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Mechanism of noradrenaline depression of cortical neurones: A species comparison
EUROPEAN JOURNAL OF PHARMACOLOGY20 (1972) 381--384. NORTH-HOLLANDPUBLISHINGCOMPANY
Short communication
MECHANISM OF NORADRENALINE
DEPRESSION OF CORTICAL NEURONES:
A SPECIES COMPARISON L.M. JORDAN, N. LAKE and J.W. PHILLIS Department of Physiology, Faculty of Medicine, University of Manitoba, 770 Bannatyne A venue, Winnipeg, Canada
Accepted 6 October 1972
Received 20 September 1972
L.M. JORDAN, N. LAKE and J.W. PHILLIS, Mechanism of noradrenaline depression of cortical neurones: a species comparison, European J. Pharmacol. 20 (1972) 381-384. The predominant action of iontophoreticaUy applied noradrenaline (NA) in sensory cortices of rats, guinea pigs and cats was one of depression, but this was not correlated with the reported differences in stimulatory effect of NA in vitro on cyclic AMP formation in the cerebral cortices of the species examined. Dibutyryl cyclic AMP did not mimic the action of NA. lontophoresis
Cerebralcortex
Noradrenaline
1. INTRODUCTION One mechanism which has been proposed for the action of catecholamines in the nervous system implicates an increased synthesis of adenosine 3',5'-monophosphate (cyclic AMP) as a result of stimulation of adenyl cyclase by noradrenaline (NA) or dopamine (cf. Siggins et al., 1971; Kebabian and Greengard, 1971). The evidence favoring an action for cyclic AMP at a central inhibitory synapse has been summarized by Hoffer et al. (1970, 1971), who interpreted their results as indicating that cyclic AMP is the intracellular mediator of the depressant action of noradrenaline on rat cerebellar Purkinje cells. Noradrenaline has a depressant action on neurones in the cat cerebral cortex (Krnjevic'and Phillis, 1963; Frederickson et al., 1971) and NA- containing fibres are widespread in rat (And4n et al., 1966, 1967; Fuxe et al., 1968) and cat (Goyette et al., 1972) cerebral cortex. The presence of large amounts of cyclic AMP and adenyl cyclase in the cerebral cortex has been well established (cf. Surtherland et al., 1962; Butcher and Sutherland, 1962; Kakiuchi and Rail, 1968; Krishna et al., 1970). Kakiuchi and Rail (1968) first showed that NA can cause stimulation of cyclic AMP
CyclicAMP
Speciescomparison
formation in slices of cerebral cortex, and subsequent studies in support of this observation in various species have been reviewed by Rail and Sattin (1970). In a comparative study, Forn and Krishna (1971) demonstrated that NA stimulates cyclic AMP formation by slices from the cerebral cortices of the rat, mouse, cat and monkey but 'not from guinea pig. The stimulant action of noradrenaline was most evident in the rat and progressively less marked in the mouse, cat and monkey. Experiments have been conducted to compare the effects of iontophoretically applied NA in rat, cat and guinea-pig cerebral cortices. The responses of NAsensitive neurones to dibutyryl cyclic AMP have also been determined, since this substance is thought to mimic the depressant action of NA on cerebellar Purkinje cells (Siggins et al., 1969, 1971), an effect which should occur if cyclic AMP were the intracellular mediator of the action of NA.
2. MATERIALS AND METHODS 6 cats, 9 rats and 11 guinea pigs anaesthetized with methoxyflurane-nitrous oxide were studied in these
382
L.M. Jordan et al.. Noradrenaline and cortical neurones
experiments. The details of the methods used for recording have been given elsewhere (Jordan and Phillis, 1972). The effects of iontophoretically applied drugs on the spontaneous and glutamate-evoked firing of neurones in the sensory cortices of all 3 species were assessed from ratemeter records. Extracellular recordings of neuronal firing were made using the central barrel, filled with 2 M sodium chloride, of multibarrelied micropipettes. The outer barrels were filled with 1-noradrenaline bitartrate, 0.2 M, pH 5.0 (Sigma); sodium 1-glutamate, 0.2 M (Baker); N6,O2-dibu tyryl adenosine 3',5'-cyclic phosphate, 0.2 M, pH 6.5 (Calbiochem.); aminophylline, 0.2 M (Sigma) or sodium chloride, 2.0 M. The technique of automatic balancing of current at the tip of the micropipette (Salmoiraghi and Weight, 1967) was employed whenever tests with dibutyryl cyclic AMP were performed.
The distributions of effects of iontophoretically applied NA in the sensory cortices of cats, rats and guinea pigs are shown in table 1. The predominant effect for all species was clearly one of depression. The characteristics of the NA depression observed in rats and guinea pigs were similar to those previously demonstrated for the depressant action of NA in cats (Frederickson et al., 1971, 1972). ×2 tests of contingency tables of the distribution of effects revealed that there was no significant difference among the three species for the effects of NA (p>0.05). The potency of noradrenaline as a depressant of firing of cortical neurones was determined by calculation of the mean threshold current required to cause depression of neuronal firing, and the threshold values for all three species were compared. In cats, the mean threshold for 50 neurones was 23 -+ 2 nA; in
rats (21 neurones), 30 +- 4 nA; and in guinea pigs (21 neurones), 26 +- 4 nA. The differences between the threshold values for NA depression in the different species were not statistically significant (p>0.05), indicating that the depressant potency of NA does not parallel the ability of NA to stimulate cyclic AMP formation in vitro. If cyclic AMP has a role in the mediation of NA depression in the cerebral cortex, then dibutyryl cyclic AMP, which is thought to penetrate diffusion barriers readily and to be less rapidly metabolized by the enzyme phosphodiesterase than cyclic AMP (Butcher et al., 1965; Posternak et al., 1962), should mimic the action of NA. Table 2 shows the results obtained when dibutyryl cyclic AMP was applied iontophoretically onto neurones which were depressed by NA. Currents of up to 200 nA were used, and the technique of current balancing at the electrode tip was employed on each neurone tested. Each neurone was also tested without current balancing, and possible current effects were assessed using a conventional current control applied from a barrel containing sodium chloride. It was rarely possible to reveal genuine effects of dibutyryl cyclic AMP, and most of the responses obtained could be attributed to current effects regardless of whether or not the current balancing technique was used. It is apparent from table 2 that dibutyryl cyclic AMP did not mimic the depressant action of NA in any of the species studied. Furthermore, no statistically significant difference could be demonstrated among the species tested for the action of dibutyryl cyclic AMP. In order to rule out the possibility that destruction of dibutyryl cyclic AMP by phosphodiesterase might prevent its action on cortical neurones, tests with dibutyryl cyclic AMP were performed following prior application of aminophylline, a substance which inhibits phosphodiesterase (Butcher and Sutherland,
Table 1 Actions of noradrenaline on cerebral cortical neurones.
Table 2 Actions of dibutyryl cyclic AMP on cerebral cortical neurones.
3. RESULTS
Species
Total ceils
Excitation
Depression
No effect
Species
Total cells
Excitation
Depression
No effect
Cat Rat Guinea pig
76 76 87
0 0 0
59 (78%) 49 (64%) 66 (76%)
17 (22%) 27 (36%) 21 (24%)
Cat Rat Guinea pig
43 17 21
4 (9%) 1 (6%) 2 (9%)
7 (16%) 2 (12%) 1 (5%)
32 (75%) 14 (82%) 18 (86%)
L.M. Jordan et al., Noradrenaline and cortical neurones
1962). The influence of aminophylline ( 5 - 3 5 nA for 2 - 5 min) was tested on 4 neurones in cat cerebral cortex which were depressed by NA but unaffected by dibutyryl cyclic AMP. No changes in the response to dibutyryl cyclic AMP were observed after aminophylline. This indicates that destruction of dibutyryl cyclic AMP by phosphodiesterase probably does not play a significant role in determining the response to iontophoretically applied dibutyryl cyclic AMP.
4. DISCUSSION The present results show that the effects of noradrenalino are comparable in the cerebral cortices of cats, rats and guinea pigs, and that the predominant action in all three species is one of depression. There is no indication that the ability of NA to cause depression parallels the distribution of the potency of NA as a stimulant of adenyl cyclase. The results obtained with guinea pigs are particularly revealing, since NA has virtually no effect on cyclic AMP formation in this species (Forn and Krishna, 1971; Shimizu et at., 1971). Extracellularly applied dibutyryl cyclic AMP failed to mimic the depressant action of NA on neurones in the cerebral cortex of these three species. This substance rarely caused depression regardless of whether or not the technique of automatic current balancing was employed. Siggins et al. (1971) have argued that iontophoretically applied dibutyryl cyclic AMP is able to traverse plasma membranes and that its application extracellularly is therefore equivalent to an 'endogenous' increase in cyclic AMP. It is unlikely, therefore, that the mediation of NA depression in the cerebral cortex can be attributed to cyclic AMP, as has been suggested for NA depression of cerebellar Purkinje cells (Siggins et al., 1969, 1971).
ACKNOWLEDGEMENTS These studies were supported by grants from the Canadian Medical Research Council. Dr. N. Lake is a postdoctoral fellow of the Council.
383
REFERENCES And6n, N.-E., A. Dahlstr6m, K. Fuxe, K. Larsson, L. Olson and U. Ungerstedt, 1966, Ascending monoamine neurones to the telencephalon and diencephalon, Acta Physiol. Scand. 67,313. And6n, N.-E., K. Fuxe and U. Ungerstedt, 1967, Monoamine pathways to the cerebellum and cerebral cortex, Experientia 23,838. Butcher, R.W. and E.W. Sutherland, 1962, Adenosine 3',5'phosphate in biological materials. I. Purification and properties of cyclic 3',5'-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3',5'-phosphate in human urine, J. Biol. Chem. 237, 1244. Butcher, R.W., R.J. Ho, H.C. Meng and E.W. Sutherland, 1965, Adenosine 3',5'-monophosphate in biological .naterials. II. The measurements of adenosine 3',5'-monophosphate in tissues and the r0le of cyclic nucleotide in the lipolytic response of fat to epinephrine, J. Biol. Chem. 240, 4515. Forn, J. and G. Krishna, 1971, Effect of norepinephrine, histamine and other drugs on cyclic 3',5'-AMP formation in brain slices of various animal species, Pharmacol. 5, 193. Frederickson, R.C.A., L.M. Jordan and J.W. Phillis, 1971, The action of noradrenaline on cortical neurones: effects of pH, Brain Research 35,556. Frederickson, R.C.A., L.M. Jordan and J.W. Phillis, 1972, A reappraisal of the actions of noradrenaline and 5-hydroxytryptamine on cerebral cortical neurones, Comp. Gen. Pharmac. (in press). Fuxe, K., B. Hamberger and T. HiSkfelt, 1968, Distribution of noradrenaline nerve terminals in cortical areas of the rat, Brain Research 8, 125. Goyette, P.J., A.M. Mouren-Mathieu and J. de Champlain, 1972, Noradrenaline in cat cerebral cortex: Histofluorescent and biochemical study, Proc. Can. Fed. Biol. Soc. 15, 101. Hoffer, B.J., G.R. Siggins and F.E. Bloom, 1970, Possible cyclic AMP-mediated adrenergic synapses to rat cerebellar Purkinje cells: combined structural, physiological, and pharmacological analysis, in: Role of Cyclic AMP in Cell Function, eds. P. Greengard and E. Costa (Raven Press, New York) p. 349. Hoffer, B.J., G.R. Siggins,A.P. Oliver and F.E. Bloom, 1971, Cyclic AMP mediation of norepinephrine inhibition in rat cerebeUar cortex: a unique class of synaptic responses, Ann. N.Y. Acad. Sci. 185,531. Jordan, L.M. and J.W. Phillis, 1972, Acetylcholine inhibition in the intact and chronically isolated cerebral cortex, Brit. J. Pharmacol. 45,584. Kakiuchi, S. and T.W. Rail, 1968, Studies on adenosine 3'5'phosphate in rabbit cerebral cortex, Mol Pharmacol. 4, 379. Kebabian, J.W. and P. Greengard, 1971, Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission, Science 174, 1346.
384
L.M. Jordan et aL, Noradrenaline and cortical neurones
Krishna, G., J. Forn, K. Voigt, M. Paul and G.L. Gessa, 1970, Dynamic aspects of neurohormonal control of cyclic 3',5'-AMP synthesis in brain, in: Role of Cyclic AMP in Cell Functions, eds. P. Greengard and E. Costa (Raven Press, New York) p. 155. Krnjevid, K. and J.W. Phillis, 1963, Actions of certain amines on cerebral cortical neurones, Brit. J. Pharmacol. 20, 471. Posternak, Th., E.W. Sutherland and W.F. Henion, 1962, Derivatives of cyclic 3',5'-adenosine monophosphate, Biochim. Biophys. Acta, 65,558. Rail, T.W. and A. Sattin, 1970, Factors influencing the accumulation of cyclic AMP in brain tissue, in: Role of Cyclic AMP in Cell Function, eds. P. Greengard and E. Costa (Raven Press, New York) p. 113. Salmoiraghi, G.C. and F.F. Weight, 1967, Micromethods in neuropharmacology: an approach to the study of anesthetics, Anesthesia 28, 54.
Shimizu, H., S. Tanaka, T. Suzuki and Y. Matsukado, 1971, The response of human cerebrum adenyl cyclase to biogenic amines, J. Neurochem. 18, 1157. Siggins, G.R., B.J. Hoffer and F.E. Bloom, 1969, Cyclic adenosine monophosphate: Possible mediator for norepinephrine effects on cerebellar Purkinje cells, Science 165, 1018. Siggins, G.R.B.J. Hoffer and F.E. Bloom, 1971, Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. Ill. Evidence for mediation of norepinephrine effects by cyclic 3',5'-monophosphate, Brain Research 25, 535. Sutherland, E.W., T.W. Rail and T. Menon, 1962, Adenyl cyclase. 1. Distribution, preparation, and properties, J. Biol. Chem. 237, 1220.
Short communication
MECHANISM OF NORADRENALINE
DEPRESSION OF CORTICAL NEURONES:
A SPECIES COMPARISON L.M. JORDAN, N. LAKE and J.W. PHILLIS Department of Physiology, Faculty of Medicine, University of Manitoba, 770 Bannatyne A venue, Winnipeg, Canada
Accepted 6 October 1972
Received 20 September 1972
L.M. JORDAN, N. LAKE and J.W. PHILLIS, Mechanism of noradrenaline depression of cortical neurones: a species comparison, European J. Pharmacol. 20 (1972) 381-384. The predominant action of iontophoreticaUy applied noradrenaline (NA) in sensory cortices of rats, guinea pigs and cats was one of depression, but this was not correlated with the reported differences in stimulatory effect of NA in vitro on cyclic AMP formation in the cerebral cortices of the species examined. Dibutyryl cyclic AMP did not mimic the action of NA. lontophoresis
Cerebralcortex
Noradrenaline
1. INTRODUCTION One mechanism which has been proposed for the action of catecholamines in the nervous system implicates an increased synthesis of adenosine 3',5'-monophosphate (cyclic AMP) as a result of stimulation of adenyl cyclase by noradrenaline (NA) or dopamine (cf. Siggins et al., 1971; Kebabian and Greengard, 1971). The evidence favoring an action for cyclic AMP at a central inhibitory synapse has been summarized by Hoffer et al. (1970, 1971), who interpreted their results as indicating that cyclic AMP is the intracellular mediator of the depressant action of noradrenaline on rat cerebellar Purkinje cells. Noradrenaline has a depressant action on neurones in the cat cerebral cortex (Krnjevic'and Phillis, 1963; Frederickson et al., 1971) and NA- containing fibres are widespread in rat (And4n et al., 1966, 1967; Fuxe et al., 1968) and cat (Goyette et al., 1972) cerebral cortex. The presence of large amounts of cyclic AMP and adenyl cyclase in the cerebral cortex has been well established (cf. Surtherland et al., 1962; Butcher and Sutherland, 1962; Kakiuchi and Rail, 1968; Krishna et al., 1970). Kakiuchi and Rail (1968) first showed that NA can cause stimulation of cyclic AMP
CyclicAMP
Speciescomparison
formation in slices of cerebral cortex, and subsequent studies in support of this observation in various species have been reviewed by Rail and Sattin (1970). In a comparative study, Forn and Krishna (1971) demonstrated that NA stimulates cyclic AMP formation by slices from the cerebral cortices of the rat, mouse, cat and monkey but 'not from guinea pig. The stimulant action of noradrenaline was most evident in the rat and progressively less marked in the mouse, cat and monkey. Experiments have been conducted to compare the effects of iontophoretically applied NA in rat, cat and guinea-pig cerebral cortices. The responses of NAsensitive neurones to dibutyryl cyclic AMP have also been determined, since this substance is thought to mimic the depressant action of NA on cerebellar Purkinje cells (Siggins et al., 1969, 1971), an effect which should occur if cyclic AMP were the intracellular mediator of the action of NA.
2. MATERIALS AND METHODS 6 cats, 9 rats and 11 guinea pigs anaesthetized with methoxyflurane-nitrous oxide were studied in these
382
L.M. Jordan et al.. Noradrenaline and cortical neurones
experiments. The details of the methods used for recording have been given elsewhere (Jordan and Phillis, 1972). The effects of iontophoretically applied drugs on the spontaneous and glutamate-evoked firing of neurones in the sensory cortices of all 3 species were assessed from ratemeter records. Extracellular recordings of neuronal firing were made using the central barrel, filled with 2 M sodium chloride, of multibarrelied micropipettes. The outer barrels were filled with 1-noradrenaline bitartrate, 0.2 M, pH 5.0 (Sigma); sodium 1-glutamate, 0.2 M (Baker); N6,O2-dibu tyryl adenosine 3',5'-cyclic phosphate, 0.2 M, pH 6.5 (Calbiochem.); aminophylline, 0.2 M (Sigma) or sodium chloride, 2.0 M. The technique of automatic balancing of current at the tip of the micropipette (Salmoiraghi and Weight, 1967) was employed whenever tests with dibutyryl cyclic AMP were performed.
The distributions of effects of iontophoretically applied NA in the sensory cortices of cats, rats and guinea pigs are shown in table 1. The predominant effect for all species was clearly one of depression. The characteristics of the NA depression observed in rats and guinea pigs were similar to those previously demonstrated for the depressant action of NA in cats (Frederickson et al., 1971, 1972). ×2 tests of contingency tables of the distribution of effects revealed that there was no significant difference among the three species for the effects of NA (p>0.05). The potency of noradrenaline as a depressant of firing of cortical neurones was determined by calculation of the mean threshold current required to cause depression of neuronal firing, and the threshold values for all three species were compared. In cats, the mean threshold for 50 neurones was 23 -+ 2 nA; in
rats (21 neurones), 30 +- 4 nA; and in guinea pigs (21 neurones), 26 +- 4 nA. The differences between the threshold values for NA depression in the different species were not statistically significant (p>0.05), indicating that the depressant potency of NA does not parallel the ability of NA to stimulate cyclic AMP formation in vitro. If cyclic AMP has a role in the mediation of NA depression in the cerebral cortex, then dibutyryl cyclic AMP, which is thought to penetrate diffusion barriers readily and to be less rapidly metabolized by the enzyme phosphodiesterase than cyclic AMP (Butcher et al., 1965; Posternak et al., 1962), should mimic the action of NA. Table 2 shows the results obtained when dibutyryl cyclic AMP was applied iontophoretically onto neurones which were depressed by NA. Currents of up to 200 nA were used, and the technique of current balancing at the electrode tip was employed on each neurone tested. Each neurone was also tested without current balancing, and possible current effects were assessed using a conventional current control applied from a barrel containing sodium chloride. It was rarely possible to reveal genuine effects of dibutyryl cyclic AMP, and most of the responses obtained could be attributed to current effects regardless of whether or not the current balancing technique was used. It is apparent from table 2 that dibutyryl cyclic AMP did not mimic the depressant action of NA in any of the species studied. Furthermore, no statistically significant difference could be demonstrated among the species tested for the action of dibutyryl cyclic AMP. In order to rule out the possibility that destruction of dibutyryl cyclic AMP by phosphodiesterase might prevent its action on cortical neurones, tests with dibutyryl cyclic AMP were performed following prior application of aminophylline, a substance which inhibits phosphodiesterase (Butcher and Sutherland,
Table 1 Actions of noradrenaline on cerebral cortical neurones.
Table 2 Actions of dibutyryl cyclic AMP on cerebral cortical neurones.
3. RESULTS
Species
Total ceils
Excitation
Depression
No effect
Species
Total cells
Excitation
Depression
No effect
Cat Rat Guinea pig
76 76 87
0 0 0
59 (78%) 49 (64%) 66 (76%)
17 (22%) 27 (36%) 21 (24%)
Cat Rat Guinea pig
43 17 21
4 (9%) 1 (6%) 2 (9%)
7 (16%) 2 (12%) 1 (5%)
32 (75%) 14 (82%) 18 (86%)
L.M. Jordan et al., Noradrenaline and cortical neurones
1962). The influence of aminophylline ( 5 - 3 5 nA for 2 - 5 min) was tested on 4 neurones in cat cerebral cortex which were depressed by NA but unaffected by dibutyryl cyclic AMP. No changes in the response to dibutyryl cyclic AMP were observed after aminophylline. This indicates that destruction of dibutyryl cyclic AMP by phosphodiesterase probably does not play a significant role in determining the response to iontophoretically applied dibutyryl cyclic AMP.
4. DISCUSSION The present results show that the effects of noradrenalino are comparable in the cerebral cortices of cats, rats and guinea pigs, and that the predominant action in all three species is one of depression. There is no indication that the ability of NA to cause depression parallels the distribution of the potency of NA as a stimulant of adenyl cyclase. The results obtained with guinea pigs are particularly revealing, since NA has virtually no effect on cyclic AMP formation in this species (Forn and Krishna, 1971; Shimizu et at., 1971). Extracellularly applied dibutyryl cyclic AMP failed to mimic the depressant action of NA on neurones in the cerebral cortex of these three species. This substance rarely caused depression regardless of whether or not the technique of automatic current balancing was employed. Siggins et al. (1971) have argued that iontophoretically applied dibutyryl cyclic AMP is able to traverse plasma membranes and that its application extracellularly is therefore equivalent to an 'endogenous' increase in cyclic AMP. It is unlikely, therefore, that the mediation of NA depression in the cerebral cortex can be attributed to cyclic AMP, as has been suggested for NA depression of cerebellar Purkinje cells (Siggins et al., 1969, 1971).
ACKNOWLEDGEMENTS These studies were supported by grants from the Canadian Medical Research Council. Dr. N. Lake is a postdoctoral fellow of the Council.
383
REFERENCES And6n, N.-E., A. Dahlstr6m, K. Fuxe, K. Larsson, L. Olson and U. Ungerstedt, 1966, Ascending monoamine neurones to the telencephalon and diencephalon, Acta Physiol. Scand. 67,313. And6n, N.-E., K. Fuxe and U. Ungerstedt, 1967, Monoamine pathways to the cerebellum and cerebral cortex, Experientia 23,838. Butcher, R.W. and E.W. Sutherland, 1962, Adenosine 3',5'phosphate in biological materials. I. Purification and properties of cyclic 3',5'-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3',5'-phosphate in human urine, J. Biol. Chem. 237, 1244. Butcher, R.W., R.J. Ho, H.C. Meng and E.W. Sutherland, 1965, Adenosine 3',5'-monophosphate in biological .naterials. II. The measurements of adenosine 3',5'-monophosphate in tissues and the r0le of cyclic nucleotide in the lipolytic response of fat to epinephrine, J. Biol. Chem. 240, 4515. Forn, J. and G. Krishna, 1971, Effect of norepinephrine, histamine and other drugs on cyclic 3',5'-AMP formation in brain slices of various animal species, Pharmacol. 5, 193. Frederickson, R.C.A., L.M. Jordan and J.W. Phillis, 1971, The action of noradrenaline on cortical neurones: effects of pH, Brain Research 35,556. Frederickson, R.C.A., L.M. Jordan and J.W. Phillis, 1972, A reappraisal of the actions of noradrenaline and 5-hydroxytryptamine on cerebral cortical neurones, Comp. Gen. Pharmac. (in press). Fuxe, K., B. Hamberger and T. HiSkfelt, 1968, Distribution of noradrenaline nerve terminals in cortical areas of the rat, Brain Research 8, 125. Goyette, P.J., A.M. Mouren-Mathieu and J. de Champlain, 1972, Noradrenaline in cat cerebral cortex: Histofluorescent and biochemical study, Proc. Can. Fed. Biol. Soc. 15, 101. Hoffer, B.J., G.R. Siggins and F.E. Bloom, 1970, Possible cyclic AMP-mediated adrenergic synapses to rat cerebellar Purkinje cells: combined structural, physiological, and pharmacological analysis, in: Role of Cyclic AMP in Cell Function, eds. P. Greengard and E. Costa (Raven Press, New York) p. 349. Hoffer, B.J., G.R. Siggins,A.P. Oliver and F.E. Bloom, 1971, Cyclic AMP mediation of norepinephrine inhibition in rat cerebeUar cortex: a unique class of synaptic responses, Ann. N.Y. Acad. Sci. 185,531. Jordan, L.M. and J.W. Phillis, 1972, Acetylcholine inhibition in the intact and chronically isolated cerebral cortex, Brit. J. Pharmacol. 45,584. Kakiuchi, S. and T.W. Rail, 1968, Studies on adenosine 3'5'phosphate in rabbit cerebral cortex, Mol Pharmacol. 4, 379. Kebabian, J.W. and P. Greengard, 1971, Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission, Science 174, 1346.
384
L.M. Jordan et aL, Noradrenaline and cortical neurones
Krishna, G., J. Forn, K. Voigt, M. Paul and G.L. Gessa, 1970, Dynamic aspects of neurohormonal control of cyclic 3',5'-AMP synthesis in brain, in: Role of Cyclic AMP in Cell Functions, eds. P. Greengard and E. Costa (Raven Press, New York) p. 155. Krnjevid, K. and J.W. Phillis, 1963, Actions of certain amines on cerebral cortical neurones, Brit. J. Pharmacol. 20, 471. Posternak, Th., E.W. Sutherland and W.F. Henion, 1962, Derivatives of cyclic 3',5'-adenosine monophosphate, Biochim. Biophys. Acta, 65,558. Rail, T.W. and A. Sattin, 1970, Factors influencing the accumulation of cyclic AMP in brain tissue, in: Role of Cyclic AMP in Cell Function, eds. P. Greengard and E. Costa (Raven Press, New York) p. 113. Salmoiraghi, G.C. and F.F. Weight, 1967, Micromethods in neuropharmacology: an approach to the study of anesthetics, Anesthesia 28, 54.
Shimizu, H., S. Tanaka, T. Suzuki and Y. Matsukado, 1971, The response of human cerebrum adenyl cyclase to biogenic amines, J. Neurochem. 18, 1157. Siggins, G.R., B.J. Hoffer and F.E. Bloom, 1969, Cyclic adenosine monophosphate: Possible mediator for norepinephrine effects on cerebellar Purkinje cells, Science 165, 1018. Siggins, G.R.B.J. Hoffer and F.E. Bloom, 1971, Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. Ill. Evidence for mediation of norepinephrine effects by cyclic 3',5'-monophosphate, Brain Research 25, 535. Sutherland, E.W., T.W. Rail and T. Menon, 1962, Adenyl cyclase. 1. Distribution, preparation, and properties, J. Biol. Chem. 237, 1220.