Abstract
Rationale
Social rank has been shown to influence dopamine (DA) D2 receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D1 receptors.
Objective
Examine the effects of a high-efficacy D1 agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D1 agonist on cocaine self-administration, as well as the effects of cocaine exposure on D2 receptor function across social ranks, as determined by positron emission tomography (PET).
Methods
Effects of the high-efficacy D1 agonist SKF 81297 and cocaine (0.3–3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D1 agonist SKF 38393 (0.1–17 mg/kg) to decrease cocaine self-administration (0.003–0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D2 receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET.
Results
SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D2 receptor levels did not differ across social ranks.
Conclusions
These results suggest that D1 receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D2 receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D2 receptor levels such that D2 receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abbott DH, Keverne EB, Bercovitch FB, Shively CA, Mendoza SP, Saltzman W, Snowdon CT, Ziegler TE, Banjevic M, Garland T Jr, Sapolsky RM (2003) Are subordinates always stressed? A comparative analysis of rank differences in cortisol levels among primates. Horm Behav 43:67–82
Bardo MT, Bowling SL, Rowlett JK, Manderscheid P, Buxton ST, Dwoskin LP (1995) Environmental enrichment attenuates locomotor sensitization, but not in vivo dopamine release, induced by amphetamine. Pharmacol Biochem Behav 51:397–405
Bergman J, Rosenzweig-Lipson S (1992) Cocaine-antagonist effects of limited-efficacy D1 agonists. NIDA Res Monogr 119:185–189
Bergman J, Kamien JB, Spealman RD (1990) Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists. Behav Pharmacol 1:355–363
Bernstein IS (1981) Dominance: the baby and the bathwater. Behav Brain Sci 4:419–457
Bowling SL, Rowlett JK, Bardo MT (1993) The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropharmacology 32:885–893
Bradberry CW (2000) Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine abuse. J Neurosci 20:7109–7115
Caine SB, Negus SS, Mello NK (2000) Effects of dopamine D1-like and D2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect curves. Psychopharmacology 148:41–51
Covington HE 3rd, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges.” Psychopharmacology 158:388–398
Czoty PW, Ginsburg BC, Howell LL (2002) Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 300:831–837
Elsworth JD, Lawrence MS, Roth RH, Taylor JR, Mailman RB, Nichols DE, Lewis MH, Redmond DE Jr (1991) D1 and D2 dopamine receptors independently regulate spontaneous eyeblink rate in the vervet monkey. J Pharmacol Exp Ther 259:595–600
Fowler SC, Johnson JS, Kallman MJ, Liou JR, Wilson MC, Hikal AH (1993) In a drug discrimination procedure isolation-reared rats generalize to lower doses of amphetamine than rats reared in an enriched environment. Psychopharmacology 110:115–118
Gariepy JL, Gendreau PL, Mailman RB, Tancer M, Lewis MH (1995) Rearing conditions alter social reactivity and D1 receptors in high- and low-aggressive mice. Pharmacol Biochem Behav 51:767–773
Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586
Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH (1998) Effect of social status on striatal dopamine D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse 29:80–83
Grech DM, Spealman RD, Bergman J (1996) Self-administration of D1 receptor agonists by squirrel monkeys. Psychopharmacology 125:97–104
Green TA, Gehrke BJ, Bardo MT (2002) Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose-response functions for fixed- and progressive ratio schedules. Psychopharmacology 162:373–378
Guisado E, Fernandez-Tome P, Garzon J, Del Rio J (1980) Increased dopamine receptor binding in the striatum of rats after long-term isolation. Eur J Pharmacol 65:463–464
Haney M, Maccari S, Le Moal M, Simon H, Piazza PV (1995) Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698:46–52
Kabbaj M, Norton CS, Kollack-Walter S, Watson SJ, Robinson TE, Akil H (2001) Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior. Psychopharmacology 158:382–387
Kaplan JR, Manuck SB (1999) Status, stress, and atherosclerosis: the role of environment and individual behavior. Ann N Y Acad Sci 896:145–161
Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM (1982) Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 2:359–368
Kaplan JR, Manuck SB, Fontenot MB, Mann JJ (2002) Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis). Neuropsychopharmacology 26:431–443
Katz JL, Witkin JM (1992) Selective effects of the D1 dopamine receptor agonist, SKF 38393, on behavior maintained by cocaine injection in squirrel monkeys. Psychopharmacology 109:241–244
Kleven MS, Koek W (1996) Differential effects of direct and indirect dopamine agonists on eye blink rate in cynomolgus monkeys. J Pharmacol Exp Ther 279:1211–1219
LeSage MG, Stafford D, Glowa JR (1999) Preclinical research on cocaine self-administration: environmental determinants and their interaction with pharmacological treatment. Neurosci Biobehav Rev 23:717–741
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, 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
Mach RH, Nader MA, Ehrenkaufer RLE, Line SW, Smith CR, Luedtke RR, Kung M-P, Kung HF, Lyons D, Morton TE (1996) A comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly to dopamine D2 receptors: in vitro binding studies and positron emission tomography. Synapse 24:322–333
Martin SP, Smith EO, Byrd LD (1990) Effects of dominance rank on d-amphetamine induced increases in aggression. Pharmacol Biochem Behav 37:493–496
Miczek KA, Gold LH (1983) d-Amphetamine in squirrel monkeys of different social status: effects on social and agonistic behavior, locomotion and stereotopies. Psychopharmacology 81:183–190
Miczek KA, Mutschler NH (1996) Activational effects of social stress on IV cocaine self-administration in rats. Psychopharmacology 128:256–264
Miczek KA, Mutschler NH, van Erp AMM, Blank AD, McInerney SC (1999) d-Amphetamine “cue” generalizes to social defeat stress: behavioral sensitization and attenuated accumbens dopamine. Psychopharmacology 147:190–199
Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998a) The effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys. Synapse 28:1–9
Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998b) The effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse 30:88–96
Morgan D, Grant KA, Prioleau OA, Nader SH, Kaplan JR, Nader MA (2000) Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation. Am J Primatol 52:115–131
Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA (2002) Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 5:169–174
Nader MA, Bowen CA (1995) The effects of different food-reinforcement histories on cocaine self-administration by rhesus monkeys. Psychopharmacology 118:287–294
Nader MA, Grant KA, Gage HD, Ehrenkaufer RL, Kaplan JR, Mach RH (1999a) PET imaging of dopamine D2 receptors with [18F]fluoroclebopride in monkeys: effects of isoflurane- and ketamine-induced anesthesia. Neuropsychopharmacology 21:589–596
Nader MA, Green KL, Luedtke RR, Mach RH (1999b) Influences of housing conditions and ethanol intake on binding characteristics of D2, 5-HT1A and benzodiazepine receptors of rats. Pharmacol Biochem Behav 52:23–928
Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR, Friedman DP, Porrino LJ (2002) Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology 27:35–46
Pettit HO, Justice JB Jr (1989) Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis. Pharmacol Biochem Behav 34:899–904
Pettit HO, Justice JB Jr (1991) Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens. Brain Res 539:94–102
Platt DM, Rowlett JK, Spealman RD (2001) Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys. Psychopharmacology 157:208–216
Rilke O, May T, Oehler J, Wolffgramm J (1995) Influences of housing conditions and ethanol intake on binding characteristics of D2, 5-HT1A, and benzodiazepine receptors of rats. Pharmacol Biochem Behav: 23–28
Rilke O, Jahkel M, Oehler J (1998) Dopaminergic parameters during social isolation in low and high-active mice. Pharmacol Biochem Behav 60:499–505
Smith S (2002) Fast robust automated brain extraction. Hum Brain Map 17:143–155
Tidey JW, Miczek KA (1997) Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology 130:203–212
Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue CY, Alpert R, Dewey SL, Logan J, Bendriem B, Christman D, Hitzemann R, Henn F (1990) Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 147:719–724
Weed MR, Woolverton WL (1995) The reinforcing effects of dopamine D1 receptor agonists in rhesus monkeys. J Pharmacol Exp Ther 275:1367–1374
Woods RP, Mazziotta JC, Cherry SR (1993) MRI-PET registration with automated algorithm. J Comp Assist Tomogr 17:536–546
Woolverton WL, Virus RM (1989) The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food. Pharmacol Biochem Behav 32:691–697
Woolverton WL, Goldberg LI, Ginos JZ (1984) Intravenous self-administration of dopamine receptor agonists by rhesus monkeys. J Pharmacol Exp Ther 230:678–683
Acknowledgements
This research was supported by the National Institute on Drug Abuse (DA-10584). The authors thank Matthew Dickens, Clifford Hubbard and Susan Nader for excellent technical assistance, Jay R. Kaplan for assistance with the scoring of social behavior and Robert H. Mach, Nancy Buchheimer, Kimberly Black and Michael Bounds for assistance with the PET imaging studies.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Czoty, P.W., Morgan, D., Shannon, E.E. et al. Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine. Psychopharmacology 174, 381–388 (2004). https://doi.org/10.1007/s00213-003-1752-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1752-z