Article date: July 1994
By: Eric P.M. Prinssen, Bart A. Ellenbroek, Alexander R. Cools, in Volume 112, Issue 3, pages 769-774
In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side‐effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test.
The α1‐adrenoceptor agonist, ST 587 but not the peripherally working α1‐agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The α1‐antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time.
The α1‐adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the α1‐antagonist rauwolscine nor by the α1‐antagonist phenoxybenzamine. Rauwolscine or the peripherally working α2‐antagonist L‐659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations.
In contrast to the β2‐adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting β‐agonist, (−)‐isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The β‐antagonist, (−)‐propranolol as well as the peripherally acting β‐antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting β1‐antagonist, atenolol, as well as low doses of the β2‐antagonist, ICI‐118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (−)‐isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.
It is concluded that blockade of central α1‐adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral β1 and/or β2‐adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the α1‐adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side‐effects.
In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side‐effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test.
The α1‐adrenoceptor agonist, ST 587 but not the peripherally working α1‐agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The α1‐antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time.
The α1‐adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the α1‐antagonist rauwolscine nor by the α1‐antagonist phenoxybenzamine. Rauwolscine or the peripherally working α2‐antagonist L‐659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations.
In contrast to the β2‐adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting β‐agonist, (−)‐isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The β‐antagonist, (−)‐propranolol as well as the peripherally acting β‐antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting β1‐antagonist, atenolol, as well as low doses of the β2‐antagonist, ICI‐118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (−)‐isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.
It is concluded that blockade of central α1‐adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral β1 and/or β2‐adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the α1‐adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side‐effects.
DOI: 10.1111/j.1476-5381.1994.tb13145.x
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