Abstract
The neuropeptides neurotensin, substance P, neurokinin-α (substance K), and met-enkephalin are present endogenously in the ventral tegmental area (VTA), site of the A10 dopaminergic (DA) cell bodies. In the present study these four peptides were injected bilaterally into the VTA in the rat, and the effects on operant behavior were assessed. Cannulae aimed at the VTA were implanted in four groups of animals, which had been trained to bar-press for food reward on a fixed-interval, 40-s schedule. A fifth group, in which the effects of systemically administered amphetamine were assessed, was also tested. Response rate across the interval was measured, and the index of quarter-life was taken as an indication of the temporal pattern of resonding. In addition, a rate-dependency analysis was carried out for all data. Neurotensin (NT, 0.0175, 0.175, 0.5 μg in 1 μl) dose-dependently decreased response rates without affecting quarter-life, and reduced the number of reinforcements obtained. Substance P (SP, 0.1, 1.0, 3.0 μg) did not affect responding, and neurokinin-α (NKA, 0.1, 1.0, 3.0 μg) induced a small increase in responding. Quarter-life was not affected by SP or NKA, but responding on the nonreinforced lever was significantly increased by both peptides. d-Ala-met-enkephalin (DALA, 0.01, 0.1, 1.0 μg) induced a dose-dependent increase in responding which was also rate-dependent, and reduced quarter-life. DALA effects were similar to the classic pattern of responding observed after systemic amphetamine. These results suggest that although all these peptides elicit behavioral activation and may affect DA neuronal activity, the behavioral responses can be differentiated with respect to operant behavior.
Similar content being viewed by others
References
Andrade R, Aghajanian GK (1981) Neurotensin selectively activates dopaminergic neurons of the substantia nigra. Soc Neurosci Abstr 7:573
Bannon MJ, Elliott PJ, Alpert JE, Goerdert M, Iversen SD, Iversen LL (1983) Role of endogenous substance P in stress-induced activation of mesocortical dopamine neurons. Nature 306:791–792
Broekkamp CLE, Phillips AG, Cools AR (1979) Stimulant effects of enkephalin microinjection into the dopaminergic A10 area. Nature 278:560–562
Cador M, Kelley AE, Le Moal M, Stinus L (1985) Behavioral analysis of the effect of neurotensin injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat. Psychopharmacology 85:187–196
Cador M, Kelley AE, Le Moal M, Stinus L (1986) Ventral tegmental area infusion of substance P, neurotensin and enkephalin: differential effects on feeding behavior. Neuroscience 18:659–669
Carr G, White NM (1983) Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Life Sci 33:2551–2557
Deutch AY, Maggio JE, Bannon M, Kalivas PW, Tam SY, Goldstein M, Roth RH (1985) Substance K and substance P differentially modulate mesolimbic and mesocortical systems. Peptides 6:113–122
Dews PB, Wenger GR (1977) Rate dependency of the behavioral effects of amphetamine. In: Thompson T, Dews PB (eds) Advances in behavioral pharmacology, vol 1. Academic Press, New York, pp 167–227
Elliott PJ, Alpert JE, Bannon MJ, Iversen SD (1986) Selective activation of mesolimbic and mesocortical dopamine metabolism in the rat brain by infusion of a stable substance P analogue into the ventral tegmental area. Brain Res 363:145–147
Emson PC, Cuello AC, Paxonos FG, Jessell T, Iversen LL (1977) The origin of substance P and acetylcholine projections to the ventral tegmental area and interpeduncular nucleus in the rat. Acta Physiol Scand [Suppl] 542:43–46
Erspamer V (1981) The tachykinin peptide family. Trends Neurosci 4:267–269
Ervin GE, Birkemo LS, Nemeroff CB, Prange AJ Jr (1981) Neurotensin blocks certain amphetamine-induced behaviors. Nature 291:73–76
Everist HD, Chieuh CC, Pert A (1983) Effects of neurotensin on dopaminergic activity following intranigral or intrastriatal injections. Soc Neurosci Abstr 9:716
Fray PJ (1980) ONLIBASIC, a system for experimental control. Trends Neurosci 3:13–14
Glimcher PW, Margolin DH, Giovino AA, Hoebel BG (1984) Neurotensin: a new “reward” peptide. Brain Res 291:119–124
Greenshaw AJ, Sanger DJ, Blackman DE (1980) The effects of pimozide and of reward omission on fixed-interval behavior of rats maintained by food and electrical brain stimulation. Pharmacol Biochem Behav 15:227–233
Gysling K, Wang RY (1983) Morphine-induced activations of A10 dopamine neurons in the rat. Brain Res 277:119–127
Harmar AJ (1984) Three tachykinins in mammalian brain. Trends Neurosci 7:57
Herrnstein RJ, Morse WH (1957) Effects of pentobarbital on intermittently reinforced behavior. Science 125:921–931
Hoebel BG, Hernandez L, McLean S, Stanley BG, Aulissi EF, Glimcher P, Margolin D (1982) Catecholamines, enkephalin and neurotensin in feeding and reward. In: Hoebel BG, Novin D (eds) The neural basis of feeding and reward. Haer Institute Press, Brunswick, Maine
Hokfelt R, Johansson O, Ljungdahl A, Lundberg JM, Schultzberg M (1980) Peptidergic neurones. Nature 284:515–521
Innis RB, Andrade R, Aghajanian GK (1985) Substance K excites dopaminergic and non-dopaminergic neurons in rat substantia nigra. Brain Res 335:381–383
Iversen LL, Elliott PJ, Bannon MJ, Alpert JE, Iversen SD (1983) Interaction of substance P with dopaminergic neurones in brain. In: Strabenek P, Powell D (eds) Substance P: proceedings of the International Symposium. Book Press, Dublin, pp 43–44
Johnson RP, Sar M, Stumpf WE (1980) A topographic localization of enkephalin on the dopamine neurons of the rat substatia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunohistochemistry. Brain Res 194: 566–571
Jolicoeur FB, Rivest R, St. Pierre S, Gagne MA, Dumais M (1985) The effects of neurotensin and [d-Tyr 11]-NT on the hyperactivity induced by intra-accumbens administration of a potent dopamine receptor agonist. Neuropeptides 6:143–156
Joyce EM, Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous activity in the rat. Neurosci Lett 14:207–212
Kalivas PW (1984) Evidence for interaction of endogenous peptides with mesolimbic dopamine system. Psychopharmacol Bull 20:354–357
Kalivas PW (1985a) Substance P modulation of the mesolimbic dopamine system. In: Lal H, Labella F, Lane J (eds) Endocoids. Liss, New York
Kalivas PW, (1985b) Interactions between neuropeptides and dopamine neurons in the ventromedial mesencephalon. Neurosci Biobehav Rev 9:573–587
Kalivas PW, Burgess PW, Nemeroff CB, Prange AJ Jr (1983a) Behavioral and neurochemical effect of neurotensin microinjection in ventral tegmental area. Neurosci 8:225–238
Kalivas PW, Widerlov E, Stanley D, Breese G, Prange AJ Jr (1983b) Enkephalin action on the mesolimbic system: a dopamine dependent and a dopamine independent increase in locomotor activity. J Pharmacol Exp Ther 227:229–237
Kalivas PW, Deutch AY, Maggio JE, Mantyh PW, Roth RH (1985) Substance K and substance P in the ventral tegmental area. Neurosci Lett 57:241–246
Kelley AE, Cador M, Stinus L (1985) Behavioral analysis of the effect of substance P injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat. Psychopharmacology 85:37–46
Kelley AE, Stinus L, Iversen SD (1979) Behavioral activation induced in the rat by substance P infusion into the ventral tegemental area: implication of dopaminergic A10 neurones. Neurosci Lett 11:335–339
Kelley AE, Stinus L, Iversen SD (1980) Interactions between d-ala-Met-enkephalin, A10 dopaminergic neurones and spontaneous behavior in the rat. Behav Brain Res 1:3–24
Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522
Ljungdahl A, Hokfelt T, Nilsson G, Goldstein M (1978) Distribution of substance P-like immunoreactivity in the central nervous system of the rat. II Light microscopic localization in relation to catecholamine containing neurones. Neuroscience 3:945–976
Llorens-Cortes C, Pollard H, Schwartz JC (1979) Localization of opiate receptors in substantia nigra: evidence by lesion studies. Neurosci Lett 12:321–326
Maggio JE, Hunter JC (1984) Regional distribution of assinin-like immunoreactivity in rat central and peripheral tissues and the effect of capsaicin. Brain Res 307:370–373
Mantyh PW, Maggio JE, Hunt SP (1984) The autoradiographic distribution of kassinin and substance K binding sites is different from the distribution of substance P binding sites in rat brain. Eur J Pharmacol 102:361–364
Minamino NK, Masuda K, Kargawa K, Matuso H (1984) Regional distribution of neuromedin K and neuromedin L in rat brain and spinal cord. Biochem Biophys Res Commun 124:731–735
Napier TC, Gay DA, Hulebak KL, Breese GR (1985) Behavioral and biochemical assessment of time-related cahnges in globus pallidus and striatal dopamine induced by intranigrally administered neurotensin. Peptides 6:1057–1068
Palacios JM, Kuhar M (1981) Neurotensin receptors are located on dopamine containing neurons in rat midbrain. Nature 294:587–589
Pellegrino LJ, Cushman AJ (1967) A stereotaxic atlas of the rat brain. Appleton-Century-Crofts, New York 1967
Phillips AG, Le Piane FG (1980) Reinforcing effects of morphine microinjection into the ventral tegmental area. Pharmacol Biochem Behav 12:965–968
Phillips AG, Le Piane FG, Fibiger HC (1983) Dopaminergic mediation of reward produced by direct injection of enkephalin into the ventral tegmental area. Life Sci 33:2505–2511
Pinnock RD (1985) Neurotensin depolarizes substantia nigra dopamine neurones. Brain Res 338:151–154
Quirion R (1983) Interactions between neurotensin and dopamine in the brain: an overview. Peptides 4:609–615
Quirion R, Chiveh CC, Everist HD, Pert A (1985) Comparative localization of neurotensin receptors on nigrostriatal and mesolimbic dopaminergic terminals. Brain Res 327:385–389
Quirion RP, Gaudreau P, St-Pierre S, Rioux F, Pert CB (1982) Autoradiographic distribution of (3H)-neurotensin receptors in rat brain: visualization by tritium-sensitive film. Peptides 3:757–763
Robbins TW, Iversen SD (1973) Amphetamine-induced disruption of temporal discrimination by response disinhibition. Nature New Biol 245:191–192
Roberts DCS, Koob GF, Klonoff P, Fibiger H (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12:781–787
Rothman RB, Danks JA, Herkenham M, Cascieri MA, Chicci GG, Liang T, Pert CB (1984a) Autoradiographic localization of a novel binding site in rat brain using the substance P analog, eledoisin. Neuropeptides 4:343–349
Rothman RB, Herkenham M, Pert CB, Liang T, Cascieri M (1984b) Visualization of rat brain receptors of the neuropeptide, substance P. Bran Res 309:47–54
Shults CW, Yajima H, Buck S, Gullner H, Burcher T, Chase TN, O'Donohue TL (1984) Demonstration and distribution of kassinin-like material (substance K) and distribution of iodinated substance K binding sites in the rat central nervous system. Soc Neurosci Abstr 10:553
Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:251–268
Stinus L, Kelley AE, Iversen SD (1978) Increased spontaneous activity following substance P infusion into A10 dopaminergic area. Nature 276:616–618
Stinus L, Koob GF, Ling N, Bloom FE, Le Moal M (1980) Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions. Proc Natl Acad Sci USA 77:2323–2327
Uhl GR, Kuhar MJ, Snyder SH (1977) Neurotensin: immunohistochemical localization in rat central nervous system. Proc Natl Acad Sci USA 74:4509–4063
Uhl GR, Goodman RR, Kuhar MJ, Childers SR, Snyder SH (1979) Immunohistochemical mapping of enkephalin-containing cell bodies, fibers and nerve terminals in the brain stem of the rat. Brain Res 166:75–94
Wagner GC, Masters DB, Tomie A (1984) Effects of phencyclidine, haloperidol, and naloxone on fixed-interval performance in rats. Psychopharmacology 84:32–38
Young WS, Kuhar MJ (1981) Neurotensin receptor localization by light microscopic autoradiography in rat brain. Brain Res 206:273–285
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kelley, A.E., Cador, M., Stinus, L. et al. Neurotensin, substance P, neurokinin-α, and enkephalin: injection into ventral tegmental area in the rat produces differential effects on operant responding. Psychopharmacology 97, 243–252 (1989). https://doi.org/10.1007/BF00442258
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00442258