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DSP4 and behavioural experiments
237
TIPS - June 1985
The use of DSP4 as a noradrenaline neurotoxin requires the recovery of the animals from the acute effects of the drug
DSP4 and behavioural experiments In a letter to TiPS entitled DSP4 and xylamine: not-so-specific noradrenergic neurotoxins, Jacobson and W i l k i n s o n report their observations that DSP4, the prototype tertiary haloalkylamine, and xyla m i n e in vitro and acutely (2h) in vivo have affinity for opiate receptors in the rat b r a i n 1. They discuss these findings in relation to the use of these c o m p o u n d s as selective neurotoxins in studies of the functional role of noradrenaline in the brain. The letter p r o m p t s me to stress the importance of the DPS4 and xylamine treated animals b e i n g allowed to recover from the acute effects before starting any behavioural experiments. The acute effects of DSP4 and xylamine at the standard dose 50 m g k g -1 are several; i n h i b i t i o n of noradrenaline uptake 2, release of noradrenaline 3, blockade of ctadrenoreceptors 4, to which n o w can be a d d e d opiate receptor stimulation 1. Since this dose is close to the lethal one, other yet
u n k n o w n acute effects of DPS4 and xylamine are likely, expressed, for example, in reduced food and water intake d u r i n g the first two days 5. Indeed, lethality itself at this dose is a problem, particularly in experiments with adult rats. A recovery period of one to two weeks is therefore n e e d e d before starting any behavioural experiments with DSP4-treated animals. This time lapse also allows the peripheral sympathetic nervous system to recover 6. Too long a recovery period, on the other hand, entails the risk of d e v e l o p m e n t of compensatory m e c h a n i s m s against secondary effects of the noradrenaline depletion, e.g. increase in ~-adrenoreceptor density and decrease in (Na + + K+)-ATPase 7. DSP4 is not a specific noradrenaline neurotoxin, but is quite selective. In the rat it also produces some (20-30%) longterm decrease in cortical serotonin that can be antagonized by a
Sub-grouping of Ca ~- antagonists, based on their possible interactions with neurotransmitter receptors, shows that verapamil and diltiazem cannot b e grouped together.
Calcium antagonist subgroups S p e d d i n g (TIPS, March, 1985) 1 has p r o v i d e d valuable information about the classification of 'Ca 2+ antagonists'. Using as his basis 'structure-activity relationships and differential effects in b i n d i n g and in functional tests', he has p r o p o s e d that 'four b i n d i n g sites and three functional classes of antagonist' might exist. Thus, a s u b g r o u p i n g of these agents is: Group I, 1,4-dihydropyridines (e.g., nifedipine, n i m o d i p i n e ) ; Group II, verapamil, diltiazem and diclofurime; and Group III, dip h e n y l a l k y l a m i n e s (e.g., flunarizine, p i m o z i d e , fendiline). Support for his contention has been obtained b y testing the lipophili-
cities of Ca 2+ antagonists, the effects of Ca 2+ antagonists on K +d e p o l a r i z e d taenia preparations of g u i n e a - p i g caecum in the absence or presence of salicylate (which increases negative surface charge at the membrane), and b y considering the different effects that these agents exert in vivo and in vitro (binding studies). Although this classification, and those p r o p o s e d b y other workers 2-s, 'can be used as a base for drug design and for the prediction of clinical effects at an early stage in drug development', such classifications seem oversimplified. To develop a more precise s u b g r o u p i n g of these
serotonin uptake inhibitor 6. In order to ascertain the specificity towards central noradrenaline systems control animals pretreated with desipramine (20 mg k g -1) prior to DSP4 are r e c o m m e n d e d 8. In properly designed experiments DSP4 is a valuable complement to other tools for studies of the functional role of noradrenaline in the brain. It has, however, the limitation that hypothalamic noradrenaline is less affected compared to the locus coeruleus noradrenaline system 2,6. SVANTE B. ROSS Biochemical Pharmacology, Research Laboratories, Astra Li~kamedel AB, S-151 85 S6dertitlje, Sweden.
References 1 Jacobson, W. and Wilkinson, M. (1985) Trends Pharmacol. Sci. 6, 16-17 2 Ross, S. B. (1976) Br. J. PharmacoL 58, 521-527 3 Landa, M. E., Rubio, M.C. and JaimEtchevey, G. (1984) ]. PharmacoL Exp. Ther. 231, 131-136 4 Ross, S. B., lohansson, J. G., Lindberg, B. and Dahlbom, R. (1973) Acta Pharm. Suec. 10, 29-42 5 Archer, T., Mohammed, A. K., Ross, S. B. and S6derberg, U. (1983) Pharmcol. Biochem. & Behav. 19, 121-130 6 Jonsson, G., Hallman, H., Ponzio, F. and Ross, S. (1981) Eur. J. Pharmacol. 72, 173188 7 Swann, A. C. (1984) Brain Res. 321, 323326 8 Archer, T., Jonsson, G. and Ross, S. B. (1984) Br. J. Pharmacol. 82, 249-257
agents, their possible effects on receptors for neurotransmitters and hormones, and on certain other cellular (molecular) processes (e.g., enzyme activity), as well as their effects on Ca 2+ channels, should perhaps be considered. In this regard, the inhibitory effect of diphenylalkylamines on calmodulin has been mentioned 1, b u t other actions of certain Ca 2+ antagonists (e.g., the anti-5-HT2 action of verapamil and gallopamil~-9; the anti-H1 action of flunarizine 1°) might be even more important with respect to 'Ca 2+ antagonist' subgrouping. Except for the classification of Glossmann et al. 3 that was based on b i n d i n g studies, all other reports thus far have assigned verapamil (a phenylalkylamine) and diltiazem (a benzothiazepine) to the same class. Indeed, verapamil and diltiazem behave similarly in many tests, as well as in certain clinical situations. As examples:
~) 1985,ElsevierSciencePublishersB.V.,Amsterdam 0165 6147/85/$02.00
TIPS - June 1985
The use of DSP4 as a noradrenaline neurotoxin requires the recovery of the animals from the acute effects of the drug
DSP4 and behavioural experiments In a letter to TiPS entitled DSP4 and xylamine: not-so-specific noradrenergic neurotoxins, Jacobson and W i l k i n s o n report their observations that DSP4, the prototype tertiary haloalkylamine, and xyla m i n e in vitro and acutely (2h) in vivo have affinity for opiate receptors in the rat b r a i n 1. They discuss these findings in relation to the use of these c o m p o u n d s as selective neurotoxins in studies of the functional role of noradrenaline in the brain. The letter p r o m p t s me to stress the importance of the DPS4 and xylamine treated animals b e i n g allowed to recover from the acute effects before starting any behavioural experiments. The acute effects of DSP4 and xylamine at the standard dose 50 m g k g -1 are several; i n h i b i t i o n of noradrenaline uptake 2, release of noradrenaline 3, blockade of ctadrenoreceptors 4, to which n o w can be a d d e d opiate receptor stimulation 1. Since this dose is close to the lethal one, other yet
u n k n o w n acute effects of DPS4 and xylamine are likely, expressed, for example, in reduced food and water intake d u r i n g the first two days 5. Indeed, lethality itself at this dose is a problem, particularly in experiments with adult rats. A recovery period of one to two weeks is therefore n e e d e d before starting any behavioural experiments with DSP4-treated animals. This time lapse also allows the peripheral sympathetic nervous system to recover 6. Too long a recovery period, on the other hand, entails the risk of d e v e l o p m e n t of compensatory m e c h a n i s m s against secondary effects of the noradrenaline depletion, e.g. increase in ~-adrenoreceptor density and decrease in (Na + + K+)-ATPase 7. DSP4 is not a specific noradrenaline neurotoxin, but is quite selective. In the rat it also produces some (20-30%) longterm decrease in cortical serotonin that can be antagonized by a
Sub-grouping of Ca ~- antagonists, based on their possible interactions with neurotransmitter receptors, shows that verapamil and diltiazem cannot b e grouped together.
Calcium antagonist subgroups S p e d d i n g (TIPS, March, 1985) 1 has p r o v i d e d valuable information about the classification of 'Ca 2+ antagonists'. Using as his basis 'structure-activity relationships and differential effects in b i n d i n g and in functional tests', he has p r o p o s e d that 'four b i n d i n g sites and three functional classes of antagonist' might exist. Thus, a s u b g r o u p i n g of these agents is: Group I, 1,4-dihydropyridines (e.g., nifedipine, n i m o d i p i n e ) ; Group II, verapamil, diltiazem and diclofurime; and Group III, dip h e n y l a l k y l a m i n e s (e.g., flunarizine, p i m o z i d e , fendiline). Support for his contention has been obtained b y testing the lipophili-
cities of Ca 2+ antagonists, the effects of Ca 2+ antagonists on K +d e p o l a r i z e d taenia preparations of g u i n e a - p i g caecum in the absence or presence of salicylate (which increases negative surface charge at the membrane), and b y considering the different effects that these agents exert in vivo and in vitro (binding studies). Although this classification, and those p r o p o s e d b y other workers 2-s, 'can be used as a base for drug design and for the prediction of clinical effects at an early stage in drug development', such classifications seem oversimplified. To develop a more precise s u b g r o u p i n g of these
serotonin uptake inhibitor 6. In order to ascertain the specificity towards central noradrenaline systems control animals pretreated with desipramine (20 mg k g -1) prior to DSP4 are r e c o m m e n d e d 8. In properly designed experiments DSP4 is a valuable complement to other tools for studies of the functional role of noradrenaline in the brain. It has, however, the limitation that hypothalamic noradrenaline is less affected compared to the locus coeruleus noradrenaline system 2,6. SVANTE B. ROSS Biochemical Pharmacology, Research Laboratories, Astra Li~kamedel AB, S-151 85 S6dertitlje, Sweden.
References 1 Jacobson, W. and Wilkinson, M. (1985) Trends Pharmacol. Sci. 6, 16-17 2 Ross, S. B. (1976) Br. J. PharmacoL 58, 521-527 3 Landa, M. E., Rubio, M.C. and JaimEtchevey, G. (1984) ]. PharmacoL Exp. Ther. 231, 131-136 4 Ross, S. B., lohansson, J. G., Lindberg, B. and Dahlbom, R. (1973) Acta Pharm. Suec. 10, 29-42 5 Archer, T., Mohammed, A. K., Ross, S. B. and S6derberg, U. (1983) Pharmcol. Biochem. & Behav. 19, 121-130 6 Jonsson, G., Hallman, H., Ponzio, F. and Ross, S. (1981) Eur. J. Pharmacol. 72, 173188 7 Swann, A. C. (1984) Brain Res. 321, 323326 8 Archer, T., Jonsson, G. and Ross, S. B. (1984) Br. J. Pharmacol. 82, 249-257
agents, their possible effects on receptors for neurotransmitters and hormones, and on certain other cellular (molecular) processes (e.g., enzyme activity), as well as their effects on Ca 2+ channels, should perhaps be considered. In this regard, the inhibitory effect of diphenylalkylamines on calmodulin has been mentioned 1, b u t other actions of certain Ca 2+ antagonists (e.g., the anti-5-HT2 action of verapamil and gallopamil~-9; the anti-H1 action of flunarizine 1°) might be even more important with respect to 'Ca 2+ antagonist' subgrouping. Except for the classification of Glossmann et al. 3 that was based on b i n d i n g studies, all other reports thus far have assigned verapamil (a phenylalkylamine) and diltiazem (a benzothiazepine) to the same class. Indeed, verapamil and diltiazem behave similarly in many tests, as well as in certain clinical situations. As examples:
~) 1985,ElsevierSciencePublishersB.V.,Amsterdam 0165 6147/85/$02.00