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Dopamine and acetylcholine neurones in striatal and limbic structures: Effect of neuroleptic drugs
DOPAMINE STRIATAL
AND ACETYLCHOLINE NEURONES IN AND LIMBIC STRUCTURES : EFFECT OF NEUROLEPTIC DRUGS
K.G. LLOYD, H. STADLERand G. BARTHOLINI Department
of Experimental
Medicine, F. Hoffmann-La Basle, Switzerland
INVOLVEMENTof
Roche & Co. Ltd.,
dopamine (DA) in schizophrenic states is suggested by several observations (METTLERand CRANDELL,1959; ROSSUMet al., 1970 GOODWIN, 1971; SNYDER,1973) but mainly by the fact that neuroleptic drugs block DA receptors whereas structurally related compounds devoid of such an effect do not show therapeutic activity (NYB.&cK,1968). DA terminals occur mainly in the neostriatum, thus the mechanism of action of neuroleptics may be connected with this structure. Neuroleptic blockade of striatal DA receptors leads to parkinsonian symptoms (HORNYKIEWICZ, 1972), not all of which, however, are directly due to impaired DA transmission, but rather to a preponderance of a striatal cholinergic system (BARTHOLINI ef al., 1973). Thus, it has been shown that neuroleptic drugs enhance the acetylcholine (ACh) liberation from the cat caudate nucleus (&ADLER et al., 1973), an effect which is reversed or prevented by dopaminergic agents (BARTHOLINIet al., this volume). This is the first direct evidence that a striatal cholinergic mechanismpossibly involved in parkinsonism-is regulated by an inhibitory dopaminergic input. Amelioration of some parkinsonian symptoms by anticholinergic drugs and their exacerbation by physostigmine (DUVOISIN,1967) supports this view. Opposite regulation of the DA system by ACh neurons is likely since anticholinergics counteract the neuroleptic-induced enhancement of DA turnover (AND~N, 1972) indicating an interregulation of the two systems. The question arising is whether or not the activation of striatal cholinergic neurons mediates also the antipsychotic action of neuroleptics. However, anticholinergic compounds ameliorate the parkinsonism caused by neuroleptics without affecting their therapeutic activity. In this respect, therefore, striatal cholinergic activation may not be involved. A possible extrastriatal site of action of neuroleptic compounds is the limbic system, which is also rich in DA and ACh neurons (FUXE, 1965; HERNANDEZ-PENN et al., 1963). As for the effect of neuroleptics, however, a fundamental difference exists between striatal and limbic structures. Thus, chlorpromazine or haloperidol (Fig. 1) failed to enhance the liberation of ACh collected by means of a push-pull cannula from the septum or nucleus accumbens of the gallamine-immobilized cat. This is in contrast to their marked effect on the caudate nucleus (BARTHOLINIet al., this volume; STADLERet al., 1973) although the DA turnover in both regions was markedly accelerated, as estimated by the rise of homovanillic acid (Table 1). These findings indicate that in septum and nucleus accumbens of the cat the activation of cholinergic neurons is not regulated by a DA input. Conversely, the lack of a cholinergic regulation on limbic DA neurons is known since anticholinergic agents do not diminish the neuroleptic-induced enhancement of limbic DA turnover (ANDBN, 1972). In conclusion, some extrapyramidal effects of neuroleptic drugs depend on the 641
642
K. G. LLOYD, H. STADLER and G.
BARTHOLINI N.caudatus
i
I/
60 j
N caudatus
N.accumbens &~p$~mmbens
minutes
FIG. I.-Output of acetylcholine (ACh) into IO-min samples of perfusate of various brain regions of the cat during the control period (O-60) and after haloperidol. Each curve indicates one experiment. The points represent averages of duplicate determinations. Time 0 indicates the beginning of collection. TABLE 1. CONCENTRATIONOF DOPAMINE(DA) AND HOMOVANILLICACID (HVA) IN DIFFERENT BRAIN REGIONSOF THE CAT. Caudate nucleus and nucleus accumbens were perfused by means of push-pull
cannulae as in the experiments for acetylcholine (see Fig. 1). Saline (control animals) or haloperidol (2 mg/kg) was injected intravenously 2 hr before sacrifice. Number of determinations in parentheses. P < 0.01 vs controls. DA
HVA
Brain region (/q/g) controls Caudate n. haloperidol
11.41 i 0.58 (9) 9.04 * 0.30 (12)
controls
3.42 + 0.28 (9)
haloperidol
3.41 f 0.22 (12)
(% control)
79.2 & 2.6*
( y0 control)
(pglg) 4.08 i 0.26 (9) 6.13 & 0.51 (12)
150.2 i
12.5*
2.15 i 0.17 (9)
N. accumbens Septum Preoptic area 99.7 & 6.4
3.07 zt 0.24 (12)
142.8 + ll.l*
activation of a striatal cholinergic mechanism due to impairment of DA transmission. The antipsychotic effect of these drugs may not be connected with cholinergic neurons in either striatum or limbic system; however, a limbic DA involvement is conceivable. REFERENCES AND~N N. E. (1972) J. Pharm. Pharmac. 24,905-906. BARTHOLINI G., STADLER H. and LLQYD K. G. (1973) In: D. B., Ed.) Raven Press, New York. DIJVOISIN R. G. (1967) Archs Neural. 17, 124-126. FUXE K. (1965) Acta Physiol. Stand. 64, (Suppl.) 247.
The Treatment
of Parkinsonism(CALNE
Dopamine
and acetylcholine
neurones in striatal and limbic structures
643
GOODWIN F. K. (1971) J. Am. Med. Am. 218, 19151920. HERNANDEZ-PENNR.. O’FLAHERTY J. J. and MAZZUCHELLI-O’FLAHERTY A. L. (1967) 1 I Bruin Res.
4,243-267. HORNYKIEWICZ0. (1972) In: Handbook qf Neurochemistry (LAJTHA A., Ed.) Vol. 6, pp. 465-501, Plenum Press, New York. MET-TLERF. A. and CRANDELLA. (1959) J. Nerv. Ment. Dis. 129, 551-563. NYBXCK H. (1968) Europ. J. Pharmacol. 14, 395-403. ROSSUMJ. M. VAN, BOISSIER J. R., JANSSENP. A. S.. JULOU L., LOEW D. M., NIELSEN I. M., MUNKVALI I., RANDRUP A., STILLEG. and TEDESCHID. H. (1970) In: Modern Problems in Pharmacopsychiatry (Neuroleptics) (BOBON J. and JANSSENP., Eds), pp. 23-33, Karger, Basel. SNYDERS. H. (1973) Am. J. Psychiat. 130, 61-67. STADLERH., LLOYD K. G., GADEA-CIRIA M. and BARTHOLINIG. (1973) Brain Res., 55,476-480.
AND ACETYLCHOLINE NEURONES IN AND LIMBIC STRUCTURES : EFFECT OF NEUROLEPTIC DRUGS
K.G. LLOYD, H. STADLERand G. BARTHOLINI Department
of Experimental
Medicine, F. Hoffmann-La Basle, Switzerland
INVOLVEMENTof
Roche & Co. Ltd.,
dopamine (DA) in schizophrenic states is suggested by several observations (METTLERand CRANDELL,1959; ROSSUMet al., 1970 GOODWIN, 1971; SNYDER,1973) but mainly by the fact that neuroleptic drugs block DA receptors whereas structurally related compounds devoid of such an effect do not show therapeutic activity (NYB.&cK,1968). DA terminals occur mainly in the neostriatum, thus the mechanism of action of neuroleptics may be connected with this structure. Neuroleptic blockade of striatal DA receptors leads to parkinsonian symptoms (HORNYKIEWICZ, 1972), not all of which, however, are directly due to impaired DA transmission, but rather to a preponderance of a striatal cholinergic system (BARTHOLINI ef al., 1973). Thus, it has been shown that neuroleptic drugs enhance the acetylcholine (ACh) liberation from the cat caudate nucleus (&ADLER et al., 1973), an effect which is reversed or prevented by dopaminergic agents (BARTHOLINIet al., this volume). This is the first direct evidence that a striatal cholinergic mechanismpossibly involved in parkinsonism-is regulated by an inhibitory dopaminergic input. Amelioration of some parkinsonian symptoms by anticholinergic drugs and their exacerbation by physostigmine (DUVOISIN,1967) supports this view. Opposite regulation of the DA system by ACh neurons is likely since anticholinergics counteract the neuroleptic-induced enhancement of DA turnover (AND~N, 1972) indicating an interregulation of the two systems. The question arising is whether or not the activation of striatal cholinergic neurons mediates also the antipsychotic action of neuroleptics. However, anticholinergic compounds ameliorate the parkinsonism caused by neuroleptics without affecting their therapeutic activity. In this respect, therefore, striatal cholinergic activation may not be involved. A possible extrastriatal site of action of neuroleptic compounds is the limbic system, which is also rich in DA and ACh neurons (FUXE, 1965; HERNANDEZ-PENN et al., 1963). As for the effect of neuroleptics, however, a fundamental difference exists between striatal and limbic structures. Thus, chlorpromazine or haloperidol (Fig. 1) failed to enhance the liberation of ACh collected by means of a push-pull cannula from the septum or nucleus accumbens of the gallamine-immobilized cat. This is in contrast to their marked effect on the caudate nucleus (BARTHOLINIet al., this volume; STADLERet al., 1973) although the DA turnover in both regions was markedly accelerated, as estimated by the rise of homovanillic acid (Table 1). These findings indicate that in septum and nucleus accumbens of the cat the activation of cholinergic neurons is not regulated by a DA input. Conversely, the lack of a cholinergic regulation on limbic DA neurons is known since anticholinergic agents do not diminish the neuroleptic-induced enhancement of limbic DA turnover (ANDBN, 1972). In conclusion, some extrapyramidal effects of neuroleptic drugs depend on the 641
642
K. G. LLOYD, H. STADLER and G.
BARTHOLINI N.caudatus
i
I/
60 j
N caudatus
N.accumbens &~p$~mmbens
minutes
FIG. I.-Output of acetylcholine (ACh) into IO-min samples of perfusate of various brain regions of the cat during the control period (O-60) and after haloperidol. Each curve indicates one experiment. The points represent averages of duplicate determinations. Time 0 indicates the beginning of collection. TABLE 1. CONCENTRATIONOF DOPAMINE(DA) AND HOMOVANILLICACID (HVA) IN DIFFERENT BRAIN REGIONSOF THE CAT. Caudate nucleus and nucleus accumbens were perfused by means of push-pull
cannulae as in the experiments for acetylcholine (see Fig. 1). Saline (control animals) or haloperidol (2 mg/kg) was injected intravenously 2 hr before sacrifice. Number of determinations in parentheses. P < 0.01 vs controls. DA
HVA
Brain region (/q/g) controls Caudate n. haloperidol
11.41 i 0.58 (9) 9.04 * 0.30 (12)
controls
3.42 + 0.28 (9)
haloperidol
3.41 f 0.22 (12)
(% control)
79.2 & 2.6*
( y0 control)
(pglg) 4.08 i 0.26 (9) 6.13 & 0.51 (12)
150.2 i
12.5*
2.15 i 0.17 (9)
N. accumbens Septum Preoptic area 99.7 & 6.4
3.07 zt 0.24 (12)
142.8 + ll.l*
activation of a striatal cholinergic mechanism due to impairment of DA transmission. The antipsychotic effect of these drugs may not be connected with cholinergic neurons in either striatum or limbic system; however, a limbic DA involvement is conceivable. REFERENCES AND~N N. E. (1972) J. Pharm. Pharmac. 24,905-906. BARTHOLINI G., STADLER H. and LLQYD K. G. (1973) In: D. B., Ed.) Raven Press, New York. DIJVOISIN R. G. (1967) Archs Neural. 17, 124-126. FUXE K. (1965) Acta Physiol. Stand. 64, (Suppl.) 247.
The Treatment
of Parkinsonism(CALNE
Dopamine
and acetylcholine
neurones in striatal and limbic structures
643
GOODWIN F. K. (1971) J. Am. Med. Am. 218, 19151920. HERNANDEZ-PENNR.. O’FLAHERTY J. J. and MAZZUCHELLI-O’FLAHERTY A. L. (1967) 1 I Bruin Res.
4,243-267. HORNYKIEWICZ0. (1972) In: Handbook qf Neurochemistry (LAJTHA A., Ed.) Vol. 6, pp. 465-501, Plenum Press, New York. MET-TLERF. A. and CRANDELLA. (1959) J. Nerv. Ment. Dis. 129, 551-563. NYBXCK H. (1968) Europ. J. Pharmacol. 14, 395-403. ROSSUMJ. M. VAN, BOISSIER J. R., JANSSENP. A. S.. JULOU L., LOEW D. M., NIELSEN I. M., MUNKVALI I., RANDRUP A., STILLEG. and TEDESCHID. H. (1970) In: Modern Problems in Pharmacopsychiatry (Neuroleptics) (BOBON J. and JANSSENP., Eds), pp. 23-33, Karger, Basel. SNYDERS. H. (1973) Am. J. Psychiat. 130, 61-67. STADLERH., LLOYD K. G., GADEA-CIRIA M. and BARTHOLINIG. (1973) Brain Res., 55,476-480.