Abstract
Positron emission tomography (PET), in combination with 11C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments, 11C-raclopride was administered at baseline and 30 min following intravenous PCP administration. In the second series of studies, γ-vinyl GABA (GVG) was used to assess whether enhanced GABAergic tone altered NMDA antagonist-induced changes in DA. Animals received an initial PET scan followed by pretreatment with GVG (300 mg/kg), then PCP 30 min prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining 11C-cocaine binding a paradigm in which PCP was coadministered with the radiotracer, we assessed the direct competition between these two compounds for the DAT. At 0.1, 0.5, and 1.0 mg/kg, PCP decreased 11C-raclopride binding by 2.1, 14.9±2.2 and 8.18±1.1%, respectively. These effects were completely attenuated by GVG (3.38±3.1% decrease in 11C-raclopride binding). Finally, PCP (0.5 mg/kg) decreased 11C-cocaine binding by 25.5±4.3%, while at 1.0 mg/kg this decrease was 13.5%, consistent with a competitive interaction at the DAT. These results suggest that PCP may be exerting some direct effects through the DAT and that GABA partially modulates NMDA-antagonist-induced increases in striatal DA.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Adams B, Moghaddam B (1998). Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J Neurosci 18: 5545–5554.
Adams BW, Bradberry CW, Moghaddam B (2002). NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys. Synapse 43: 12–18.
Blin J, Denis A, Yamaguchi T, Crouzel C, MacKenzie ET, Baron JC (1991). PET studies of [18F]methyl-MK-801, a potential NMDA receptor complex radioligand. Neurosci Lett 121: 183–186.
Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L et al (1998). Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 29: 142–147.
Carlezon WA, Wise RA (1996). Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16: 3112–3122.
Dewey SL, Brodie JD, Fowler JS, MacGregor RR, Schlyer DJ, King PT et al (1990). Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain. Synapse 6: 321–327.
Dewey SL, Morgan AE, Ashby Jr CR, Horan B, Kushner SA, Logan J et al (1998). A novel strategy for the treatment of cocaine addiction. Synapse 30: 119–129.
Dewey SL, Smith GS, Logan J, Alexoff D, Ding YS, King P et al (1995). Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis. J Neurosci 15: 821–829.
Dewey SL, Smith GS, Logan J, Brodie JD (1993a). Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates. Neuropsychopharmacology 8: 371–376.
Dewey SL, Smith GS, Logan J, Brodie JD, Simkowitz P, MacGregor RR et al (1993b). Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects. Proc Natl Acad Sci USA 90: 11816–11820.
Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri RA et al (1992). GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 12: 3773–3780.
Drevets WC, Price JC, Kupfer DJ, Kinahan PE, Lopresti B, Holt D et al (1999). PET measures of amphetamine-induced dopamine release in ventral vs dorsal striatum. Neuropsychopharmacology 21: 694–709.
Farde L, Eriksson L, Blomquist G, Halldin C (1989). Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET–a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9: 696–708.
Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, Macgregor RR et al (1989). Mapping cocaine binding sites in human and baboon brain in vivo. Synapse 4: 371–377.
Gatley SJ, Volkow ND, Fowler JS, Dewey SL, Logan J (1995). Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine. Synapse 20: 137–144.
Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW et al (1996). NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16: 2034–2043.
Hondo H, Nakahara T, Nakamura K, Hirano M, Uchimura H, Tashiro N (1995). The effect of phencyclidine on the basal and high potassium evoked extracellular GABA levels in the striatum of freely moving rats: an in vivo microdialysis study. Brain Res 671: 54–62.
Johnson KM, Snell LD (1985). Effects of phencyclidine (PCP)-like drugs on turning behavior, 3H-dopamine uptake, and 3H-PCP binding. Pharmacol Biochem Behav 22: 731–735.
Jung MJ, Lippert B, Metcalf BW, Bohlen P, Schechter PJ (1977). gamma-Vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem 29: 797–802.
Kagawa S, Nakano T, Inoue O, Nishimura T (2002). Effect of glutamatergic systems on in vivo binding of [(125)I]beta-CIT in the brain of a rat model of Parkinson's disease. Synapse 46: 38–44.
Kapur S, Seeman P (2001). Ketamine has equal affinity for NMDA receptors and the high-affinity state of the dopamine D2 receptor. Biol Psychiatry 49: 954–957.
Kapur S, Seeman P (2002). NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry 7: 837–844.
Kegeles LS, Martinez D, Kochan LD, Hwang DR, Huang Y, Mawlawi O et al (2002). NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse 43: 19–29.
Li Q, Clark S, Lewis DV, Wilson WA (2002). NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity. J Neurosci 22: 3070–3080.
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ et al (1990). Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10: 740–747.
Logan J, Volkow ND, Fowler JS, Wang GJ, Dewey SL, MacGregor R et al (1994). Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data. J Cereb Blood Flow Metab 14: 995–1010.
Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD (1989). Effects of cocaine and related drugs in nonhuman primates. I. [3H]cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther 251: 131–141.
Maurice T, Vignon J, Kamenka JM, Chicheportiche R (1991). Differential interaction of phencyclidine-like drugs with the dopamine uptake complex in vivo. J Neurochem 56: 553–559.
Mele A, Wozniak KM, Hall FS, Pert A (1998). The role of striatal dopaminergic mechanisms in rotational behavior induced by phencyclidine and phencyclidine-like drugs. Psychopharmacology 135: 107–118.
Nakano T, Takatoku K, Matoba Y, Iwamoto B, Nishiura M, Inoue O et al (1998). Enhancement of in vivo binding of [123I]beta-CIT by MK-801 in rat brain. Synapse 30: 402–408.
Olney JW, Farber NB (1995). Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52: 998–1007.
Page G, Peeters M, Maloteaux JM, Hermans E (2000). Increased dopamine uptake in striatal synaptosomes after treatment of rats with amantadine. Eur J Pharmacol 403: 75–80.
Palfreyman MG, Schechter PJ, Buckett WR, Tell GP, Koch-Weser J (1981). The pharmacology of GABA-transaminase inhibitors. Biochem Pharmacol 30: 817–824.
Rodefer JS, Carroll ME (1999). Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys. Psychopharmacology (Berl) 144: 163–174.
Schiffer WK, Gerasimov M, Hofmann L, Marsteller D, Ashby CR, Brodie JD et al (2001a). Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical vs mesolimbic DA transmission. Neuropsychopharmacology 25: 704–712.
Schiffer WK, Gerasimov MR, Fowler JS, Volkow ND, Gifford A, Ashby CR et al (2001b). MK-801 increases dopamine transporter (DAT) availability: a positron emission tomography (PET) investigation in non-human primates. J Nucl Med 42: 56.
Schloesser R, Simkowitz P, Bartlett EJ, Wolkin A, Smith GS, Dewey SL et al (1996). The study of neurotransmitter interactions using positron emission tomography and functional coupling. Clin Neuropharmacol 19: 371–389.
Seiler N, Grauffel C (1992). Antagonism of phencyclidine-induced hyperactivity in mice by elevated brain GABA concentrations. Pharmacol Biochem Behav 41: 603–606.
Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA et al (1998). Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 18: 18–25.
Tsukada H, Harada N, Nishiyama S, Ohba H, Sato K, Fukumoto D et al (2000). Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric PET studies combined with microdialysis analysis. Synapse 37: 95–103.
Tsukada H, Nishiyama S, Kakiuchi T, Ohba H, Sato K, Harada N (2001). Ketamine alters the availability of striatal dopamine transporter as measured by [(11)C]beta-CFT and [(11)C]beta-CIT-FE in the monkey brain. Synapse 42: 273–280.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C et al (1999). Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther 291: 409–415.
Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL (2000). Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 34: 35–43.
Westerink BH, Kwint HF, deVries JB (1996). The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain. J Neurosci 16: 2605–2611.
Willins D (1993). The role of dopamine and AMPA/kainate receptors in the nucleus accumbens in the hypermotility response to MK-801. Pharmacol Biochem Behav 46: 881–887.
Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H (1998). Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol 341: 45–56.
Acknowledgements
We gratefully acknowledge J Fowler, P Vaska, D Alexoff, D Schlyer, P King, P Carter, N Pappas, M Gerasimov, C Shea, V Garza, and R Ferrieri. Hoescht Marion Roussel and ChiroTech supplied the GVG. This research was carried out at Brookhaven National Laboratory under contract with the US Department of Energy Office of Biological and Environmental Research (USDOE/OBER DE-AC02-98CH10886), and partially funded by NIH awards to WKS (F31-DA15874) and SLD (DA015041).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schiffer, W., Logan, J. & Dewey, S. Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine. Neuropsychopharmacol 28, 2192–2198 (2003). https://doi.org/10.1038/sj.npp.1300258
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300258
Keywords
This article is cited by
-
Dopamine transporter imaging with [123I]FP-CIT SPECT: potential effects of drugs
European Journal of Nuclear Medicine and Molecular Imaging (2008)
-
Functional reactivity of the dopaminergic system following acute and chronic ketamine treatments
Naunyn-Schmiedeberg's Archives of Pharmacology (2008)
-
Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site
European Archives of Psychiatry and Clinical Neuroscience (2007)
-
Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors
Neuropsychopharmacology (2005)
-
N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives
Psychopharmacology (2005)
