- Email: [email protected]
β-phenylethylamine regulation of dopaminergic nigrostriatal cell activity
BRAIN RESEARCH ELSEVIER
Brain Research 703 (1995) 201-204
Research report
¢l-Phenylethylamine regulation of dopaminergic nigrostriatal cell activity Manuel Rodriguez *, Natalia Barroso Laboratory of Behavioural Neurochemistry, Department of Physiology, Faculty of Medicine, University of La Laguna, Tenerife, Canary Islands, Spain Accepted 15 August 1995
Abstract
In the present paper, the action of /3-phenylethylamine on electrophysiological activity of dopaminergic nigrostriatal neurons is described. 10 s after its i.v. injiectionand during 2-4 min, /3-phenylethylamine decreased the firing rate, the number of spikes within and out of burst and the number of bursts per second of these neurons. This was a dose-related action with statistical differences starting from 1.4 mg/kg for total and out of burst firing rate and from 2.4 mg/kg for within burst firing rate and for the number of bursts per second. The standard deviation and the variation coefficient of inter-spike intervals increased in a dose-related way. The marked effect found after low-dose administration suggests that under physiological conditions endogenous /3-phenylethylamine levels regulate the nigrostriatal dopaminergic cell activity. After peripheral low dose administration, fl-phenylethylamine behaves as a dopaminergic agonist with a very fast and brief action. Keywords: /3-Phenylethylamine; Dopamine; Nigrostriatal cell
1. Introduction
/3-Phenylethylamine (2-phenylethylamine; PE) is a biogenic amine found in the nervous tissue of vertebrate and invertebrate species [8,16,18]. Its highest concentration has been reported for mesolimbic and caudate-putamen structures [16,18]. Striatal PE Jis synthesized by dopaminergic neurons of the nigrostriatal system (A9; [11,14,16]) at a rate (1.5 n m o l / g / h in the rat) similar to that reported for dopamine. However, under the action of an extremely rapid turnover (half-life of 0.4 min), PE is metabolized to phenylacetic acid by monoamine oxidase type-B or to phenylethanolamine by dopamine-fl-hydroxylase. As Paterson et al. [16] have pointed out, its low endogenous concentration ( < 10 n g / g ) and its relatively low potency to modify some behaviour have led some researchers to conclude thai: in mammals PE possessed no physiological role at all, being merely a metabolic byproduct. In the present work the functional role of PE in dopaminergic neurotransmission was evaluated with an in vivo sensitive procedure. The electrophysiological A9 cells' response to i.v. injection of low PE doses was quantified.
* Corresponding author. Fax: (34) (22) 603529. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved
SSDI 0 0 0 6 - 8 9 9 3 ( 9 5 ) 0 1 0 9 8 . - X
2. Materials and methods
Experiments were carried out on male Sprague-Dawley rats (Letica, Barcelona) weighing 300-350 g. Animals were housed at 22°C, two per cage, under normal laboratory conditions on a standard light/dark schedule (12:12 h, lights on 03.00-15.00) and with free access to food and water. One day before drug testing, a silastic (Medical-grade tubing of Dow Corning with 0.020 inch i.d. and 0.037 inch o.d.) cannula was implanted in the jugular vein using the procedure reported by Harms and Ojeda [12]. On the test day,. rats were anaesthetized with chloral hydrate (400 m g / k g i.p.) and, using a procedure previously reported [2-4], the extracellular activity of A9 dopaminergic neurons was monitored. Briefly, animals were mounted in a stereotaxic apparatus and once the scalp was reflected, the skull overlying the right- or left-substantia nigra was removed. In order to record extracellular activity, electrodes (glass tubing filled with 2 M NaC1 containing 2% Pontamine sky blue) with 6 to 9 M ~ (at 1000 Hz) impedance were used. All recordings were obtained in the substantia nigra (2.8-3.4 mm anterior to lambda, 1.8-2.4 mm lateral to the midline and 6 - 7 mm below the cortical surface; Paxinos and Watson [17]) from neurons that could be antidromically activated from the head of the caudate
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
202
nucleus (8.6 mm anterior to lambda, 3.2 mm lateral to lambda and 5 mm ventral to the brain surface). During the recording session, body temperature was monitored and maintained between 36.5 and 37.5°C. The brain signal was amplified and filtered (100 to 5000 Hz) in a CAN96T model by Telcan. The signal was digitized and stored on a 80486 based computer by using a 16 bits analog-to-digital converter (LTI-C30). According to previously established criteria [5,9], cells were identified as nigrostriatal DA neurons if they: (1) displayed biphasic or triphasic action potentials with a positive first phase; (2) presented action potentials of 2.5-5 ms; (3) had a firing rate below 10 Hz; (4) could be antidromically activated from caudate nucleus; (5) had a conduction velocity of approximately 0.5-0.6 m / s . Bursting activity was determined according to Grace and Bunney [10]. The antidromic activation was performed using an S-8800 model by Grass and commercially available concentric stimulating electrodes (Kopf, SNE-100). Stimulations were given in 0.2-1 mA and 0.3 ms square pulses. Neurons were considered antidromically activated when presented during high rate stimulation (50 Hz) an antidromic spike per stimulus and a fixed latency from the stimulus artefact. All neurons here included showed collision between the spontaneously occurring action potentials and the stimulation-elicited spikes. 10 min after the electrophysiological identification of each A9 cell, saline vehicle or /3-phenylethylamine hydrochloride (Sigma) were i.v. injected. All injections were made without any direct manipulation of the rat and using a polythene tubing (i.d. 0.76 mm) connected to the cannula
implanted 24 h before. 25 /zl was always the injection volume. Statistical analyses was performed using the one-way ANOVA followed by the paired two-tail t-test. Analysis was done using the Statistic-SX program (NH Analytical Software). Statistical significance was defined as a P < 0.05.
3. Results Fig. 1 shows an example of firing rate modification induced by i.v. injection of different PE doses. Drug injection decreased the firing rate in a dose-related manner. This electrophysiological effect began 10-15 s after PE injection and persisted only for a few minutes. Both amplitude and duration were dose-related. Fig. 2 shows the modification of extracellular electrophysiological behaviour accumulated during the first 3 min after drug injection. PE decreased the number of spikes per second (total firing rate), the number of spikes within burst (firing rate within burst) and the number of spikes out of burst (firing rate out of burst). These effects are dose-related and present statistical differences starting from 1.4 m g / k g for total and out of burst firing rate and from 2.4 m g / k g for within burst firing rate (Fig. 2). PE also decreased the number of bursts (Fig. 2). The standard deviation and the variation coefficient of inter-spike intervals increased after PE administration. A dose-related response was also found in these cases.
"7 '-'T .o
1
0
' l i t
0
. . . . . . . . . . . . . . . . . . . . . . . . .
4
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. . . . .
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. . . . . . . . . . . . .
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, , n a , l , l , ,
12
. . . . . . . . . . . . . . . . . . . . .
, i , i I . . . . . . . . . . . .
16
Minutes Fig. 1. fl-Phenylcthylamine action on firing rate of nigrostriata] dopamincrgic neurons: an c×arnple.
. . . . . . . . . . .
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
4. Discussion In the present study, evidence is reported that low PE doses can modify the activity of nigrostriatal dopaminergic
Total Firing Rate
203
cells. PE has a high affinity for non-neural tissues (lung, liver, kidney) and only less than 1% of i.v. injected PE reaches the brain [19]. After peripheral injection, its distribution in the brain is not homogeneous and less than 20%
,.
Burst / sec
I00 IW
/
gO
~
•
Firing Rate Out of Burst
Firing Rate Within Burst
Standard Deviation :,
"t
Variation Coefficient
140. 206.
100
lm
O0 W'
1M
40.
148
20.
125
O"
lOS
0.4
1.4 mg/kg
2.4
3.4
0.4
1.4
2.4
3.4
mg/kg
Fig. 2. fl-Phenylethylamine action on total firing rate (all spikes), firing rate out of burst (spikes not included in burst), firing rate within burst (spikes not included in burst), number of bursts per second, standard deviation of inter-spike intervals and the variation coefficient of inter-spike intervals. Values are
the percentage of that found after saline solution injection and are shown as mean + standard error. * P < 0.05 vs. saline injection, * * P < 0.01 vs. saline injection, * * * P < 0.001 vs. saline injection.
204
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
of the PE that reaches the brain is taken up by the striatum. Thus, only a small portion of administered PE reaches the nigrostriatal dopaminergic system. This distribution and the relatively low potency previously found for PE action on some behavioural patterns [16] has conditioned the use of doses between 20-100 m g / k g [1,6,7,13]. As shown in Fig. 1, a decrease in A9 cells' firing rate can be induced after a dose as low as 0.4 mg/kg. The 1.4 m g / k g dose decreased the number of spikes out of burst but did not modify the spikes within burst or the number of bursts per second (Fig. 2). With a dose of 2.4 m g / k g the number of bursts and the number of spikes within burst also decreased. With a dose of 3.4 m g / k g a marked inhibition of burst behaviour was found with a number of bursts per second and a firing rate within burst near to zero. With this dose the spikes out of burst also presented an important decrease but only to 50% of their initial value (Fig. 2). Thus, after administration of the higher dose the great majority of spikes are displayed out of burst. In addition, after administration of the higher dose spikes presented an irregular and non-periodic behaviour. Both standard deviation and variation coefficient showed a marked increase between the doses 2.4 and 3.4 mg/kg. After administration of 3.4 mg/kg, an important percentage of rats presented different types of coordinated movement during the 2 - 3 min that followed PE injection, suggesting a shortlasting recovery of the anaesthetic effect of chloral hydrate. 3 min after drug injection animals returned to the initial unreactive condition. Taken together, the present data suggest that endogenous PE could be an important regulating factor for nigrostriatal dopaminergic cells. All dopaminergic agonists decrease firing rate of A9 cells [5]. Apomorphine (APO) has been considered to be the dopaminergic agonist with the lowest half-life. APO induces a progressive decrease in firing rate that starts 3 - 4 min after injection and persists for more than 45 min [4,5]. In this study, the PE effect started a few seconds after injection and persisted for only 2-4 min (Fig. 1). Thus, PE is probably the DA-agonist with the fastest (it readily crosses the blood-brain barrier) and briefest (it has a very high turnover) action. 'On-off' phenomenon is a short-lasting (a few minutes) motor disturbance that is often found in advanced Parkinson's disease [15]. In recent years, apomorphine has been used to control 'on-off' episodes. Because of its very short-lasting effect, PE could be useful in the treatment of this motor disturbance. The biological substrate of the 'on-off' phenomenon is unknown, and it cannot be ruled out that an endogenous product with very a high turnover such as PE could be involved in the physiopathology of this motor complication.
Acknowledgements We wish to thank P. Agnew for her assistance in preparing the manuscript.
References [1] Antelman, S.M., Edwards, D.L. and Lin, M., Phenylethylamine: evidence for a direct, postsynaptic dopamine-receptor stimulating action, Brain Res., 127 (1977) 317-322. [2] Castellano, M.A. and Rodriguez, M., Nigrostriatal dopaminergic cell activity is under control by substantia nigra of the contralateral brain side: electrophysiologicai evidence, Brain Res. BulL, 27 (1991) 213-218. [3] Castellano, M.A., Rivero, F.L. and Rodriguez, M., Spontaneous firing of nigrostriatal dopaminergic neurons in split-brain rats, Neurosci. Lett., 162 (1993) 1-4. [4] Castro, R., Abreu, P., Calzadilla, C.H. and Rodriguez, M., Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage intervals, Psychopharmacology, 85 (1985) 333-339. [5] Chiodo, L.A., Dopamine-containing neurons in the mammalian central nervous system: electrophysiology and pharmacology, Neurosci. Biobehav. Rev., 12 (1988) 49-91. [6] Dourish, C.T., A pharmacological analysis of the hyperactivity syndrome induced by fl-phenylethylamine in the mouse, Br. J. Pharmacol., 77 (1982) 129-139. [7] Dourish, C.T. and Cooper, S.J., Environmental experience produces qualitative changes in the stimulant effects of/3-phenylethylamine in rats, Psychopharmacology, 84 (1984) 132-135. [8] Durden, D.A., Philips, S.R. and Boulton, A.A., Identification and distribution of /3-phenylethylmine in the rat, Can. J. Biochem., 51 (1973) 995-1002. [9] Grace, A.A. and Bunney, B.S., Intracellular and extracellular electrophysiology of nigral dopaminergic neurons-1. Identification and characterization, Neuroscience, 10 (1983) 301-315. [10] Grace A.A. and Bunney B.S., The control of firing pattern in nigral dopaminergic neurons: burst firing, J. Neurosci., 4 (1984) 28772890. [11] Greenshaw, A., Juorio, A.V. and Nguyen, T.V., Depletion of striatal /3-phenylethylamine following dopamine but not 5-HT denervation, Brain Res. Bull., 17 (1986) 477-484. [12] Harms, P.G. and Ojeda S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein, J. Appl. Physiol., 36 (1974) 391-396. [13] Jackson, D.M. and Smythe, D.B., The distribution of fl-phenylethylamine in discrete regions of the rat brain and its effect on brain noradrenaline, dopamine and 5-hydroxytryptamine levels, Neuropharmacology, 12 (1973) 663-668. [14] Juorio, A.V., Paterson, I.A., Zhu, M.Y. and Matte, G., Electrical stimulation of the substantia nigra and changes of 2-phenylethylamine synthesis in the rat striatum, J. Neurochem., 56 4(1991) 213-220. [15] Obeso, J.A., Grandas, F., Vaamonde, J., Luquin, M.R., Artieda, J., Lera, G., Rodriguez M.E. and Martinez-Lage, J.M., Motor complications associated with chronic levodopa therapy in Parkinson's disease, Neurology, 39 (Suppl. 2)(1989) 11-19. [16] Paterson, I.A., Juorio, A.V. and Boulton, A.A., 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system?, J. Neurochem., 55 (1990) 1827-1837. [17] Paxinos, G. and Watson, C. The Rat Brain in Stereotaxic Coordinates, Academic Press, Sydney. [18] Philips, S.R., Rozdilsky, B. and Boulton, A.A., Evidence for the presence of m-tyramine, tryptamine and phenylethylamine in the rat brain and several areas of human brain, Biol. Psychiatry, 13 (1978) 51-57. [19] Wu, P.H. and Boulton, A.A., Metabolism, distribution and disappearance of injected/3-phenylethylamine in the rat, Can. J. Biochem., 53 (1975) 142-194.
Brain Research 703 (1995) 201-204
Research report
¢l-Phenylethylamine regulation of dopaminergic nigrostriatal cell activity Manuel Rodriguez *, Natalia Barroso Laboratory of Behavioural Neurochemistry, Department of Physiology, Faculty of Medicine, University of La Laguna, Tenerife, Canary Islands, Spain Accepted 15 August 1995
Abstract
In the present paper, the action of /3-phenylethylamine on electrophysiological activity of dopaminergic nigrostriatal neurons is described. 10 s after its i.v. injiectionand during 2-4 min, /3-phenylethylamine decreased the firing rate, the number of spikes within and out of burst and the number of bursts per second of these neurons. This was a dose-related action with statistical differences starting from 1.4 mg/kg for total and out of burst firing rate and from 2.4 mg/kg for within burst firing rate and for the number of bursts per second. The standard deviation and the variation coefficient of inter-spike intervals increased in a dose-related way. The marked effect found after low-dose administration suggests that under physiological conditions endogenous /3-phenylethylamine levels regulate the nigrostriatal dopaminergic cell activity. After peripheral low dose administration, fl-phenylethylamine behaves as a dopaminergic agonist with a very fast and brief action. Keywords: /3-Phenylethylamine; Dopamine; Nigrostriatal cell
1. Introduction
/3-Phenylethylamine (2-phenylethylamine; PE) is a biogenic amine found in the nervous tissue of vertebrate and invertebrate species [8,16,18]. Its highest concentration has been reported for mesolimbic and caudate-putamen structures [16,18]. Striatal PE Jis synthesized by dopaminergic neurons of the nigrostriatal system (A9; [11,14,16]) at a rate (1.5 n m o l / g / h in the rat) similar to that reported for dopamine. However, under the action of an extremely rapid turnover (half-life of 0.4 min), PE is metabolized to phenylacetic acid by monoamine oxidase type-B or to phenylethanolamine by dopamine-fl-hydroxylase. As Paterson et al. [16] have pointed out, its low endogenous concentration ( < 10 n g / g ) and its relatively low potency to modify some behaviour have led some researchers to conclude thai: in mammals PE possessed no physiological role at all, being merely a metabolic byproduct. In the present work the functional role of PE in dopaminergic neurotransmission was evaluated with an in vivo sensitive procedure. The electrophysiological A9 cells' response to i.v. injection of low PE doses was quantified.
* Corresponding author. Fax: (34) (22) 603529. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved
SSDI 0 0 0 6 - 8 9 9 3 ( 9 5 ) 0 1 0 9 8 . - X
2. Materials and methods
Experiments were carried out on male Sprague-Dawley rats (Letica, Barcelona) weighing 300-350 g. Animals were housed at 22°C, two per cage, under normal laboratory conditions on a standard light/dark schedule (12:12 h, lights on 03.00-15.00) and with free access to food and water. One day before drug testing, a silastic (Medical-grade tubing of Dow Corning with 0.020 inch i.d. and 0.037 inch o.d.) cannula was implanted in the jugular vein using the procedure reported by Harms and Ojeda [12]. On the test day,. rats were anaesthetized with chloral hydrate (400 m g / k g i.p.) and, using a procedure previously reported [2-4], the extracellular activity of A9 dopaminergic neurons was monitored. Briefly, animals were mounted in a stereotaxic apparatus and once the scalp was reflected, the skull overlying the right- or left-substantia nigra was removed. In order to record extracellular activity, electrodes (glass tubing filled with 2 M NaC1 containing 2% Pontamine sky blue) with 6 to 9 M ~ (at 1000 Hz) impedance were used. All recordings were obtained in the substantia nigra (2.8-3.4 mm anterior to lambda, 1.8-2.4 mm lateral to the midline and 6 - 7 mm below the cortical surface; Paxinos and Watson [17]) from neurons that could be antidromically activated from the head of the caudate
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
202
nucleus (8.6 mm anterior to lambda, 3.2 mm lateral to lambda and 5 mm ventral to the brain surface). During the recording session, body temperature was monitored and maintained between 36.5 and 37.5°C. The brain signal was amplified and filtered (100 to 5000 Hz) in a CAN96T model by Telcan. The signal was digitized and stored on a 80486 based computer by using a 16 bits analog-to-digital converter (LTI-C30). According to previously established criteria [5,9], cells were identified as nigrostriatal DA neurons if they: (1) displayed biphasic or triphasic action potentials with a positive first phase; (2) presented action potentials of 2.5-5 ms; (3) had a firing rate below 10 Hz; (4) could be antidromically activated from caudate nucleus; (5) had a conduction velocity of approximately 0.5-0.6 m / s . Bursting activity was determined according to Grace and Bunney [10]. The antidromic activation was performed using an S-8800 model by Grass and commercially available concentric stimulating electrodes (Kopf, SNE-100). Stimulations were given in 0.2-1 mA and 0.3 ms square pulses. Neurons were considered antidromically activated when presented during high rate stimulation (50 Hz) an antidromic spike per stimulus and a fixed latency from the stimulus artefact. All neurons here included showed collision between the spontaneously occurring action potentials and the stimulation-elicited spikes. 10 min after the electrophysiological identification of each A9 cell, saline vehicle or /3-phenylethylamine hydrochloride (Sigma) were i.v. injected. All injections were made without any direct manipulation of the rat and using a polythene tubing (i.d. 0.76 mm) connected to the cannula
implanted 24 h before. 25 /zl was always the injection volume. Statistical analyses was performed using the one-way ANOVA followed by the paired two-tail t-test. Analysis was done using the Statistic-SX program (NH Analytical Software). Statistical significance was defined as a P < 0.05.
3. Results Fig. 1 shows an example of firing rate modification induced by i.v. injection of different PE doses. Drug injection decreased the firing rate in a dose-related manner. This electrophysiological effect began 10-15 s after PE injection and persisted only for a few minutes. Both amplitude and duration were dose-related. Fig. 2 shows the modification of extracellular electrophysiological behaviour accumulated during the first 3 min after drug injection. PE decreased the number of spikes per second (total firing rate), the number of spikes within burst (firing rate within burst) and the number of spikes out of burst (firing rate out of burst). These effects are dose-related and present statistical differences starting from 1.4 m g / k g for total and out of burst firing rate and from 2.4 m g / k g for within burst firing rate (Fig. 2). PE also decreased the number of bursts (Fig. 2). The standard deviation and the variation coefficient of inter-spike intervals increased after PE administration. A dose-related response was also found in these cases.
"7 '-'T .o
1
0
' l i t
0
. . . . . . . . . . . . . . . . . . . . . . . . .
4
i,i
. . . . .
Ii11111111
. . . . . . . . . . . . .
$
, , n a , l , l , ,
12
. . . . . . . . . . . . . . . . . . . . .
, i , i I . . . . . . . . . . . .
16
Minutes Fig. 1. fl-Phenylcthylamine action on firing rate of nigrostriata] dopamincrgic neurons: an c×arnple.
. . . . . . . . . . .
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
4. Discussion In the present study, evidence is reported that low PE doses can modify the activity of nigrostriatal dopaminergic
Total Firing Rate
203
cells. PE has a high affinity for non-neural tissues (lung, liver, kidney) and only less than 1% of i.v. injected PE reaches the brain [19]. After peripheral injection, its distribution in the brain is not homogeneous and less than 20%
,.
Burst / sec
I00 IW
/
gO
~
•
Firing Rate Out of Burst
Firing Rate Within Burst
Standard Deviation :,
"t
Variation Coefficient
140. 206.
100
lm
O0 W'
1M
40.
148
20.
125
O"
lOS
0.4
1.4 mg/kg
2.4
3.4
0.4
1.4
2.4
3.4
mg/kg
Fig. 2. fl-Phenylethylamine action on total firing rate (all spikes), firing rate out of burst (spikes not included in burst), firing rate within burst (spikes not included in burst), number of bursts per second, standard deviation of inter-spike intervals and the variation coefficient of inter-spike intervals. Values are
the percentage of that found after saline solution injection and are shown as mean + standard error. * P < 0.05 vs. saline injection, * * P < 0.01 vs. saline injection, * * * P < 0.001 vs. saline injection.
204
M. Rodriguez, N. Barroso / Brain Research 703 (1995) 201-204
of the PE that reaches the brain is taken up by the striatum. Thus, only a small portion of administered PE reaches the nigrostriatal dopaminergic system. This distribution and the relatively low potency previously found for PE action on some behavioural patterns [16] has conditioned the use of doses between 20-100 m g / k g [1,6,7,13]. As shown in Fig. 1, a decrease in A9 cells' firing rate can be induced after a dose as low as 0.4 mg/kg. The 1.4 m g / k g dose decreased the number of spikes out of burst but did not modify the spikes within burst or the number of bursts per second (Fig. 2). With a dose of 2.4 m g / k g the number of bursts and the number of spikes within burst also decreased. With a dose of 3.4 m g / k g a marked inhibition of burst behaviour was found with a number of bursts per second and a firing rate within burst near to zero. With this dose the spikes out of burst also presented an important decrease but only to 50% of their initial value (Fig. 2). Thus, after administration of the higher dose the great majority of spikes are displayed out of burst. In addition, after administration of the higher dose spikes presented an irregular and non-periodic behaviour. Both standard deviation and variation coefficient showed a marked increase between the doses 2.4 and 3.4 mg/kg. After administration of 3.4 mg/kg, an important percentage of rats presented different types of coordinated movement during the 2 - 3 min that followed PE injection, suggesting a shortlasting recovery of the anaesthetic effect of chloral hydrate. 3 min after drug injection animals returned to the initial unreactive condition. Taken together, the present data suggest that endogenous PE could be an important regulating factor for nigrostriatal dopaminergic cells. All dopaminergic agonists decrease firing rate of A9 cells [5]. Apomorphine (APO) has been considered to be the dopaminergic agonist with the lowest half-life. APO induces a progressive decrease in firing rate that starts 3 - 4 min after injection and persists for more than 45 min [4,5]. In this study, the PE effect started a few seconds after injection and persisted for only 2-4 min (Fig. 1). Thus, PE is probably the DA-agonist with the fastest (it readily crosses the blood-brain barrier) and briefest (it has a very high turnover) action. 'On-off' phenomenon is a short-lasting (a few minutes) motor disturbance that is often found in advanced Parkinson's disease [15]. In recent years, apomorphine has been used to control 'on-off' episodes. Because of its very short-lasting effect, PE could be useful in the treatment of this motor disturbance. The biological substrate of the 'on-off' phenomenon is unknown, and it cannot be ruled out that an endogenous product with very a high turnover such as PE could be involved in the physiopathology of this motor complication.
Acknowledgements We wish to thank P. Agnew for her assistance in preparing the manuscript.
References [1] Antelman, S.M., Edwards, D.L. and Lin, M., Phenylethylamine: evidence for a direct, postsynaptic dopamine-receptor stimulating action, Brain Res., 127 (1977) 317-322. [2] Castellano, M.A. and Rodriguez, M., Nigrostriatal dopaminergic cell activity is under control by substantia nigra of the contralateral brain side: electrophysiologicai evidence, Brain Res. BulL, 27 (1991) 213-218. [3] Castellano, M.A., Rivero, F.L. and Rodriguez, M., Spontaneous firing of nigrostriatal dopaminergic neurons in split-brain rats, Neurosci. Lett., 162 (1993) 1-4. [4] Castro, R., Abreu, P., Calzadilla, C.H. and Rodriguez, M., Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage intervals, Psychopharmacology, 85 (1985) 333-339. [5] Chiodo, L.A., Dopamine-containing neurons in the mammalian central nervous system: electrophysiology and pharmacology, Neurosci. Biobehav. Rev., 12 (1988) 49-91. [6] Dourish, C.T., A pharmacological analysis of the hyperactivity syndrome induced by fl-phenylethylamine in the mouse, Br. J. Pharmacol., 77 (1982) 129-139. [7] Dourish, C.T. and Cooper, S.J., Environmental experience produces qualitative changes in the stimulant effects of/3-phenylethylamine in rats, Psychopharmacology, 84 (1984) 132-135. [8] Durden, D.A., Philips, S.R. and Boulton, A.A., Identification and distribution of /3-phenylethylmine in the rat, Can. J. Biochem., 51 (1973) 995-1002. [9] Grace, A.A. and Bunney, B.S., Intracellular and extracellular electrophysiology of nigral dopaminergic neurons-1. Identification and characterization, Neuroscience, 10 (1983) 301-315. [10] Grace A.A. and Bunney B.S., The control of firing pattern in nigral dopaminergic neurons: burst firing, J. Neurosci., 4 (1984) 28772890. [11] Greenshaw, A., Juorio, A.V. and Nguyen, T.V., Depletion of striatal /3-phenylethylamine following dopamine but not 5-HT denervation, Brain Res. Bull., 17 (1986) 477-484. [12] Harms, P.G. and Ojeda S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein, J. Appl. Physiol., 36 (1974) 391-396. [13] Jackson, D.M. and Smythe, D.B., The distribution of fl-phenylethylamine in discrete regions of the rat brain and its effect on brain noradrenaline, dopamine and 5-hydroxytryptamine levels, Neuropharmacology, 12 (1973) 663-668. [14] Juorio, A.V., Paterson, I.A., Zhu, M.Y. and Matte, G., Electrical stimulation of the substantia nigra and changes of 2-phenylethylamine synthesis in the rat striatum, J. Neurochem., 56 4(1991) 213-220. [15] Obeso, J.A., Grandas, F., Vaamonde, J., Luquin, M.R., Artieda, J., Lera, G., Rodriguez M.E. and Martinez-Lage, J.M., Motor complications associated with chronic levodopa therapy in Parkinson's disease, Neurology, 39 (Suppl. 2)(1989) 11-19. [16] Paterson, I.A., Juorio, A.V. and Boulton, A.A., 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system?, J. Neurochem., 55 (1990) 1827-1837. [17] Paxinos, G. and Watson, C. The Rat Brain in Stereotaxic Coordinates, Academic Press, Sydney. [18] Philips, S.R., Rozdilsky, B. and Boulton, A.A., Evidence for the presence of m-tyramine, tryptamine and phenylethylamine in the rat brain and several areas of human brain, Biol. Psychiatry, 13 (1978) 51-57. [19] Wu, P.H. and Boulton, A.A., Metabolism, distribution and disappearance of injected/3-phenylethylamine in the rat, Can. J. Biochem., 53 (1975) 142-194.