- Email: [email protected]
σ-Receptors: Implication for the control of neuronal activity of nigral dopamine-containing neurons
Ewopemt Jomrol of Pllarrmwolo~. 201 ( 199 1) 199-202 i’s 1991 Elsevier Science Puhlishers B.V. All rights resewed 0014-~999/Yl/$O3.j0 ADONIS
0011299991ori549J
EJP SlYX7
G&-an Engberg
and Hikan
Wikstriim
Dt~purtnwnt of Phartnaco~om. Chkcrsity of Ciitehor~, P.O. Box 33031. 400 33 Giirehorg, Stvedetl Received !5 November 1990. revised MS received 12 March 1991. accepted 28 May 1991
Using extracellular dopamine
(DA)
single unit recording
neurons
1,2,3,4,4a,5,6,10b-octahydrobenzo[flquinolinc aysociatcd
with
techniques,
in the zona compacta
any change
in the firing
(HW
ligand f + J-3-(3-hydroxyphenylkN-I-propyllpiperidinc rate, the firing pattern
of the DA
role in the control
regulation
-r-Receptors;
neurons.
Substantia
receptor
of cr-receptors
Administration
of racemic
in the ncuronal
pretreatment
agonist apomorphinc In contrast
with
for u-receptors.
in the substantia
or the mixed
to the effects of HW nigra. Rather,
was not
the drug did not affect DA
the
agonist/u-ret:ptor
173 on the DA
changed by Ihe drug. The data suggest that u-receptors
neurons
control of
trans-9-methoxy-4-benzyl-
high and specific affinity
Furthermore,
t( + 13-PPP).
cells was significantly
of the firing rate of DA
of the firing pattern
the significance
nigra.
1731, a drug displaying
rate of DA
curve for the inhibitory effects of the DA
dose-response
pivotal
we analyzed
of the substantia
cell firing
do not play a
they may have a function
in the
of these neurons.
nigra; Dopamine
neurons; Apomorphine;
1. Introduction
Previous radioligand binding data have revealed that several antipsychotic drugs, including haloperidol, display affinity for specific brain structures designated a-receptors (Largent et al., 1988a, b). These findings inter alia formed the basis for the hypothesis that some of the therapeutic benefits of these antipsychotic drugs are related to their ability to interfere with these receptors (Deutsch et al., 1988; Tam et al., 1988; Snyder and Largent, 1989). u Sites are reported to be distributed heterogeneously throughout the brain, with dopamine (DA&containing neurons in the zona compacta of the substantia nigra displaying a high density (Gundlach et al., 198.5; 1986). In addition, several reports suggest that u-receptors are involved in the regulation of neuronal activity of midbrain DA neurons (Freeman and Bunney, 1984; Ceci et al., 1988: Steinfels et al., 1989; Steinfels and Tam, 1989). The overall interpretation of these elcctrophysiological findings, however, is hampered by the relative lack of specificity of many drugs used as tool to evaluate the significance of Ir-receptors in this respect.
Correspondewe to: G. Engherg. Department uf Pharmacology. University ol’ Giiteborg. P.O. Box 33031. 400 3.1Giitehrwg. Swcdcn. Tel. .x3 I .xs34L3,
( + )-3-PPP (( + I-3-(3-hydroxyphenylkN-f
I-propyl)piperidine)
In the present electrophysiological study the role of a-receptors in the regulation of nigral DA neurons was analyzed with HW 173, a drug displaying high affinity and selectivity for u-receptors (Largent et al., 1988b).
2. Materials and methods
2. I. Single
tttzil recordittgs
A”?:: Sprague-Dawley rats (200-250 g) were anesthetized with chloral hydrate (400 mg/kg. intraperitoneally) and mounted in a stereotaxic apparatus. Additional anesthetics and drugs were given via a lateral tail vein. A micropipette with a tip diameter of approximately l-2 pm and filled with 2 M NaCl saturated with fast green was lowered by means of a hydraulic microdrive (David Kopf Instr., Tujunga, CA, USA) into the zona compacta region of the substantia nigla (approximately 2 mm anterior to lambda and 2 mm lateral to the midline). The in vitro impedancs of the electrodes was 3-4 MR, measured in saline at 135 Hz. Single unit potentials were passed through a high input-impedance amplifier and filters. The impulses were discriminated from background noise and fed intc a digital counter, which was reset every 10 s, and finally displayed on a storage oscilloscope (TRIO. Tokyo,
’
Smin
pacta of the substantia nigra (Grace and 13unney. 1983). An interspike time interval histogram ,was recorded 2-S min prior to drug administration and was compared with that recorded 2-5 min after drug administration. The body temperature of the animals was maintained at 37 “C by means of a heating pad. The position of the electrode was marked at the end of each experiment by iontophoretic ejection of fast green. The rats were then perfused with 10% buffered formatin solution and the brains were subjected to conventional histological procedures. Only cells within the zona compacta of the substantia nigra were included in this study.
’
2.2. Raciioligatui bittdittg assays
The ability of HW 173 to displace [‘HIMK-801 from rat brain membranes was assessed as described previously (Reynolds et al.. 1987).
Racemic trans-9-methoxy-4-benzyl-1,2,3,4,4a, 5,6,1Ob-octahydrobenzo[f]quinoline (HW 173); synthesized in this laboratory (WikstrGm et al., 1982)). ( + )3-3-(hydroxyphenyl-N-n-propyllpiperidine (( + )-3-PPP; Research Biochemicals, Inc., Wayland, MA, USA). Apomorphine (Apoteksbolaget, Giiteborg, Sweden). Japan). an audiomonitor (Grass Instr., Quincy. MA, USA) and a strip chart recorder
3. Results HW !73 was found not to inhibit [‘HIMK-801 binding to extensively washed rai brain membranes, even at concentrations up to 70 FM. Intravenously administered HW 173 (0.1-6.4 mg/4g) did not influence the firing rate of the majority of DA cells recorded (fig. 1). After administration of 3.2 mg/kg of the drug, five out of 18 units responded with a slight excitation (5-l%%), five units responded with a slight inhibition (5-10%/c),,and the remaining eight cells
s E 2 :s 3
loo8060-
s = 40s ‘Z 2 20s &? o10
100 dose ape.
Fice.2. Logarithmicdose-reponsr
control
--C
HW 173
100
wkg
curve for the inhibitory action of (a) :Ipomorphine and (h)
-c+
1000 dose
(+)+PPP.
pg’kg
( + j-3-PPP on the firing rate of zona compacta DA
neurons in ccmtrol rats and in rats pretreated with HW 17.7(3.2 mg/kg iv.).
control
HW 173
Fig. 3. Degree of regularity of zona compacta DA cell firing, expressed as variation coefficients. in control rats and in rats treated with HW I73 (3.2 ms/kg i.v.;n = 8). * P < 0.025 (paired t-test).
were unaffected. Pretreatment with HW 173 (3.2 nip/kg i.v.1 did not affect the ability of (+ )-3-PPP or apomorphine to inhibit the DA neurons. Thus, the dose-response curves for the inhibitory action of apomorphine or ( + I-3-PPP were not significantly shifted in any direction by pretreatment with HW 173 (fig. 2a, b). HW 173 (3.2 mg/kg, i.v.1 significantly changed the firing of nigral DA ceils into a more regularized pattern. Although the compound did not significantly alter the burst activity of the DA neurons (data not shown), the variation coefficient was slightly, but consistently, lowered in the postdrug interspike time interval histograms (48.5 f 6) compared to that of the predrug histograms (33.0 + 6; fig. 3).
4. Discussion Based on electrophysiological studies, it was recently proposed that a-receptors, which are richly distributed in the substantia nigra (Gundlach et al., 1985; 1986), mediate the inhibitory action of (+ I-3-PPP on nigral DA neurons (Steinfels and Tam, 1989; Steinfels et al., 19891. Similarly, the excitation of these neurons by BMY 14802, as well as the prevention of (+I-3PPP-induced inhibition, was attributed to a g-receptor antagonistic action of BMY 14802 CSteinfels and Tam, 1989; Steinfels et al., 1989). Both drugs display high affinity for u sites, but they also bind to DA receptors (Largent et al., 1988a; Wikstrom et al.. 1987). Previous radioligand binding studies with [“HI spiperone have shown that HW 173 displays high and selective affinity for o-receptors, but is apparently devoid of DA-receptor affinity (Wikstrom et al., 1987; Largent et al., 3988b3). The lack of affinity for DA receptors is also supported by the electrophysiological results of the present study, where pretreatment with HW 173 failed to affect the dose-response curve for the inhibitory effect of the DA receptor agonist apomorphine on nigral DA neurons. Furthermore, as clearly revealed from o:tr radioligand binding studies,
HW 173 did not affect [“H]MK-801 binding. Taken together, HW 173, which is highly lipophilic and should easily penetrate the blood-brain barrier, appears to be a valuable compound for studying the functions of the c-receptor. The results of the present study clearly show that HW 173, in doses that are likely to give a large occupancy of u-receptors due to the very high affinity of HW 173 for o-receptors (Largent et al., 1988b), does not significantly affect the firing rate of nigral DA neurons in any direction. These observations do not support the notion of a significant u-receptor-mediated regulation of the firing rate of DA neurons. Furthermore, the ability of (+ I-3-PPP to inhibit nigral DA neurons was not affected by pretreatment with HW 173. Thus, although it is not clear whether HW 173 acts as a c+-receptor agonist or antagonist, or both, the present data show that the a-receptor ligand ( + )-3-PPP does not exert its inhibitory action on nigral DA neurons via activation of u-receptors. Rather, the present results support the previous view, based on a large body of electrophysiological, behavioral and biochemical data from our laboratory (Clark et al., 1985; Hjorth et al., 1985), that (+ I-ZPPP exerts its inhibitory action on the nigral DA system via a stimulation of DA autoreceptors. Our data are not in full agreement with previous observations that SKF 10,047, a potent u-receptor ligand essentially without DA receptor affinity, slightly increased the firing rate of nigral DA neurons (Freeman and Bunney, 1984). However, as revealed from radiohgand binding experiments (Largent et al., 1988b). SKF 10.047 display an affinity for a-receptors that is about 70 times lower than that of HW 173. Furthermore, the specificity of SKF 10,047 in this regard might be questioned since the drug labels phencylidine sites equipotently (McCann et al., 1989). making previous electrophysiological results obtained with SKF 10,047 less reliable. Whereas nigral u-receptors are not involved in the regulation of the firing rate of DA neurons in the substantia nigra, our results indicate that these receptors may have a function in the regulation of the firing pattern. Given the functional role of the firing pattern in transmitter release (Gonon, 1986; 19881, the regularizcd activity of DA neurons induced by HW 173 may result in R relatively decreased utilization of brain DA. Such a mechanism might contribute to the reduction in schizophrenic symptoms following treatment with antipsychotics displaying affinity for fl--recePtm.
Acknowledgements This study was supported hy the Swedish Medical Research Council (No. 74HJ). We wish to thank Drs. Solomon H. Snyder and
A.. 51. Smith and E.D. French, IYSS. Activation of the A,,, mesotimhic ry~rm h> the cr-rrceptor agonist ( + !SKF ItW7 ~111 be k&&d b! simcarok. ;! novel putatkc antipsychotic. Eur. J.
cecf.
Pharm.X,& IF-l. 52. c&ok. I).. G. Enghcrg. E. Pilrblnd. T.H. S\enswn. A. Carlwn. A.S. Fwem:m and B.S. Bunny. 1YS.i. An rlectroph~siological analyak of the actions of .3-PPP enantiomsr; Dcut4t.
S.I.. A. Weizman.
Fhr: +ma
on the nigrostriatal
Arch. Pharmacol.
&um!n-Schmiedeh. rwrptor:
M.E.
Goldman
A nweE
33.
and J.M. Morihisa.
site implicated
A.S. and B.S. Bunnry.
IWX.
in psychosis and
UIFipsychOtiC drug efficacy. Clin. Neuropharmacol. Freeman.
system.
3-U.
I I. 105.
1YS-t. The effects of phencyclidinr
and N-allvlnormetazc~ine on midbrain dopamine nruronal activit?. Eur. J. Pharmacol. 10-1. Xi’. Cianon. F.G.. IYSh. control oi dopaminc releavz hy dopaminr recrpFJ~ ;md b! impulse t?w 3s studied by in tivo wltammrt~. Ann. N.Y. Acsd. Sci. 473. Ihtl. Gonon. F.G.. 19&S.Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminrrgic neurons as studied by in viw rlrctrochemist~. Neuroscience 24. IO. Grdey.
X.A.
and B.S. Bunne)-.
rlectrophpiology
of nipral
and characterization.
1YX3. Intracellular dopamine
Neuroscience
neurons.
and extracellular 1. Identification
IO. 301.
A.L.. B.L. Largent and S.H. Snyder. IYXi, Phencyclidine and fl opiate receptors in brain: biochemical and autoradiographical differentiation. Eur. J. Pharmacol. 113. 465. Gundl;lch. AL.. B.L. Largent and S.H. Snyder. IYXh. Autoradiographic localization of wrrcrptors hinding sites in guinea pig and rat central nervous qstem with ( + )3H-3-(3_hydroxyphenyl)-N\ I-propyl)piperidine. J. Neurosci. 6. 17.57. Hjorth. S.. D. Clark and A. Carlsson. 1985. Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: Dibcrrpancies hctwen in vitro and in vivo observations, Life Sci. 37. 673.
Ciundlach.
Largent. B.L.. H. Wikstrcim. A.M. Snowman and S.H. Snyder. IYXXa. Novel antiphychotic drugs share high affinity for cr receptors, Eur. J. Pharmacol. 115. 345. Largent. B.L.. H. Wikstriim. A.L. Gundlach and S.H. Snyder. 1988b, Structural determinants of (r receptor affinity. Mol. Pharmacol. 32, 77’. McCann. D.J.. R.A. R&in. S. Rens-Domiano and J.C. Winter. 1989. Phenylcyclidine/SKF-10.047 hinding sites: evaluation of function. Pharmacol. Biochem. Behav. 32. 87. Reynolds. I.J.. S.N. Murphy and R.J. Miller. 1987. >H-Labeled MK-XOI binding to the excitatory amino acid receptor complex frcim rat twain is enhanced hy glycine. Pror iuatl. Acad. Sci. lI.S.A. 84. 7744. Snyder. S.H. and B. Largent. 19X9, Receptor mechanisms in antipsychotic drug action: Focus on sigma receptors. J. Neuropsych. Clin. Neurosci. I. 7. Steinfels. G.F. and S.W. Tam. 1989. Selective u-receptor agonist and antagonist effect dopamine neuronal activity. Eur. J. Pharmacol. 163. 167. Steinfels. G.F.. S.W. Tam and L. Cook, 1989. Electrophysiological effects of selective w-receptor agonists. antagonists. and the selective phencyclidine receptor agonist MK-801 on midbrain dopamine neurons, neuropsychopharmacology 2, 201. Tam. S.W.. G.F. Steinfels and L. Cook. 1988, Biochemical and behavioral aspects of o- and phencyclidine receptors: similarities and differences. in: cr- and Phencyclidine-like Compounds as Molecular Probes in Biology. eds. E.F. Domino. and J.M. Kamenka (NPP Books. Ann Arbor, Michigan) p. 383. Werner. G. and V.B. Mountcastle. 1963. The variability of central neuronal activity in a sensory system, and its implication for the central reflection of sensory events. J. Neurophysiol. 26. 9%. Wikstriim. H., D. Sanchez, P. Lindberg, L.-E. Atvidsson, U. Hacksell. A. Joharlsson, J.L.G. Nilsson, S. Hjorth and A. Carlsson, 1982. Monophenolic octahydrobenzo[f]quinolines: central dopamine- and serotonin-receptor stimulating activity, J. Med. Chem. 25. 925. Wikstriim. H., B. Andersson. T. Elebring. K. Svensson. A. Carlsson and B. Largent. 1987, N-Substituted 1,2,3.4,4a,5.6,10b-octahydrobenzo[f]quinolines and 3-phenylpiperidines: effects in central dopamine and D receptors, J. Med. Chem. 30. 2169.
0011299991ori549J
EJP SlYX7
G&-an Engberg
and Hikan
Wikstriim
Dt~purtnwnt of Phartnaco~om. Chkcrsity of Ciitehor~, P.O. Box 33031. 400 33 Giirehorg, Stvedetl Received !5 November 1990. revised MS received 12 March 1991. accepted 28 May 1991
Using extracellular dopamine
(DA)
single unit recording
neurons
1,2,3,4,4a,5,6,10b-octahydrobenzo[flquinolinc aysociatcd
with
techniques,
in the zona compacta
any change
in the firing
(HW
ligand f + J-3-(3-hydroxyphenylkN-I-propyllpiperidinc rate, the firing pattern
of the DA
role in the control
regulation
-r-Receptors;
neurons.
Substantia
receptor
of cr-receptors
Administration
of racemic
in the ncuronal
pretreatment
agonist apomorphinc In contrast
with
for u-receptors.
in the substantia
or the mixed
to the effects of HW nigra. Rather,
was not
the drug did not affect DA
the
agonist/u-ret:ptor
173 on the DA
changed by Ihe drug. The data suggest that u-receptors
neurons
control of
trans-9-methoxy-4-benzyl-
high and specific affinity
Furthermore,
t( + 13-PPP).
cells was significantly
of the firing rate of DA
of the firing pattern
the significance
nigra.
1731, a drug displaying
rate of DA
curve for the inhibitory effects of the DA
dose-response
pivotal
we analyzed
of the substantia
cell firing
do not play a
they may have a function
in the
of these neurons.
nigra; Dopamine
neurons; Apomorphine;
1. Introduction
Previous radioligand binding data have revealed that several antipsychotic drugs, including haloperidol, display affinity for specific brain structures designated a-receptors (Largent et al., 1988a, b). These findings inter alia formed the basis for the hypothesis that some of the therapeutic benefits of these antipsychotic drugs are related to their ability to interfere with these receptors (Deutsch et al., 1988; Tam et al., 1988; Snyder and Largent, 1989). u Sites are reported to be distributed heterogeneously throughout the brain, with dopamine (DA&containing neurons in the zona compacta of the substantia nigra displaying a high density (Gundlach et al., 198.5; 1986). In addition, several reports suggest that u-receptors are involved in the regulation of neuronal activity of midbrain DA neurons (Freeman and Bunney, 1984; Ceci et al., 1988: Steinfels et al., 1989; Steinfels and Tam, 1989). The overall interpretation of these elcctrophysiological findings, however, is hampered by the relative lack of specificity of many drugs used as tool to evaluate the significance of Ir-receptors in this respect.
Correspondewe to: G. Engherg. Department uf Pharmacology. University ol’ Giiteborg. P.O. Box 33031. 400 3.1Giitehrwg. Swcdcn. Tel. .x3 I .xs34L3,
( + )-3-PPP (( + I-3-(3-hydroxyphenylkN-f
I-propyl)piperidine)
In the present electrophysiological study the role of a-receptors in the regulation of nigral DA neurons was analyzed with HW 173, a drug displaying high affinity and selectivity for u-receptors (Largent et al., 1988b).
2. Materials and methods
2. I. Single
tttzil recordittgs
A”?:: Sprague-Dawley rats (200-250 g) were anesthetized with chloral hydrate (400 mg/kg. intraperitoneally) and mounted in a stereotaxic apparatus. Additional anesthetics and drugs were given via a lateral tail vein. A micropipette with a tip diameter of approximately l-2 pm and filled with 2 M NaCl saturated with fast green was lowered by means of a hydraulic microdrive (David Kopf Instr., Tujunga, CA, USA) into the zona compacta region of the substantia nigla (approximately 2 mm anterior to lambda and 2 mm lateral to the midline). The in vitro impedancs of the electrodes was 3-4 MR, measured in saline at 135 Hz. Single unit potentials were passed through a high input-impedance amplifier and filters. The impulses were discriminated from background noise and fed intc a digital counter, which was reset every 10 s, and finally displayed on a storage oscilloscope (TRIO. Tokyo,
’
Smin
pacta of the substantia nigra (Grace and 13unney. 1983). An interspike time interval histogram ,was recorded 2-S min prior to drug administration and was compared with that recorded 2-5 min after drug administration. The body temperature of the animals was maintained at 37 “C by means of a heating pad. The position of the electrode was marked at the end of each experiment by iontophoretic ejection of fast green. The rats were then perfused with 10% buffered formatin solution and the brains were subjected to conventional histological procedures. Only cells within the zona compacta of the substantia nigra were included in this study.
’
2.2. Raciioligatui bittdittg assays
The ability of HW 173 to displace [‘HIMK-801 from rat brain membranes was assessed as described previously (Reynolds et al.. 1987).
Racemic trans-9-methoxy-4-benzyl-1,2,3,4,4a, 5,6,1Ob-octahydrobenzo[f]quinoline (HW 173); synthesized in this laboratory (WikstrGm et al., 1982)). ( + )3-3-(hydroxyphenyl-N-n-propyllpiperidine (( + )-3-PPP; Research Biochemicals, Inc., Wayland, MA, USA). Apomorphine (Apoteksbolaget, Giiteborg, Sweden). Japan). an audiomonitor (Grass Instr., Quincy. MA, USA) and a strip chart recorder
3. Results HW !73 was found not to inhibit [‘HIMK-801 binding to extensively washed rai brain membranes, even at concentrations up to 70 FM. Intravenously administered HW 173 (0.1-6.4 mg/4g) did not influence the firing rate of the majority of DA cells recorded (fig. 1). After administration of 3.2 mg/kg of the drug, five out of 18 units responded with a slight excitation (5-l%%), five units responded with a slight inhibition (5-10%/c),,and the remaining eight cells
s E 2 :s 3
loo8060-
s = 40s ‘Z 2 20s &? o10
100 dose ape.
Fice.2. Logarithmicdose-reponsr
control
--C
HW 173
100
wkg
curve for the inhibitory action of (a) :Ipomorphine and (h)
-c+
1000 dose
(+)+PPP.
pg’kg
( + j-3-PPP on the firing rate of zona compacta DA
neurons in ccmtrol rats and in rats pretreated with HW 17.7(3.2 mg/kg iv.).
control
HW 173
Fig. 3. Degree of regularity of zona compacta DA cell firing, expressed as variation coefficients. in control rats and in rats treated with HW I73 (3.2 ms/kg i.v.;n = 8). * P < 0.025 (paired t-test).
were unaffected. Pretreatment with HW 173 (3.2 nip/kg i.v.1 did not affect the ability of (+ )-3-PPP or apomorphine to inhibit the DA neurons. Thus, the dose-response curves for the inhibitory action of apomorphine or ( + I-3-PPP were not significantly shifted in any direction by pretreatment with HW 173 (fig. 2a, b). HW 173 (3.2 mg/kg, i.v.1 significantly changed the firing of nigral DA ceils into a more regularized pattern. Although the compound did not significantly alter the burst activity of the DA neurons (data not shown), the variation coefficient was slightly, but consistently, lowered in the postdrug interspike time interval histograms (48.5 f 6) compared to that of the predrug histograms (33.0 + 6; fig. 3).
4. Discussion Based on electrophysiological studies, it was recently proposed that a-receptors, which are richly distributed in the substantia nigra (Gundlach et al., 1985; 1986), mediate the inhibitory action of (+ I-3-PPP on nigral DA neurons (Steinfels and Tam, 1989; Steinfels et al., 19891. Similarly, the excitation of these neurons by BMY 14802, as well as the prevention of (+I-3PPP-induced inhibition, was attributed to a g-receptor antagonistic action of BMY 14802 CSteinfels and Tam, 1989; Steinfels et al., 1989). Both drugs display high affinity for u sites, but they also bind to DA receptors (Largent et al., 1988a; Wikstrom et al.. 1987). Previous radioligand binding studies with [“HI spiperone have shown that HW 173 displays high and selective affinity for o-receptors, but is apparently devoid of DA-receptor affinity (Wikstrom et al., 1987; Largent et al., 3988b3). The lack of affinity for DA receptors is also supported by the electrophysiological results of the present study, where pretreatment with HW 173 failed to affect the dose-response curve for the inhibitory effect of the DA receptor agonist apomorphine on nigral DA neurons. Furthermore, as clearly revealed from o:tr radioligand binding studies,
HW 173 did not affect [“H]MK-801 binding. Taken together, HW 173, which is highly lipophilic and should easily penetrate the blood-brain barrier, appears to be a valuable compound for studying the functions of the c-receptor. The results of the present study clearly show that HW 173, in doses that are likely to give a large occupancy of u-receptors due to the very high affinity of HW 173 for o-receptors (Largent et al., 1988b), does not significantly affect the firing rate of nigral DA neurons in any direction. These observations do not support the notion of a significant u-receptor-mediated regulation of the firing rate of DA neurons. Furthermore, the ability of (+ I-3-PPP to inhibit nigral DA neurons was not affected by pretreatment with HW 173. Thus, although it is not clear whether HW 173 acts as a c+-receptor agonist or antagonist, or both, the present data show that the a-receptor ligand ( + )-3-PPP does not exert its inhibitory action on nigral DA neurons via activation of u-receptors. Rather, the present results support the previous view, based on a large body of electrophysiological, behavioral and biochemical data from our laboratory (Clark et al., 1985; Hjorth et al., 1985), that (+ I-ZPPP exerts its inhibitory action on the nigral DA system via a stimulation of DA autoreceptors. Our data are not in full agreement with previous observations that SKF 10,047, a potent u-receptor ligand essentially without DA receptor affinity, slightly increased the firing rate of nigral DA neurons (Freeman and Bunney, 1984). However, as revealed from radiohgand binding experiments (Largent et al., 1988b). SKF 10.047 display an affinity for a-receptors that is about 70 times lower than that of HW 173. Furthermore, the specificity of SKF 10,047 in this regard might be questioned since the drug labels phencylidine sites equipotently (McCann et al., 1989). making previous electrophysiological results obtained with SKF 10,047 less reliable. Whereas nigral u-receptors are not involved in the regulation of the firing rate of DA neurons in the substantia nigra, our results indicate that these receptors may have a function in the regulation of the firing pattern. Given the functional role of the firing pattern in transmitter release (Gonon, 1986; 19881, the regularizcd activity of DA neurons induced by HW 173 may result in R relatively decreased utilization of brain DA. Such a mechanism might contribute to the reduction in schizophrenic symptoms following treatment with antipsychotics displaying affinity for fl--recePtm.
Acknowledgements This study was supported hy the Swedish Medical Research Council (No. 74HJ). We wish to thank Drs. Solomon H. Snyder and
A.. 51. Smith and E.D. French, IYSS. Activation of the A,,, mesotimhic ry~rm h> the cr-rrceptor agonist ( + !SKF ItW7 ~111 be k&&d b! simcarok. ;! novel putatkc antipsychotic. Eur. J.
cecf.
Pharm.X,& IF-l. 52. c&ok. I).. G. Enghcrg. E. Pilrblnd. T.H. S\enswn. A. Carlwn. A.S. Fwem:m and B.S. Bunny. 1YS.i. An rlectroph~siological analyak of the actions of .3-PPP enantiomsr; Dcut4t.
S.I.. A. Weizman.
Fhr: +ma
on the nigrostriatal
Arch. Pharmacol.
&um!n-Schmiedeh. rwrptor:
M.E.
Goldman
A nweE
33.
and J.M. Morihisa.
site implicated
A.S. and B.S. Bunnry.
IWX.
in psychosis and
UIFipsychOtiC drug efficacy. Clin. Neuropharmacol. Freeman.
system.
3-U.
I I. 105.
1YS-t. The effects of phencyclidinr
and N-allvlnormetazc~ine on midbrain dopamine nruronal activit?. Eur. J. Pharmacol. 10-1. Xi’. Cianon. F.G.. IYSh. control oi dopaminc releavz hy dopaminr recrpFJ~ ;md b! impulse t?w 3s studied by in tivo wltammrt~. Ann. N.Y. Acsd. Sci. 473. Ihtl. Gonon. F.G.. 19&S.Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminrrgic neurons as studied by in viw rlrctrochemist~. Neuroscience 24. IO. Grdey.
X.A.
and B.S. Bunne)-.
rlectrophpiology
of nipral
and characterization.
1YX3. Intracellular dopamine
Neuroscience
neurons.
and extracellular 1. Identification
IO. 301.
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