Abstract
Rationale
There are considerable individual differences in vulnerability to drug addiction, but the mechanisms underlying such differences are poorly understood. Cocaine has potent reinforcing effects that support operant responding. However, cocaine also elicits aversive reactions and produces an approach-avoidance conflict in rats. We hypothesized that preexisting individual differences in open arm exploration on the elevated plus-maze, a well-known model for the study of clinically effective anxiolytic drugs, would predict individual differences in cocaine-motivated behavior.
Objectives
To assess whether individual differences in sensitivity to anxiety-like behavior on the plus-maze predict motivation to self-administer intravenous (i.v.) cocaine.
Materials and methods
Rats were assessed drug-free for individual differences in open arm exploration on the elevated plus-maze, and later trained to perform an operant response for i.v. cocaine (0, 0.1, 0.3, 0.6, 0.9, 1.2, and 1.5 mg kg−1 infusion−1) on a progressive-ratio reinforcement schedule. Rats were split at the median into low and high open arm explorers based on time spent in the open arms of the plus-maze. Self-administration levels were compared across groups.
Results
Rats identified as high open arm explorers on the elevated plus-maze attained higher levels of operant responding for cocaine. Open arm times and break points were significantly correlated at the highest cocaine doses (1.2 and 1.5 mg kg−1 infusion−1).
Conclusions
These results indicate that individual differences in anxiety-like behavior on the elevated plus-maze predict motivation to self-administer cocaine, and suggest the possibility that reduced sensitivity to aversive stimuli may be associated with increased vulnerability to the rewarding properties of cocaine.
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References
Anthony JC, Tien AY, Petronis KR (1989) Epidemiologic evidence on cocaine use and panic attacks. Am J Epidemiol 129:543–549
Anthony JC, Warner LA, Kessler RC (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2:244–268
Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 125:141–149
Costall B, Kelly ME, Naylor RJ, Onaivi ES (1989) The actions of nicotine and cocaine in a mouse model of anxiety. Pharmacol Biochem Behav 33:197–203
David V, Gold LH, Koob GF, Cazala P (2001) Anxiogenic-like effects limit rewarding effects of cocaine in balb/cbyj mice. Neuropsychopharmacology 24:300–318
Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW (1993) Parameters of self-administration of cocaine in rats under a progressive-ratio schedule. Pharmacol Biochem Behav 45:539–548
Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017
DeSousa NJ, Wunderlich GR, De Cabo C, Vaccarino FJ (1998) Individual differences in sucrose intake predict behavioral reactivity in rodent models of anxiety. Pharmacol Biochem Behav 60:841–846
DeSousa NJ, Bush DEA, Vaccarino FJ (2000) Self-administration of intravenous amphetamine is predicted by individual differences in sucrose feeding in rats. Psychopharmacology (Berl) 148:52–58
DeVries AC, Pert A (1998) Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor. Psychopharmacology (Berl) 137:333–340
Ettenberg A (2004) Opponent process properties of self-administered cocaine. Neurosci Biobehav Rev 27:721–728
Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology (Berl) 103:455–461
File SE (1993) The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res 58:199–202
File SE, Zangrossi H Jr (1993) “One-trial tolerance” to the anxiolytic actions of benzodiazepines in the elevated plus-maze, or the development of a phobic state? Psychopharmacology (Berl) 110:240–244
Fontana DJ, Commissaris RL (1989) Effects of cocaine on conflict behavior in the rat. Life Sci 45:819–827
Geist TD, Ettenberg A (1990) A simple method for studying intravenous drug reinforcement in a runaway. Pharmacol Biochem Behav 36:703–706
Geist TD, Ettenberg A (1997) Concurrent positive and negative goalbox events produce runway behaviors comparable to those of cocaine-reinforced rats. Pharmacol Biochem Behav 57:145–150
Geracioti TD Jr, Post RM (1991) Onset of panic disorder associated with rare use of cocaine. Biol Psychiatry 29:403–406
Gosnell BA (2000) Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology (Berl) 149:286–292
Handley SL, Mithani S (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of ‘fear’-motivated behaviour. Naunyn Schmiedebergs Arch Pharmacol 327:1–5
Higgins GA, Sills TL, Tomkins DM, Sellers EM, Vaccarino FJ (1994) Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion. Pharmacol Biochem Behav 48:1019–1024
Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944
Homberg JR, van den Akker M, Raasø HS, Wardeh G, Binnekade R, Schoffelmeer ANM, de Vries TJ (2002) Enhanced motivation to self-administer cocaine is predicted by self-grooming behaviour and relates to dopamine release in the rat medial prefrontal cortex and amygdala. Eur J Neurosci 15:1542–1550
Hooks MS, Jones GH, Smith AD, Neill DB, Justice JB Jr (1991) Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine. Synapse 9:121–128
Marinelli M, Piazza PV (2002) Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci 16:387–394
Montgomery KC (1955) The relation between fear induced by novelty stimulation and exploratory behaviour. J Comp Physiol Psychol 48:254–260
Paine TA, Jackman SL, Olmstead MC (2002) Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine. Behav Pharmacol 13:511–523
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Piazza PV, Le Moal M (1997) Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications. Brain Res Brain Res Rev 25:359–372
Piazza PV, Deminière JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513
Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA 88:2088–2092
Piazza PV, Deroche V, Deminiere JM, Maccari S, Le Moal M, Simon H (1993) Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors. Proc Natl Acad Sci USA 90:11738–11742
Piazza PV, Deroche-Gamonet V, Rougé-Pont F, Le Moal M (2000) Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20:4226–4232
Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11
Roberts DCS (1989) Breaking points on a progressive ratio schedule reinforced by intravenous apomorphine increase daily following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 32:43–47
Rodgers RJ, Dalvi A (1997) Anxiety, defense and the elevated plus-maze. Neurosci Biobehav Rev 21:801–810
Rogerio R, Takahashi RN (1992) Anxiogenic properties of cocaine in the rat evaluated with the elevated plus-maze. Pharmacol Biochem Behav 43:631–633
Sills TL, Crawley JN (1996) Individual differences in sugar consumption predict amphetamine-induced dopamine overflow in nucleus accumbens. Eur J Pharmacol 303:177–181
Sills TL, Vaccarino FJ (1991) Facilitation and inhibition of feeding by a single dose of amphetamine: relationship to baseline intake and accumbens CCK. Psychopharmacology (Berl) 105:329–334
Sills TL, Onalaja AO, Crawley JN (1998) Mesolimbic dopaminergic mechanisms underlying individual differences in sugar consumption and amphetamine hyperlocomotion in Wistar rats. Eur J Neurosci 10:1895–1902
Treit D, Menard J, Royan C (1993) Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 44:463–469
Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019
Walfish S, Massey R, Krone A (1990) Anxiety and anger among abusers of different substances. Drug Alcohol Depend 25:253–256
Yang XM, Gorman AL, Dunn AJ, Goeders NE (1992) Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies. Pharmacol Biochem Behav 41:643–650
Acknowledgments
We are grateful to Antonia De Cristofaro and Carmela Presta for their assistance with the elevated plus-maze and sugar feeding procedures. This work was supported by an operating grant from the Canadian Institutes of Health Research to F. J. Vaccarino.
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Bush, D.E.A., Vaccarino, F.J. Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats. Psychopharmacology 194, 211–219 (2007). https://doi.org/10.1007/s00213-007-0835-7
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DOI: https://doi.org/10.1007/s00213-007-0835-7