Catecholamine receptor mechanisms in vertebrates

CATECHOLAMINE

RECEPTOR MECHANISMS VERTEBRATES

IN

NILS-ERIK ANDBN Departmentof Pharmacology, Universityof Goteborg,Goteborg,Sweden Two CENTRALcatecholamine

(CA) neuron systems can conveniently be completely lesioned without damaging other CA neurons, i.e., the dopamine (DA) neurons to the corpus striatum and the noradrenaline (NA) neurons to the spinal cord. The functions of these neuron systems can also be studied easily and selectively. They are, therefore, suitable for investigations of central DA and NA receptor mechanisms. THE STRIATAL

DOPAMINE

SYSTEM

The DA

in the corpus striatum belongs to neurons with the cell bodies in the substantia nigra and the terminals in the neostriatum, i.e., the caudate nucleus plus putamen (ANDBN, CARLZSSON, DAHLSTR~~M, FUXE, HILLARPand LARSSON,1964). The function of the uncrossed nigro-neostriatal DA neurons can be revealed as asymmetries in body position after one of the following unilateral manipulations: (1) chronic lesion of the ascending axons, causing loss of the DA terminals on the operated side (ANDBN, 1966;

ANDBN, DAHLSTR~~M,FUXE and LARSSON, 1966a;

1968); (2)

UNGERSTEDT,

acute removal of the corpus striatum, causing loss of both the DA terminals and the effector cells with the DA receptors on the operated side (ANDBN et al., 1966a); (3) administration of drugs into the neostriatum on one side (UNGERSTEDT, BUTCHER,BUTCHER,FUXE and ANDBN, 1969). Strangely enough, unilateral removal of the corpus striatum or unilateral lesion of the ascending DA pathway chronically (more than 7 days) does not induce any clear-cut asymmetry of the body position and movements, perhaps due to compensatory mechanisms or to damage of antagonistic or efferent pathways (ANDBN et al., 1966a). In general, the results are easier to interpret after acute removal of the corpus striatum on one side. Injection of L-dopa after inhibition of the monoamine: oxygen oxidoreductase (EC 1.4.3.4, monoamine oxidase) or the peripheral 3,4-dihydroxy-t-phenylalanine carboxy-lyase (EC 4.1 .I .26, dopa decarboxylase) causes a rat with a unilateral striatectomy to turn its head and tail to the operated side (ANDBN et al., 1966a). Simultaneously, it becomes very excited and rotates vigorously to the operated side. Since striatal DA terminals and receptors are present only on the unoperated side, the effect is evoked via stimulation of DA receptors in the intact neostriatum. This view is strengthened by the finding that administration of DA (after inhibition of the monoamine oxidase) into the neostriatum on one side induces turning of the head and tail to the contralateral side (UNGERSTEDTet al., 1969). Release of endogenous DA, by treatment with reserpine after inhibition of the monoamine oxidase, also induces turning to the operated side, both after acute removal of the corpus striatum and after chronic axotomy (ANDBN et al., 1966a). This effect must be evoked from the intact neostriatum since there is no striatal DA to release on the lesioned side. However, treatment with L-dopa after chronic lesion of the ascending DA pathway produces turning to the unoperated side, i.e., the opposite effect to that seen after unilateral 539

540

NILS-ERIK ANDBN

striatectomy. The formation of DA from L-dopa in the neostriatum is markedly reduced but not completely inhibited on the axotomized side, indicating that the smaller amount of DA on the operated side has a more pronounced functional effect than the greater amount in the intact neostriatum, perhaps due to denervation supersensitivity (ANDBN,1966; ANDBNet al., 1966a; UNGERSTEDT,1971). An effect similar to that produced by L-dopa in unilaterally acutely striatectomized rats is also observed after treatment with amphetamine and with apomorphine (AND~~N,RUBENSON,FUXE and H~~KFELT,1967a). The amphetamine-induced asymmetry is inhibited by pretreatment with a-methyltyrosine (plus reserpine), indicating that amphetamine acts via release of DA from the nerve terminals. On the other hand, apomorphine acts also in the absence of DA and it probably directly stimulates the DA receptors on the effector cells (ERNST, 1967; AND&Net al., 1967a). After chronic axotomy, apomorphine induces the opposite effect, i.e., turning to the unoperated side, whereas treatment with amphetamine causes turning to the operated side (UNGERSTEDT,1971). Again, the effect of apomorphine can be explained by a denervation supersensitivity of the DA receptors on the operated side and the effect of amphetamine is probably due to release of DA in the intact neostriatum. Piribedil (Trivastal@, ET 495) appears to directly stimulate the DA receptors in the above-mentioned models, although it also has some releasing action (CORRODI, FARNEBO,FUXE, HAMBERGER and UNGERSTEDT,1972). The neostriatal DA receptors are stimulated also by metatyramine (formed from metatyrosine) and by a-methyl-DA (formed from a-methyl-dopa) (ANDBN, BUTCHERand ENGEL, 1970a), but these drugs are less potent than DA. Treatment with 5hydroxytryptophan does not produce any turning of unilaterally operated rats, despite a considerable formation of S-hydroxytryptamine (5-HT) and marked behavioural changes such as tremor and extension of the hindlegs, showing that 5-HT and DA act on different receptors (ANDBNet al., 1966a). Likewise, unilateral injections of 5-HT into the neostriatum of rats pretreated with reserpine, cc-methyltyrosine and nialamide do not cause any asymmetry. On the other hand, intrastriatal administration of NA induces in such a preparation a moderate turning to the contralateral side, indicating that NA can stimulate the DA receptors though more weakly than DA (UNGERSTEDTet al., 1969). When reserpine is given to a rat with a striatectomy or with a chronic axotomy of the nigro-neostriatal DA neurons on one side, the head and tail are turned to the unoperated side (AND~~Net ul., 1966a). Injection of L-dopa or apomorphine to a unilaterally striatectomized, reserpine-treated rat causes turning from the unoperated to the operated side, showing that the reserpine-induced asymmetry is due to a lack of DA on the receptors of the effector cells in the neostriatum on the unoperated side. The asymmetry produced by reserpine is the result of a muscle rigidity on the unoperated side caused by an increased activity of the a-motoneurons and a decreased activity of the y-motoneurons (AND&, LARSSONand STEG, 1971). The same asymmetry of unilaterally operated rats as produced by reserpine is also seen after treatment with neuroleptic drugs such as chlorpromazine, haloperidol and pimozide (ANDBNet al., 1966a; ANDBN,BUTCHER,CORRODI,FUXEand UNGERSTEDT, 1970b). The turning seen after injection of these drugs is, however, unchanged by the subsequent administration of L-dopa, apomorphine or amphetamine, indicating that the neuroleptic drugs block the postsynaptic DA receptors whereas reserpine prevents the release of DA from the presynaptic nerve terminals. Adrenergic a-receptor

Catecholamine

receptor mechanisms

in vertebrates

541

blocking agents such as phenoxybenzamine, and adrenergic p-receptor blocking agents such as propranolol, neither induce any asymmetry of operated rats nor reduce the L-dopa-induced turning, showing that the DA receptors are different from the NA receptors in the periphery. Nor do sedative drugs such as barbiturates and promethazine produce any asymmetry. The neuroleptic-induced asymmetry of unilaterally operated rats is reduced by anticholinergic drugs. Thus, an acetylcholine mechanism must antagonize the effects of DA beyond the DA receptors on the effector cells in the neostriatum (ANDBNand BBDARD,1971). Also, the unilateral intrastriatal administration of potassium ions can influence the striatal function after treatment with neuroleptic drugs, causing the rats to turn to the contralateral side (STOCK, MAGNUSSON and ANDBN, 1973). This effect may be the result of a persistent depolarization of the effector cells in the neostriatum. Systemic treatment with apomorphine antagonizes this potassium-induced turning (KELLER,BARTHOLINI,PIERI and PLETSCHER,1972; STOCKet al., 1973). This effect can be explained as a hyperpolarization of the effector cells due to DA receptor stimulation, in agreement with electrophysiological data. THE SPINAL NORADRENALINE SYSTEM The NA in the spinal cord is localized in nerve terminals of neurons whose cell bodies are present in the lower brain stem (ANDBN, H;~GGENDAL,MAGNUSSONand ROSENGREN,1964; DAHLSTR~~M and FUXE, 1965). Hence, a mid-thoracic spinal cord transection separates the NA nerve terminals in the caudal part of the spinal cord from the cell bodies of the same neurons. Injection of L-dopa induces a marked increase in flexor reflex activity of acutely spinalized animals (CARLSSON,MAGNUSSONand ROSENGREN,1963 ; ANDBN,JUKES, LUNDBERGand VYKLICK~,1966b). L-dopa has been shown to act via the formation of CAs and the release of NA which diffuses to and stimulates NA receptors on the effector cells (ANDJ?N,JUKESand LUNDBERG,1966c). The NA may inhibit inhibitory interneurons, thereby releasing a massive and longlasting flexor reflex which is normally concealed in the spinal animal (ANDBNet al., 1966b). Treatment either with amphetamine or the antihypertensive agent clonidine (Catapresan@) induces an increase in flexor reflex activity, similar to that observed after injection of L-dopa (ANDBN, CORRODI,FUXE, H~KFELT, H~~KFELT,RYDIN and SVENSSON,1970). Pretreatment with reserpine plus a-methyltyrosine blocks this effect of amphetamine but not that of clonidine, indicating an indirect action of amphetamine but a direct action of clonidine on the NA receptors. Incidently, apomorphine has no effect on the spinal NA receptors whereas clonidine has no effect on the neostriatal DA receptors. The flexor reflex activity is markedly enhanced after treatment with a-methyl-dopa due to the formation of a-methyl-NA which is a strong stimulating agent of these NA receptors (ANDBNet a/., 1970a). After inhibition of the DA-@hydroxylase, the L-dopa-induced increase in flexor reflex activity is clearly but not completely inhibited, suggesting that DA has only a weak effect on the central NA receptors (ANDBN,ENGEL and RUBENSON,1972). Injection of 5-hydroxytryptophan induces no increase in flexor reflex activity, but induces other reflex changes, suggesting that 5-HT and NA act on different receptors (ANDI?N,1968). The increase in flexor reflex activity seen after treatment with t-dopa or clonidine is eliminated by many neuroleptic drugs, e.g., chlorpromazine and haloperidol, thus

NILS-ERIK AN&N

indicating a blockade of the NA receptors (ANDBN et al., 1966~; ANDBN, CORRODI, FUXE and H~~KFELT, 1967b). There are, however, neuroleptic drugs without any apparent NA receptor blocking ability, e.g., the diphenylbutylpiperidine derivative pimozide (ANDBN et al., 1970b). On the other hand, the cr-adrenergic blocking agent phenoxybenzamine efficiently inhibits the L-dopa- or clonidine-induced reflex changes, whereas b-adrenergic blocking agents such as propranolol appear to lack this effect (AND&N et al., 1966~; 1967b). On the whole, the NA receptors in the spinal cord are influenced by drugs in about the same manner as the peripheral cr-receptors, provided that the compounds can enter the central nervous system. Also in the brain, NA receptors of the cc-type may be of importance, judging from the inhibitory effect of phenoxybenzamine on the L-dopa- or clonidine-induced behavioural changes (ANDBN, 1967). These findings do not exclude the existence of other types of NA receptors, e.g., of the B-type, in the brain and in the spinal cord. REGULATION OF CATECHOLAMINE TURNOVER FROM CATECHOLAMINE RECEPTORS The drugs acting on the CA receptors of the effector cells normally change the activity of the presynaptic CA neuron : when the CA receptors are blocked, the turnover of the CA is increased, and the reverse chemical effect is observed when the receptors are stimulated (HENNING, this symposium). If the receptor activity is changed for only one of the two CAs, the turnover of the corresponding CA can be influenced selectively. Thus, the DA receptor stimulating agent apomorphine decelerates the turnover of DA but not that of NA, and the NA receptor blocking agent phenoxybenzamine accelerates the turnover of NA but not that of DA. There are also exceptions, e.g., a slight deceleration of the DA turnover after treatment with the NA receptor stimulating agent clonidine and an acceleration of the NA turnover after treatment with the DA receptor blocking agent pimozide. Generally, the changes in turnover may be considered as compensatory to the alterations of the receptor activity. They may be evoked via a neuronal or humoral feedback mechanism from the effector cells. There is, however, also the possibility that the CA neuron possesses CA receptors, either on its terminals or on its cell body or both, which regulate the turnover of the transmitter. These hypothetical presynaptic CA receptors should then have properties similar to those on its innervated postsynaptic cell, to judge from the ability of some drugs to act selectively, both functionally and chemically, on only one CA. REFERENCES ANDBN N.-E.

(1966) In: Mechanisms of Release of Biogenic Amines. (EULER U. S. von, ROSELL S. and Uv~iis B., Eds.) pp. 357-359. Pergamon Press, Oxford. AN&N N.-E. (1967) In: Progress in Neuro-Genetics. (BARBEAU A. and BRUNETT J. R., Eds.) pp.

265-271. Excerpta Medica Foundation, Amsterdam. ANDBN N.-E. (1968) Ado. Pharmacol. 6A, 347-349. ANDEN N.-E. and BEDARD P. (1971) J. Pharm. Pharmacol. 23,460-462. AND~N N.-E., BUTCHER S. G., CORRODIH., FUXE K. and UNGERSTEDTU. (1970b)

Europ. J. Pharm-

acol. 11, 303-314. AND~N N.-E., BUTCHER S. G. and ENGEL J. (1970a) J. Pharm.. Pharmacol. AND~N N.-E., CARLSSON A., DAHLSTR~~M A., FUXE K., HILLARP N.-A.

22, 548-550. and LARSSONK. (1964)

L’fe Sci. 3, 523-530. ANDBN N.-E., ANDEN N.-E.,

CORRODIH., FUXE K. and H~~KFELTT. (1967b) Europ. J. Pharmacol. 2, 59-64. CORRODIH., FUXE K., H~KFELT B., H~KFELT T., RYDIN C. and SVENSSONT. (1970) Life Sci. 9, 513-523.

Catecholamine AND~N N.-E.,

DAHLSTR~M A.,

receptor mechanisms in vertebrates

FUXE K. and LARSSON K. (1966a)

543

Acta pharmacol. toxicol. 24,

263-274. AND~N N.-E., ENGEL J. and RUBENSONA. (1972) Naunyn-Schmiedeberg’s Arch. Pharmacol. 273, I-10. AND~N N.-E., H~~GGENDAL J., MAGNUSWN T. and ROSENGRENE. (1964) Acta physiol. stand. 62, 115-118. AND~N N.-E., JUKESM. G. M. and LUNDBERGA. (1966~) Actaphysiol. stand. 67,387-397. AND~N N.-E., JUKES M. G. M., LUNDBERGA. and VYKLICK~ L. (1966b) Actaphysiol. stand. 67,

373-386.

AND~N N.-E., LARSSONK. and STEG G. (1971) Actaphysiol. stand. 82,268-271. AND~N N.-E., RUBENSONA., FUXE K. and H&FELT T. (1967a) J. Pharm. Pharmacol. 19, 627-629. CARLSS~NA., MAGNUSSON T. and RO~ENGRENE. (1963) Experientia 19, 359-360. CORRODI H., FARNEBOL.-O., FUXE K., HAMBERGERB. and UNGERSTEDTU. (1972) Europ. J. Pharmacol. 20, 195-204. DAHLSTR~~M A. and FUXE K. (1965) Actaphysiol. stand. (64), Suppl. 247, 39-85. ERNST A. M. (1967) Psychopharmacologia 10, 316-323. KELLERH. H., BARTHOLINIG., PIERI L. and PLETSCHERA. (1972) Europ. J. Pharmacol. 20,287-290. STOCK G., MAGNUSSONT. and AND~N N.-E. (1973) Naunyn-Schmiedeberg’s Arch. Pharmacol.

278, 347-361. UNGERSTEDTU. (1968) Europ. J. Pharmacol. 5, 107-l 10. UNGERSTEDTU. (1971) Acta physiol. stand. Suppl. 367, 69-93. UNGERSTEDTU., BUTCHER L. L., BUTCHER S. G., AND~N N.-E. and FUXE K. (1969) Brain Res.

14, 461-471.