod and in terms of overt sedation assessed visually. Following intracerebroventricular injection, xylazine, naphazoline and methoxamine, but not phenylephrine, produced similar effects. 3 The sedation caused by intraperitoneal injection of clonidine was antagonized by intracerebroventricularly injected phentolamine, yohimbine, piperoxan and tolazoline but not by labetalol, thymoxamine or prazosin. 4 The relative potencies of the agonists in causing sedation and of the antagonists in inhibiting the sedative effect of clonidine clearly demonstrated that the central α‐adrenoceptors mediating clonidine‐induced sedation are the same as the peripheral presynaptic α2‐adrenoceptors. 5 All the α‐adrenoceptor agonists caused hypothermia after intracerebroventricular injection, but their order of potency was different from that in producing sedation. The hypothermic effect of intraperitoneally injected clonidine was little affected by any of the antagonists administered intracerebroventricularly. No conclusions could be drawn concerning the type of receptor responsible for mediating hypothermia.

ucb L059, a novel anti-convulsant drug : pharmacological profile in animals

The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.

PHARMACOLOGICAL EVIDENCE FOR THE SUBCLASSIFICATION OF CENTRAL DOPAMINE RECEPTORS IN THE RAT

1 The relative potencies of dopamine receptor agonists in causing stereotypy in rats when injected into the olfactory tubercles, and contralateral rotation when injected unilaterally into the caudate nucleus of rats with lesions of the nigro‐striatal dopamine pathway, were determined. The actions of some agonists in eliciting these responses following peripheral injection, and the relative potencies of dopamine receptor antagonists in inhibiting them were also determined. 2 Dopamine, apomorphine and 2‐amino‐5, 6 and 2‐amino‐6, 7‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene (A‐5, 6 DTN, A‐6, 7 DTN) and N,N dipropyl A‐5, 6DTN induced both responses. In contrast, 2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐3‐benzazepine HCl (SK & F 38393) whether injected intracerebrally or peripherally, induced contralateral rotation but not stereotypy. 3 Contralateral rotation and stereotypy induced by apomorphine or N,N dipropyl A‐5, 6 DTN were inhibited by haloperidol, pimozide and fluphenazine but these drugs failed to inhibit rotation induced by SK & F 38393. Clozapine inhibited rotation induced by SK & F 38393, apomorphine or N,N dipropyl A‐5, 6 DTN but failed to inhibit stereotypy. Loxapine was more potent in inhibiting stereotypy than rotation, whereas clothiapine inhibited rotation and stereotypy at similar doses irrespective of the agonist used to elicit the response. 4 Contralateral rotation induced by SK & F 38393 was not inhibited by yohimbine, prazosin, atropine, methysergide, mepyramine or propranolol. 5 The results provide evidence that contralateral rotation induced by dopamine receptor agonists is mediated by two different classes of dopamine receptors and that these receptors differ from those mediating the stereotypy response. 6 The receptors mediating these responses appear classifiable in terms of their sensitivity to the agonist actions of SK & F 38393 or apomorphine respectively. SK & F 38393‐sensitive receptors are susceptible to blockade by clozapine but are not blocked by haloperidol, pimozide or fluphenazine. Apomorphine‐sensitive receptors are susceptible to blockade by haloperidol, pimozide and fluphenazine but appear divisible into two sub‐classes depending on whether or not they are blocked by clozapine and on their sensitivity to blockade by loxapine.

Central and peripheral effects of the dihydropyridine calcium channel activator BAY K 8644 in the rat

Following intraperitoneal (i.p.) administration BAY K 8644 (0.5-4 mg/kg) induced an increase in blood pressure associated with bradycardia, increased tail-flick latency in response to radiant heat, decreased locomotion, induced muscle contraction, postural changes and also reduced reflex activity. Only the postural changes and reduced locomotion were seen after intracerebroventricular administration (5-20 micrograms/kg), suggesting that the other effects are mediated peripherally. All the above effects were antagonised by the calcium channel blocker nifedipine. BAY K 8644 (4 mg/kg i.p.) also significantly increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in the cortex and striatum, an effect which could also be reversed by nifedipine. Apart from inducing hypotension and tachycardia, nifedipine alone had no effect on any of the above parameters. The analgesic-like activity of BAY K 8644 observed in the tail-flick test appears to be related to its vasoconstrictor effects as the peripherally acting vasodilator phenylephrine had similar analgesic activity. These results show that both central and peripheral dihydropyridine-sensitive calcium channels mediate the effects of BAY K 8644. Although a physiological role for the dihydropyridine-sensitive voltage-operated calcium channel in the CNS remains to be demonstrated, activation of these channels can clearly have functional effects.

The effects of dihydropyridine compounds in behavioural tests of dopaminergic activity.

1 The effects of the dihydropyridine calcium channel blocker nifedipine and the activator Bay K 8644 were investigated in different behavioural tests involving dopaminergic systems. These were the discriminative stimulus induced by amphetamine, rotational behaviour in rats with unilateral 6‐hydroxydopamine (6‐OHDA) lesions and apomorphine‐induced yawning in rats. 2 The yawning induced by apomorphine (40 μg kg−1 s.c.) was significantly potentiated by nifedipine (5–10 mg kg−1 i.p.). Bay K 8644 (0.05‐0.5 mg kg−1 i.p.) dose‐dependently inhibited yawning induced by apomorphine (80 μg kg−1 s.c.) and, at 0.4 mg kg−1, inhibited the nifedipine potentiation of apomorphine‐induced yawning. In contrast to their effects on apomorphine‐induced yawning, nifedipine and Bay K 8644 had no effect on apomorphine‐induced penile erection. 3 Bay K 8644 (0.06‐0.5 mg kg−1 i.p.) and nifedipine (5–20 mg kg−1 i.p.) had no dose‐related effect on the discrimination performance of rats trained to discriminate amphetamine from saline. However, nifedipine dose‐dependently reduced the response rate of amphetamine‐treated rats. Bay K 8644 had no effect on this measure except at high doses that also caused disruption. 4 Neither nifedipine (5–10 mg kg−1 i.p.) nor Bay K 8644 (0.06‐0.5 mg kg−1 i.p.) affected the turning behaviour induced by amphetamine (1 mg kg−1 i.p.) in rats with unilateral 6‐OHDA lesion of the medial forebrain bundle, and did not induce turning themselves. 5 As the dihydropyridine compounds affected apomorphine‐induced yawning but not penile erection, and did not affect amphetamine‐induced rotation or drug discrimination, it seems unlikely that they are affecting dopamine release in vivo.

Anxiolytic profile of the antiepileptic drug levetiracetam in the Vogel conflict test in the rat.

The novel antiepileptic drug levetiracetam has been shown to reverse anxiogenic effects of benzodiazepine withdrawal in mice tested in an elevated plus-maze without altering the behaviour of normal mice in this model. This could suggest that the effect of levetiracetam is dependent upon the level of stress/anxiety of the animals. Levetiracetam was therefore further examined in another widely used animal model of anxiety, the Vogel conflict test. In the first experiment, water-deprived rats were submitted to a free drinking period (habituation) in a chamber equipped with a bottle of water. Twenty-four hours later, animals were returned to the same chamber but the licks to the water bottle were then punished with a foot shock (0.5 mA, 90 ms). In the second experiment, the procedure was modified by administering a foot shock at the end of the habituation period in order to induce a state of stress/anxiety (conditioned fear/ anticipatory anxiety) for subsequent testing. Levetiracetam (17 and 54 mg/kg) and chlordiazepoxide (5 mg/kg) were administered via the intraperitoneal route. The results indicated that in the first experiment only chlordiazepoxide showed a statistically significant anxiolytic effect. In contrast, in the second experiment, where the shock was given at the end of the habituation period, levetiracetam (54 mg/kg) revealed significant anxiolytic activity similar to chlordiazepoxide. This suggests that levetiracetam may have potential anxiolytic effects and may provide therapeutic benefits to individual with anxiety spectrum disorders.