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Effects ofd-fenfluramine and metergoline on responding for conditioned reward and the response potentiating effect of nucleus accumbensd-amphetamine

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Abstract

These studies investigated the effects of the 5-hydroxytryptamine (5-HT) releaser, and re-uptake inhibitor,d-fenfluramine, and the non-selective 5-HT receptor antagonist metergoline, on responding for conditioned reward (CR), and on the potentiation of responding for CR following amphetamine injected into the nucleus accumbens. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase, water was not delivered but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers; responding on the other lever was not reinforced. Overall, rats responded at a higher rate on the lever delivering the CR.d-Amphetamine (1, 3 and 10 µg) injected into the nucleus accumbens dose-dependently enhanced responding on the CR lever. Treatment withd-fenfluramine (0.5 and 1 mg/kg) reduced responding for the CR, and abolished the potentiating effect ofd-amphetamine. Responding on the inactive lever was also reduced by 1 mg/kg but not 0.5 mg/kgd-fenfluramine. The reduction ofd-amphetamine's effect on responding for CR was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Control experiments showed that changes in thirst and motor performance, as well as deficits in learning ability, cannot account for the effects ofd-fenfluramine in this paradigm. In a separate experiment, 1 mg/kg metergoline failed to enhance responding for CR, and to augment the response potentiating effect of a low dose (2 µg) ofd-amphetamine injected into the nucleus accumbens. Thus, elevating brain 5-HT activity appears to reduce the ability of secondary reinforcing stimuli to elicit and maintain behaviour, and antagonizes the effects of enhanced dopamine activity within the nucleus accumbens. However, reduced 5-HT function induced by blockade of 5-HT1/2 receptors does not appear to influence responding for CR, or the response potentiating effect ofd-amphetamine. These results suggest that 5-HT may play an important role in mediating incentive motivation.

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References

  • Bendotti C, Borsini F, Zanini MG, Samanin R, Garattini S (1980) Effect of fenfluramine and norfenfluramine stereoisomers on stimulant effects ofd-amphetamine and apomorphine in the rat. Pharmacol Res Commun 12:567–574

    Google Scholar 

  • Beninger RJ (1983) The role of dopamine in locomotor activity and learning. Brain Res Rev 6:173–196

    Google Scholar 

  • Beninger RJ, Ranaldi R (1992) The effects of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats. Behav Pharmacol 3:155–163

    Google Scholar 

  • Blackburn JR, Phillips AG, Fibiger HC (1987) Dopamine and preparatory behaviour. I. effects of pimozide. Behav Neurosci 101:352–360

    Google Scholar 

  • Blackburn JR, Phillips AG, Jakubovic A, Fibiger HC (1989) Dopamine and preparatory behaviour. II. a neurochemical analysis. Behav Neurosci 103:15–23

    Google Scholar 

  • Blundell JE (1984) Serotonin and appetite. Neuropharmacology 23:1537–1551

    Google Scholar 

  • Cador M, Taylor JR, Robbins TW (1991) Potentiation of the effects of reward-related stimuli by dopaminergic-dependent mechanisms in the nucleus accumbens. Psychopharmacology 104:377–385

    Google Scholar 

  • Carr GD, White NM (1983) Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Life Sci 33:2551–2557

    Google Scholar 

  • Carter CJ, Pycock CJ (1978) Differential effects of central serotonin manipulation on hyperactive and stereotyped behaviour. Life Sci 23:953–960

    Google Scholar 

  • Carroll ME, Lac ST, Asencio M, Kragh R (1990) Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 35:237–244

    Google Scholar 

  • Chu B, Kelley AE (1992) Potentiation of reward-related responding by psychostimulant infusion into nucleus accumbens: role of dopamine receptor sub-types. Psychobiology 20:153–162

    Google Scholar 

  • Cunningham ST, Kelley AE (1992) Opiate infusion into the nucleus accumbens: contrasting effects on motor activity and responding for conditioned reward. Brain Res 588:104–114

    Google Scholar 

  • Davis WM, Smith SG, Khalsa JH (1975) Noradrenergic role in the self-administration of morphine or amphetamine. Pharmacol Biochem Behav 9:369–374

    Google Scholar 

  • Delfs JM, Schreiber L, Kelley AE (1990) Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat. J Neurosci 10:303–310

    Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143

    Google Scholar 

  • de Wit H, Wise RA (1977) Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol 31:195–203

    Google Scholar 

  • Fibiger HC, Phillips AG (1986) Reward, motivation, cognition: psychobiology of mesotelencephalic dopamine systems. In: Mountcastle VB, Bloom FE, Geiger SR (eds) Handbook of physiology: the nervous system (vol 4). American Physiological Society, Bethesda, Maryland, pp 647–675

    Google Scholar 

  • Fletcher PJ (1991) Dopamine receptor blockade in nucleus accumbens or caudate nucleus differentially affects feeding induced by 8-OH-DPAT injected into dorsal or median raphe. Brain Res 552:181–189

    Google Scholar 

  • Fletcher PJ, Ming ZH, Higgins GA (1993) Conditioned place preference induced by microinjection of 8-OH-DPAT into the dorsal or median raphe nuclei. Psychopharmacology 113:31–36

    Google Scholar 

  • Fletcher PJ, Tampakeras M, Yeomans JS (In press) Median raphe injections of 8-OH-DPAT lower frequency thresholds for laterial hypothalamic self-stimulation. Pharmacol Biochem Behav

  • Gerson SC, Baldessarini RJ (1980) Motor effects of serotonin in the central nervous system. Life Sci 27:1435–1451

    Google Scholar 

  • Higgins GA, Tomkins DM, Fletcher PJ, Sellers EM (1992) Effect of drugs influencing 5-HT function on ethanol drinking and feeding behaviour in rats: studies using a drinkometer system. Neurosci Biobehav Rev 16:535–552

    Google Scholar 

  • Higgins GA, Wang Y, Sellers EM (1993) Preliminary findings with the indirect 5-HT agonist dexfenfluramine on heroin discrimination and self-administration in rats. Pharmacol Biochem Behav 45:963–966

    Google Scholar 

  • Hoebel BG, Monaco AP, Hernandez L, Aulisi EF, Stanley BG, Lenard L (1983) Self-injection of amphetamine directly into the brain. Psychopharmacology 81:158–163

    Google Scholar 

  • Kelley AE, Delfs JM (1991) Dopamine and conditioned reinforcement I. Differential effects of amphetamine microinjections into striatal subregions. Psychopharmacology 103:187–196

    Google Scholar 

  • Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and striatum. Brain Res 94:507–522

    Google Scholar 

  • Kruszewska A, Romanidini S, Samanin R (1986) Different effects of zimelidine on the reinforcing properties ofd-amphetamine and morphine on conditioned place preference in rats. Eur J Pharmacol 125:283–286

    Google Scholar 

  • Lacosta S, Roberts DCS (1993) MDL 72222, ketanserin and methysergide pretreatments fail to alter breaking points on a progressive ratio schedule reinforced by intravenous cocaine. Pharmacol Biochem Behav 44:161–165

    Google Scholar 

  • Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology 101:262–266

    Google Scholar 

  • Lyness WH, Moore KE (1983) Increased self-administration ofd-amphetamine by rats pretreated with metergoline. Pharmacol Biochem Behav 18:721–724

    Google Scholar 

  • Lyness WH, Friedle NM, Moore KE (1979) Destruction of dopaminergic nerve terminals in nucleus accumbens: effects ond-amphetamine self-administration. Pharmacol Biochem Behav 11:553–556

    Google Scholar 

  • Lyness WH, Friedle NM, Moore KE (1980) Increased self-administration ofd-amphetamine after destruction of 5-hydroxytryptaminergic neurons. Pharmacol Biochem Behav 12:937–941

    Google Scholar 

  • McClelland RC, Sarfaty T, Hernandez L, Hoebel BG (1989) The appetite suppressantd-fenfluramine decreases self-stimulation at a feeding site in the lateral hypothalamus. Pharmacol Biochem Behav 32:411–414

    Google Scholar 

  • Montgomery AMJ, Rose IC and Herberg LJ (1991) 5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward. J Neural Transm 83:139–148

    Google Scholar 

  • Neill JC, Cooper SJ (1989) Evidence thatd-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 97:213–218

    Google Scholar 

  • Papp M, Willner P (1991) 8-OH-DPAT -induced place preference and place aversion: effects of PCPA and dopamine antagonists. Psychopharmacology 103:99–102

    Google Scholar 

  • Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Co-ordinates. 2nd edn. Academic Press, New York

    Google Scholar 

  • Pijnenburg AJJ, Honig WMM, Van Der Heyden JAM, Van Rossum JM (1976) Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity. Eur J Pharmacol 35:45–58

    Google Scholar 

  • Poschel BPH, Ninteman FW (1971) Intracranial reward and the forebrain's serotonergic mechanism: studies employingpara-chlorophenylalanine andpara-chloroamphetamine. Pharmacol Biochem Behav 7:39–46

    Google Scholar 

  • Richardson NR, Roberts DCS (1991) Fluoxetine pretreatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine self-administration in the rat. Life Sci 49:833–840

    Google Scholar 

  • Robbins TW (1978) The acquisition of responding with conditioned reinforcement: effects of pipradrol, methylphenidate,d-amphetamine and nomifensine. Psychopharmacology 58:79–87

    Google Scholar 

  • Robbins TW, Watson BA, Gaskin M, Ennis C (1983) Contrasting interactions of pipradrol,d-amphetamine, cocaine, cocaine analogues, apomorphine and other drugs with conditioned reinforcement. Psychopharmacology 80:113–119

    Google Scholar 

  • Roberts DCS, Corcoran ME, Fibiger HC (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6:615–620

    Google Scholar 

  • Rowland NE, Carlton J (1986). Neurobiology of an anorectic durg: fenfluramine. Prog Neurobiol 27:13–62

    Google Scholar 

  • Smith FL, Yu DSL, Smith DG, Leccese AP, Lyness WH (1986) Dietary tryptophan supplements attenuate amphetamine self-administration in the rat. Pharmacol Biochem Behav 25:849–855

    Google Scholar 

  • Smith JE, Shultz K, Co C, Goeders NE, Dworkin SI (1987) Effects of 5,7-dihydroxytryptamine lesions of the nucleus accumbens on rat intravenous morphine self-administration. Pharmacol Biochem Behav 26:607–612

    Google Scholar 

  • Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections ofd-amphetamine into the nucleus accumbens. Psychopharmacology 84:405–412

    Google Scholar 

  • Taylor JR, Robbins TW (1986) 6-hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate responding with reward-related stimuli produced by intra-accumbensd-amphetamine. Psychopharmacology 90:390–397

    Google Scholar 

  • Tomkins DM, Sellers EM, Fletcher PJ (1994) Median and dorsal raphe injections of the 5-HT1A agonist, 8-OH-DPAT, and the GABAA agonist, muscimol, increase voluntary ethanol intake in Wistar rats. Neuropharmacology 33:349–358

    Google Scholar 

  • Weingarten HP (1984) Meal initiation controlled by learned cues: basic behavioral properties. Appetite 5:147–158

    Google Scholar 

  • Wise RA (1987) The role of reward pathways in the development of drug dependence. Pharmaco Ther 35:227–263

    Google Scholar 

  • Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48:311–318

    Google Scholar 

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  1. Section of Biopsychology, Clarke Institute of Psychiatry, 250 College Street, M5T 1R8, Toronto, Ontario, Canada

    P. J. Fletcher

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Fletcher, P.J. Effects ofd-fenfluramine and metergoline on responding for conditioned reward and the response potentiating effect of nucleus accumbensd-amphetamine. Psychopharmacology 118, 155–163 (1995). https://doi.org/10.1007/BF02245834

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