J Neural Transm [P-DSect] (1991) 3:81-87
__ Journal o f Neural Transmission 9 Springer-Verlag 1991 Printed in Austria
Effect of yohimbine on brain monoamines: an in vivo study T. Brannan, J. Martinez-Tica, and M. D. Yahr
Department of Neurology, Mount Sinai School of Medicine, New York, U.S.A. Accepted February 6, 1991
Summary. Following the administration of yohimbine, an a2-adrenoreceptor antagonist, the levels of norepinephrine (NE), dihydroxyphenylaceticacid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) increased significantly in the lateral ventricular fluid of rats. These increases were abolished when animals were pretreated with ~-methyl-para-tyrosine or reserpine. Dopamine (DA) was not detected in ventricular fluid either before or after yohimbine administration. Yohimbine administration did, however, increase intracellular DA levels in the corpus striatum. These findings indicate that yohimbine promotes NE and DA release in the brain and suggest that it also modifies the activity of the serotonin system.
Keywords: Yohimbine, norepinephrine, dopamine, cerebral microdialysis, lateral ventricle, striatum.
Introduction Yohimbine is an indole alkaloid which has been widely used as a selective a2adrenoreceptor antagonist (reviewed by Goldberg and Robertson, 1983). Yohimbine administration stimulates sympathetic outflow and increases plasma NE levels (Onrot etal., 1987). Yohimbine administration promotes NE release in the brain as evidenced by measurements of NE release from brain tissue slices (Hedler etal., 1981) and increases in NE metabolites in CSF and brain tissue (Mignot etal., 1982; Edwards and Sorisio, 1988). In addition to its effects on the NE system, yohimbine may potentially act on other neurotransmitter systems. For example, yohimbine has been reported to increase brain DA synthesis and metabolism (Scatton et al., 1973) and increase brain tissue serotonin levels (Papeschi et al., 1971). In general, however, studies of yohimbine on DA and serotonin metabolism have been regarded as contradictory and inconclusive (Goldberg and Robertson, 1983). In the present study, we have used the cerebral microdialysis technique to monitor the concentrations of NE, DA, HVA, DOPAC, and 5HIAA in the
82
T. Brannan et al.
cerebrospinal fluid of the lateral ventricle and the extracellular fluid of the corpus striatum of rats. The measurements were m a d e before and after yohimbine administration.
Materials and methods Cerebral dialysis and analytical techniques were as previously described (Slivka et al., 1988; Brannan etal., 1990). Briefly, male Sprague-Dawley rats (weight 200-260 g) were anesthesized intraperitoneally (IP) with choral hydrate (400 mg/kg) and placed in a stereotaxic device for insertion of the microdialysis probe into the right lateral ventricle. Different rats were used in each series of experiments; each rat was studied only once. The dialysis probes (Bioanalytical Systems) had a tip length of 2 mm and were perfused with an artificial CSF solution at a rate of 1.4 gl/minute. The microdialysis samples were collected at 15 minute intervals. Catecholamines and 5HIAA were measured by high performance liquid chromatography with electrochemical detection. Yohimbine and MHPG (the major NE metabolite) were not detectable under analytical conditions of this study. The detection limit of the analytical system for DA and NE was 1 pg. Anesthesia was maintained throughout the experiment. In all experiments, 6 samples were first collected to allow catecholamine levels to reach stable levels. The last sample before yohimbine administration was used to establish the baseline catecholamine values for that animal. In the first series of experiments, yohimbine (2.5 mg/kg IP, n = 4; 5 mg/kg, n = 6; or 10 mg/kg, n = 8) was administered following the baseline measurements. In the second series of experiments, animals were pretreated with a-methyl-para-tyrosine (AMPT, 400mg/kg IP, n= 6) on the evening prior to yohimbine administration (10mg/kg). In the third series of experiments, reserpine (5 mg/kg IP, n= 6) was administered 1 hour prior to yohimbine administration (10 mg/kg). In the fourth series of experiments, the probe was inserted into the corpus striatum (instead of the lateral ventricle) and yohimbine (5mg/kg IP, n= 6; or 10mg/kg IP, n--6) was administered. The experimental data were analyzed by analysis of variance with a repeated measurement design. Simultaneous multiple comparisons were based on the least significant difference test. The null hypothesis was rejected at the 0.05 level.
Results The concentration of N E in the microdialysis samples from the ventricular fluid did n o t increase following 2.5 or 5 m g / k g yohimbine administration. However, following 10 m g / k g yohimbine, N E concentrations increased 154% from a baseline level of 2 9 . 5 + 4 (SEM) pg/15 minutes to a maximal level of 74.94-8pg/ 15 min at 105 min (p < 0.001) and remained elevated for the 3 h o u r m o n i t o r i n g p e r i o d (Fig. 1). D A was n o t detectable in the lateral ventricular fluid either before or after yohimbine administration (2.5-10 mg/kg). The major D A metabolites D O P A C and H V A did n o t increase following 2.5 m g / k g yohimbine; however, following 5 m g / k g yohimbine, D O P A C concentrations increased 66% (p < 0.02) and H V A increased 122% (p < 0.001). D O P A C and H V A increased 200% and 480% respectively following 1 0 m g / k g yohimbine administration (p < 0.001, Fig. 2). 5 H I A A concentrations did n o t increase following 2.5 or 5 m g / k g yohimbine but increased 42% following 10 m g / k g yohimbine (p = 0.03).
Effect of yohimbine on brain monoamines
83
90" 80 70 60 50
&
40 30
z
2010 -
~0
0 0
I
I
30
60
I
l
i
i
90 120 150 180 Time (rain)
Fig. 1. Effect of yohimbine administration on norepinephrine levels in cerebrospinal fluid from the lateral ventricle. Yohimbine (10 mg/kg IP) was injected immediately following the baseline (time = 0 minute) sample. Values are group means :t=SEM
Yohimbine 10 mg/kg combined with A M P T or reserpine P r e t r e a t m e n t with A M P T decreased basal N E levels to 4 . 7 + 2 p g / 1 5 m i n (p < 0.001) a n d abolished the increase in N E levels following yohimbine. Similarly, p r e t r e a t m e n t with reserpine decreased basal N E levels to 1.3 4- 1 pg/15 min (p < 0.001) and also abolished the increase in N E levels following yohimbine. The increase in the levels o f D O P A C a n d H V A was abolished by p r e t r e a t m e n t with either A M P T or reserpine.
200 180 160 140
12o-
~
100"
e~ 8O" 60" 40"
DOPAC 20 I~ 0
J
0
30
60
90
120
-
i
150
-
9
180
Time (rain)
Fig. 2. Effect of yohimbine administration on HVA and DOPAC levels in cerebrospinal fluid from the lateral ventricle. Yohimbine (10 mg/kg IP) was injected immediately following the baseline (time = 0 minute) sample. Values are group means :~ SEM
84
T. Brannan et al. 40
36 32 28
2.4
16 "~
12 8
30
60
90
120
Time (rain) Fig. 3. Effect of yohimbine administration on extracellular dopamine levels in the corpus striatum. Yobimbine(10 mg/kg IP) was injectedimmediatelyfollowingthe baseline(time= 0 minute) sample. Values are group means + SEM
D A measurements in the corpus striatum
Since the increase in DA metabolites in the ventricular fluid suggested that yohimbine may promote DA release, we decided to monitor the effect of yohimbine administration on DA levels in the extracellular fluid of the corpus striatum, a structure which contains a rich DA innervation. Following 10 mg/ kg yohimbine (Fig. 3), DA levels increased 220% from a baseline of 9.0 + 0.4 pg/ 15min to a maximum of 2 8 . 7 + l l p g / 1 5 m i n at 45 minutes post injection (p= 0.01). Following 5mg/kg yohimbine administration, DA levels increased by a maximum of 60% at 30-60 minutes post injection; however, this increase was not significant (p = 0.067). Discussion
Our data indicate that yohimbine administration (10 mg/kg) increases NE levels in ventricular CSF. NE in the ventricular fluid originates in nerve terminals projecting from the locus coeruleus to the hippocampus (which lies adjacent to the lateral ventricles) and cerebral cortex (Lindvall and Bjorklund, 1983). This extends the findings of previous studies which have indicated that yohimbine (1-10mg/kg) stimulates brain NE release (Hedler etal., 1981; Mignot etal., 1982; Goldberg and Robertson, 1983; Edwards and Sorisio, 1988). Yohimbine at doses of 1-5 mg/kg produces behavioral effects (see Goldberg and Robertson, 1983) in freely moving animals. It is possible that we failed to measure an increase in ventricular NE levels following 2.5 and 5 mg/kg yohimbine administration because the released NE was metabolized before it reached the ventricular CSF. An alternative explanation is that NE release is enhanced by the additional blockade of al-adrenoreceptors which occurs with higher doses of
Effect of yohimbine on brain monoamines
85
yohimbine (Goldberg and Robertson, 1983). It is also possible that the chloral hydrate anesthesia used in our study may have modified the dose-response curve of yohimbine. Administration of AMPT depletes brain tissue NE and DA levels by inhibiting the enzyme tyrosine hydroxylase which is essential for catecholamine synthesis. Reserpine also depletes brain tissue NE and DA but by a different mechanism; i.e., by preventing vesicular storage in nerve terminals. As expected, our study showed that pretreatment with these catecholamine depleting agents decreased ventricular NE levels and abolished the increase of NE and DA metabolites that follows yohimbine administration. The finding that NE levels do not increase when yohimbine is administered following pretreatment with AMPT or reserpine also excluded the possibility that a yohimbine metabolite might have contributed to the peak which we ascribed to NE. Although DA metabolites increased following yohimbine administration (5-10mg/kg), ventricular fluid DA concentrations remained below detectable limits. This is probably because the sites of DA release in the forebrain (corpus striatum and mesial limbic system) are sufficiently distant from the ventricular CSF that the released DA is removed either by reuptake or metabolism before it reaches the dialysis probe. When we monitored DA levels in the striatum, a structure which contains a rich DA innervation, we were able to demonstrate significant DA release after yohimbine administration. Pharmacological and behavioral studies have suggested that yohimbine is a dopamine receptor antagonist (Boissier et al., 1968; Scatton et al., 1973; Papeschi, 1974). On the other hand, the effect of yohimbine on DA transmission may be secondary to activation of NE systems since NE neurons from the locus coeruleus terminate on DA neurons in the substantia nigra (Anden and Grabowska, 1976). Our data indicate that yohimbine does have a DA releasing effect; however, whether this DA release is mediated by activation of the NE system or by blockade of DA receptors (either pre- or post-synaptic) remains to be determined. Studies of the effect of yohimbine on the serotonin system have been contradictory-either showing no effect (see Goldberg and Robertson, 1983) or an antiserotonergic effect (Papeschi et al., 1971; Dwoskin et al., 1988). Our data indicate that 5HIAA concentrations do increase modestly following yohimbine administration. This finding confirms an effect on serotonin transmission, but does not indicate if this occurs as a result of blockade of serotonin receptors (either pre- or post-synaptic) or by multisynaptic mechanism (e.g. secondary to activation of the NE system). Clinically, yohimbine has been used for the treatment of impotence (see Goldberg and Robertson, 1983). In addition, orthostatic hypotension has been treated with yohimbine both in the setting of multi-system atrophy (Onrot et al., 1987) and in Parkinson's disease (Montastruc et al., 1981). The "freezing" phenomena that accompanies Parkinson's disease may also result from a NE deficit (Narabayashi, 1983) and might respond to treatment with yohimbine. In this regard, a preliminary report has suggested that yohimbine does improve the
86
T. Brannan et al.
functional capacity of Parkinson patients with gait disturbances (Montastruc et al., 1981). In summary, our data clearly indicate that yohimbine administration increases N E release in the brain. In addition, we have demonstrated that yohimbine administration increases striatal levels of D A and increases ventricular fluid levels of 5HIAA. The findings related to N E release suggest that yohimbine might be useful for treating central nervous system disorders associated with N E deficits.
References Anden N-E, Grabowska M (1976) Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain. Eur J Pharmacol 39:275-282 Boissier JR, Simon P, Guidicelli JF (1968) Effects centraux de quelques substances adreno et/ou sympatholytiques. III. Ptosis, catalepsie, antagonisme vis-a-vis de l'apomorpine et de l'amphetamine. Arch Int Pharmacodyn 171:68-80 Brannan T, Bhardwaj A, Yahr MD (1990) L-threodops increases extracellular norepinephrine levels in the brain: an in vivo study. Neurology 40:1134-1135 Dwoskin LP, Neal BS, Sparber SB (1988) Evidence for antiserotonergic properties of yohimbine. Pharmacol Biochem Behav 31:321-326 Edwards DJ, Sorisio DA (1988) Differential effects of yohimbine and phenoxybenzamine on norepinephrine metabolites in rat brain. Res Commun Chem Pathol Pharmacol 62: 195-206 Goldberg MR, Robertson D (1983) Yohimbine: a pharmacological probe for study of the a2-adrenoreceptor. Pharmacol Rev 35:143-180 Hedler L, Stamm G, Weitzell R, Starke K (1981) Functional characterization of central a-adrenoreceptors by yohimbine diastereomers. Eur J Pharmacol 70:43-52 Lindvall O, Bjorklund A (1983) Dopamine and norepinephrine containing neuron systems: their anatomy in the rat brain. In: Emson PC (ed) Chemical neuroanatomy. Raven Press, New York, pp 229-254 Mignot E, Laude D, Elghozi JL, Le Quan-bui KH, Meyer P (1982) Central administration of yohimbine increased free 3-methoxyl-4-hydrophenylglycol in the cerebrospinal fluid of the rat. Eur J Pharmacol 83:135-138 Montastruc JL, Puech AJ, Clanet M, Guirand-Chaumeil B, Rascol A (1981) La yohimbine dans le traitment de la maladie de Parkinson: Resultat preliminaire. Nouv Presse Med 10:1331-1332 Narabayashi H (1983) Pharmacological basis of akinesia on Parkinson's disease. J Neural Transm [Suppl] 19:143-151 Onrot J, Goldberg MR, Biaggioni I, Wiley RG, Hollister AS, Robertson D (1987) Oral yohimbine in human autonomic failure. Neurology 37:215-220 Papeschi R, Sourkes TL, Youdim MBH (1971) The effect of yohimbine on brain serotonin metabolism, motor behavior and body temperature of the rat. Eur J Pharmacol 15: 318-326 Papeschi R (1974) An investigation on the behavioral and hypothermic effects of yohimbine: interaction with drugs affecting central and peripheral monoamines. Arch Int Pharmacodyn Ther 208:61-74 Scatton B, Zivkovic B, Dedek J (1973) Antidopaminergic properties of yohimbine. J Pharmacol Exp Ther 215:494M99
Effect of yohimbine on brain monoamines
87
Slivka A, Brannan TS, Weinberger J, Knott P J, Cohen G (1988) Increase in extracellular dopamine in the striatum during cerebral ischemia: a study utilizing cerebral microdialysis. J Neurochem 50:1714-1718 Authors' address: Dr. T. Brannan, Department of Neurology, Mount Sinai School of Medicine, Box 1137, One Gustave L. Levy Place, New York, N.Y. 10029, U.S.A. Received December 20, 1990
__ Journal o f Neural Transmission 9 Springer-Verlag 1991 Printed in Austria
Effect of yohimbine on brain monoamines: an in vivo study T. Brannan, J. Martinez-Tica, and M. D. Yahr
Department of Neurology, Mount Sinai School of Medicine, New York, U.S.A. Accepted February 6, 1991
Summary. Following the administration of yohimbine, an a2-adrenoreceptor antagonist, the levels of norepinephrine (NE), dihydroxyphenylaceticacid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) increased significantly in the lateral ventricular fluid of rats. These increases were abolished when animals were pretreated with ~-methyl-para-tyrosine or reserpine. Dopamine (DA) was not detected in ventricular fluid either before or after yohimbine administration. Yohimbine administration did, however, increase intracellular DA levels in the corpus striatum. These findings indicate that yohimbine promotes NE and DA release in the brain and suggest that it also modifies the activity of the serotonin system.
Keywords: Yohimbine, norepinephrine, dopamine, cerebral microdialysis, lateral ventricle, striatum.
Introduction Yohimbine is an indole alkaloid which has been widely used as a selective a2adrenoreceptor antagonist (reviewed by Goldberg and Robertson, 1983). Yohimbine administration stimulates sympathetic outflow and increases plasma NE levels (Onrot etal., 1987). Yohimbine administration promotes NE release in the brain as evidenced by measurements of NE release from brain tissue slices (Hedler etal., 1981) and increases in NE metabolites in CSF and brain tissue (Mignot etal., 1982; Edwards and Sorisio, 1988). In addition to its effects on the NE system, yohimbine may potentially act on other neurotransmitter systems. For example, yohimbine has been reported to increase brain DA synthesis and metabolism (Scatton et al., 1973) and increase brain tissue serotonin levels (Papeschi et al., 1971). In general, however, studies of yohimbine on DA and serotonin metabolism have been regarded as contradictory and inconclusive (Goldberg and Robertson, 1983). In the present study, we have used the cerebral microdialysis technique to monitor the concentrations of NE, DA, HVA, DOPAC, and 5HIAA in the
82
T. Brannan et al.
cerebrospinal fluid of the lateral ventricle and the extracellular fluid of the corpus striatum of rats. The measurements were m a d e before and after yohimbine administration.
Materials and methods Cerebral dialysis and analytical techniques were as previously described (Slivka et al., 1988; Brannan etal., 1990). Briefly, male Sprague-Dawley rats (weight 200-260 g) were anesthesized intraperitoneally (IP) with choral hydrate (400 mg/kg) and placed in a stereotaxic device for insertion of the microdialysis probe into the right lateral ventricle. Different rats were used in each series of experiments; each rat was studied only once. The dialysis probes (Bioanalytical Systems) had a tip length of 2 mm and were perfused with an artificial CSF solution at a rate of 1.4 gl/minute. The microdialysis samples were collected at 15 minute intervals. Catecholamines and 5HIAA were measured by high performance liquid chromatography with electrochemical detection. Yohimbine and MHPG (the major NE metabolite) were not detectable under analytical conditions of this study. The detection limit of the analytical system for DA and NE was 1 pg. Anesthesia was maintained throughout the experiment. In all experiments, 6 samples were first collected to allow catecholamine levels to reach stable levels. The last sample before yohimbine administration was used to establish the baseline catecholamine values for that animal. In the first series of experiments, yohimbine (2.5 mg/kg IP, n = 4; 5 mg/kg, n = 6; or 10 mg/kg, n = 8) was administered following the baseline measurements. In the second series of experiments, animals were pretreated with a-methyl-para-tyrosine (AMPT, 400mg/kg IP, n= 6) on the evening prior to yohimbine administration (10mg/kg). In the third series of experiments, reserpine (5 mg/kg IP, n= 6) was administered 1 hour prior to yohimbine administration (10 mg/kg). In the fourth series of experiments, the probe was inserted into the corpus striatum (instead of the lateral ventricle) and yohimbine (5mg/kg IP, n= 6; or 10mg/kg IP, n--6) was administered. The experimental data were analyzed by analysis of variance with a repeated measurement design. Simultaneous multiple comparisons were based on the least significant difference test. The null hypothesis was rejected at the 0.05 level.
Results The concentration of N E in the microdialysis samples from the ventricular fluid did n o t increase following 2.5 or 5 m g / k g yohimbine administration. However, following 10 m g / k g yohimbine, N E concentrations increased 154% from a baseline level of 2 9 . 5 + 4 (SEM) pg/15 minutes to a maximal level of 74.94-8pg/ 15 min at 105 min (p < 0.001) and remained elevated for the 3 h o u r m o n i t o r i n g p e r i o d (Fig. 1). D A was n o t detectable in the lateral ventricular fluid either before or after yohimbine administration (2.5-10 mg/kg). The major D A metabolites D O P A C and H V A did n o t increase following 2.5 m g / k g yohimbine; however, following 5 m g / k g yohimbine, D O P A C concentrations increased 66% (p < 0.02) and H V A increased 122% (p < 0.001). D O P A C and H V A increased 200% and 480% respectively following 1 0 m g / k g yohimbine administration (p < 0.001, Fig. 2). 5 H I A A concentrations did n o t increase following 2.5 or 5 m g / k g yohimbine but increased 42% following 10 m g / k g yohimbine (p = 0.03).
Effect of yohimbine on brain monoamines
83
90" 80 70 60 50
&
40 30
z
2010 -
~0
0 0
I
I
30
60
I
l
i
i
90 120 150 180 Time (rain)
Fig. 1. Effect of yohimbine administration on norepinephrine levels in cerebrospinal fluid from the lateral ventricle. Yohimbine (10 mg/kg IP) was injected immediately following the baseline (time = 0 minute) sample. Values are group means :t=SEM
Yohimbine 10 mg/kg combined with A M P T or reserpine P r e t r e a t m e n t with A M P T decreased basal N E levels to 4 . 7 + 2 p g / 1 5 m i n (p < 0.001) a n d abolished the increase in N E levels following yohimbine. Similarly, p r e t r e a t m e n t with reserpine decreased basal N E levels to 1.3 4- 1 pg/15 min (p < 0.001) and also abolished the increase in N E levels following yohimbine. The increase in the levels o f D O P A C a n d H V A was abolished by p r e t r e a t m e n t with either A M P T or reserpine.
200 180 160 140
12o-
~
100"
e~ 8O" 60" 40"
DOPAC 20 I~ 0
J
0
30
60
90
120
-
i
150
-
9
180
Time (rain)
Fig. 2. Effect of yohimbine administration on HVA and DOPAC levels in cerebrospinal fluid from the lateral ventricle. Yohimbine (10 mg/kg IP) was injected immediately following the baseline (time = 0 minute) sample. Values are group means :~ SEM
84
T. Brannan et al. 40
36 32 28
2.4
16 "~
12 8
30
60
90
120
Time (rain) Fig. 3. Effect of yohimbine administration on extracellular dopamine levels in the corpus striatum. Yobimbine(10 mg/kg IP) was injectedimmediatelyfollowingthe baseline(time= 0 minute) sample. Values are group means + SEM
D A measurements in the corpus striatum
Since the increase in DA metabolites in the ventricular fluid suggested that yohimbine may promote DA release, we decided to monitor the effect of yohimbine administration on DA levels in the extracellular fluid of the corpus striatum, a structure which contains a rich DA innervation. Following 10 mg/ kg yohimbine (Fig. 3), DA levels increased 220% from a baseline of 9.0 + 0.4 pg/ 15min to a maximum of 2 8 . 7 + l l p g / 1 5 m i n at 45 minutes post injection (p= 0.01). Following 5mg/kg yohimbine administration, DA levels increased by a maximum of 60% at 30-60 minutes post injection; however, this increase was not significant (p = 0.067). Discussion
Our data indicate that yohimbine administration (10 mg/kg) increases NE levels in ventricular CSF. NE in the ventricular fluid originates in nerve terminals projecting from the locus coeruleus to the hippocampus (which lies adjacent to the lateral ventricles) and cerebral cortex (Lindvall and Bjorklund, 1983). This extends the findings of previous studies which have indicated that yohimbine (1-10mg/kg) stimulates brain NE release (Hedler etal., 1981; Mignot etal., 1982; Goldberg and Robertson, 1983; Edwards and Sorisio, 1988). Yohimbine at doses of 1-5 mg/kg produces behavioral effects (see Goldberg and Robertson, 1983) in freely moving animals. It is possible that we failed to measure an increase in ventricular NE levels following 2.5 and 5 mg/kg yohimbine administration because the released NE was metabolized before it reached the ventricular CSF. An alternative explanation is that NE release is enhanced by the additional blockade of al-adrenoreceptors which occurs with higher doses of
Effect of yohimbine on brain monoamines
85
yohimbine (Goldberg and Robertson, 1983). It is also possible that the chloral hydrate anesthesia used in our study may have modified the dose-response curve of yohimbine. Administration of AMPT depletes brain tissue NE and DA levels by inhibiting the enzyme tyrosine hydroxylase which is essential for catecholamine synthesis. Reserpine also depletes brain tissue NE and DA but by a different mechanism; i.e., by preventing vesicular storage in nerve terminals. As expected, our study showed that pretreatment with these catecholamine depleting agents decreased ventricular NE levels and abolished the increase of NE and DA metabolites that follows yohimbine administration. The finding that NE levels do not increase when yohimbine is administered following pretreatment with AMPT or reserpine also excluded the possibility that a yohimbine metabolite might have contributed to the peak which we ascribed to NE. Although DA metabolites increased following yohimbine administration (5-10mg/kg), ventricular fluid DA concentrations remained below detectable limits. This is probably because the sites of DA release in the forebrain (corpus striatum and mesial limbic system) are sufficiently distant from the ventricular CSF that the released DA is removed either by reuptake or metabolism before it reaches the dialysis probe. When we monitored DA levels in the striatum, a structure which contains a rich DA innervation, we were able to demonstrate significant DA release after yohimbine administration. Pharmacological and behavioral studies have suggested that yohimbine is a dopamine receptor antagonist (Boissier et al., 1968; Scatton et al., 1973; Papeschi, 1974). On the other hand, the effect of yohimbine on DA transmission may be secondary to activation of NE systems since NE neurons from the locus coeruleus terminate on DA neurons in the substantia nigra (Anden and Grabowska, 1976). Our data indicate that yohimbine does have a DA releasing effect; however, whether this DA release is mediated by activation of the NE system or by blockade of DA receptors (either pre- or post-synaptic) remains to be determined. Studies of the effect of yohimbine on the serotonin system have been contradictory-either showing no effect (see Goldberg and Robertson, 1983) or an antiserotonergic effect (Papeschi et al., 1971; Dwoskin et al., 1988). Our data indicate that 5HIAA concentrations do increase modestly following yohimbine administration. This finding confirms an effect on serotonin transmission, but does not indicate if this occurs as a result of blockade of serotonin receptors (either pre- or post-synaptic) or by multisynaptic mechanism (e.g. secondary to activation of the NE system). Clinically, yohimbine has been used for the treatment of impotence (see Goldberg and Robertson, 1983). In addition, orthostatic hypotension has been treated with yohimbine both in the setting of multi-system atrophy (Onrot et al., 1987) and in Parkinson's disease (Montastruc et al., 1981). The "freezing" phenomena that accompanies Parkinson's disease may also result from a NE deficit (Narabayashi, 1983) and might respond to treatment with yohimbine. In this regard, a preliminary report has suggested that yohimbine does improve the
86
T. Brannan et al.
functional capacity of Parkinson patients with gait disturbances (Montastruc et al., 1981). In summary, our data clearly indicate that yohimbine administration increases N E release in the brain. In addition, we have demonstrated that yohimbine administration increases striatal levels of D A and increases ventricular fluid levels of 5HIAA. The findings related to N E release suggest that yohimbine might be useful for treating central nervous system disorders associated with N E deficits.
References Anden N-E, Grabowska M (1976) Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain. Eur J Pharmacol 39:275-282 Boissier JR, Simon P, Guidicelli JF (1968) Effects centraux de quelques substances adreno et/ou sympatholytiques. III. Ptosis, catalepsie, antagonisme vis-a-vis de l'apomorpine et de l'amphetamine. Arch Int Pharmacodyn 171:68-80 Brannan T, Bhardwaj A, Yahr MD (1990) L-threodops increases extracellular norepinephrine levels in the brain: an in vivo study. Neurology 40:1134-1135 Dwoskin LP, Neal BS, Sparber SB (1988) Evidence for antiserotonergic properties of yohimbine. Pharmacol Biochem Behav 31:321-326 Edwards DJ, Sorisio DA (1988) Differential effects of yohimbine and phenoxybenzamine on norepinephrine metabolites in rat brain. Res Commun Chem Pathol Pharmacol 62: 195-206 Goldberg MR, Robertson D (1983) Yohimbine: a pharmacological probe for study of the a2-adrenoreceptor. Pharmacol Rev 35:143-180 Hedler L, Stamm G, Weitzell R, Starke K (1981) Functional characterization of central a-adrenoreceptors by yohimbine diastereomers. Eur J Pharmacol 70:43-52 Lindvall O, Bjorklund A (1983) Dopamine and norepinephrine containing neuron systems: their anatomy in the rat brain. In: Emson PC (ed) Chemical neuroanatomy. Raven Press, New York, pp 229-254 Mignot E, Laude D, Elghozi JL, Le Quan-bui KH, Meyer P (1982) Central administration of yohimbine increased free 3-methoxyl-4-hydrophenylglycol in the cerebrospinal fluid of the rat. Eur J Pharmacol 83:135-138 Montastruc JL, Puech AJ, Clanet M, Guirand-Chaumeil B, Rascol A (1981) La yohimbine dans le traitment de la maladie de Parkinson: Resultat preliminaire. Nouv Presse Med 10:1331-1332 Narabayashi H (1983) Pharmacological basis of akinesia on Parkinson's disease. J Neural Transm [Suppl] 19:143-151 Onrot J, Goldberg MR, Biaggioni I, Wiley RG, Hollister AS, Robertson D (1987) Oral yohimbine in human autonomic failure. Neurology 37:215-220 Papeschi R, Sourkes TL, Youdim MBH (1971) The effect of yohimbine on brain serotonin metabolism, motor behavior and body temperature of the rat. Eur J Pharmacol 15: 318-326 Papeschi R (1974) An investigation on the behavioral and hypothermic effects of yohimbine: interaction with drugs affecting central and peripheral monoamines. Arch Int Pharmacodyn Ther 208:61-74 Scatton B, Zivkovic B, Dedek J (1973) Antidopaminergic properties of yohimbine. J Pharmacol Exp Ther 215:494M99
Effect of yohimbine on brain monoamines
87
Slivka A, Brannan TS, Weinberger J, Knott P J, Cohen G (1988) Increase in extracellular dopamine in the striatum during cerebral ischemia: a study utilizing cerebral microdialysis. J Neurochem 50:1714-1718 Authors' address: Dr. T. Brannan, Department of Neurology, Mount Sinai School of Medicine, Box 1137, One Gustave L. Levy Place, New York, N.Y. 10029, U.S.A. Received December 20, 1990
