Skip to main content
SpringerLink
Log in

Unconditional hyperactivity and transient reinforcing effects of NMDA administration into the ventral tegmental area in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens plays an important role in positive reinforcement and locomotion. Intra-VTA administration of many drugs capable of activating these neurons has been shown to be reinforcing and induce locomotion. Administration of the excitatory amino acid NMDA (N-methyl-d-aspartate) into the VTA may likewise be positively reinforcing, because it stimulates the meso-accumbens dopamine system and locomotion.

Objectives and methods

Locomotor-rearing experiments were conducted to pinpoint the range of NMDA concentrations that induce significant locomotion and rearing, and to determine whether co-administration of the glycine binding site agonist d-serine would enhance the effects of NMDA administration into the VTA. Reinforcing effects of NMDA were assessed by intracranial self-administration procedures: a lever-press delivered a 75-nl infusion containing NMDA (0.1, 0.3 or 1.0 mM) plus serine into the VTA or an adjacent region, the supramammillary nucleus.

Results

Co-administration of serine slightly enhanced rearing induced by NMDA administration. Administration of NMDA at concentrations of 0.3 or 1.0 mM (500 nl) induced vigorous locomotion and rearing. NMDA (0.3 mM) was self-administered into the VTA slightly more than vehicle in the first or second sessions, yet this small reinforcing effect became irregular in subsequent sessions. The rats did not learn to self-administer NMDA into the supramammillary nucleus.

Conclusions

Ventral tegmental NMDA injections, in the concentration range that induced marked unconditional hyperactivity, supported only marginal and transient self-administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ahlenius S, Hillegaart V, Thorell G, Magnusson O, Fowler CJ (1987) Suppression of exploratory locomotor activity and increase in dopamine turnover following the local application of cis-flupenthixol into limbic projection areas of the rat striatum. Brain Res 402:131–138

    Article  CAS  PubMed  Google Scholar 

  • Arnt J, Scheel-Kruger J (1979) GABA in the ventral tegmental area: differential regional effects on locomotion, aggression and food intake after microinjection of GABA agonists and antagonists. Life Sci 25:1351–1360

    CAS  PubMed  Google Scholar 

  • Boehm SL, 2nd, Piercy MM, Bergstrom HC, Phillips TJ (2002) Ventral tegmental area region governs GABA(B) receptor modulation of ethanol-stimulated activity in mice. Neuroscience 115:185–200

    Article  CAS  PubMed  Google Scholar 

  • Bonci A, Malenka RC (1999) Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci 19:3723–3730

    CAS  PubMed  Google Scholar 

  • Bozarth MA, Wise RA (1981) Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci 28:551–555

    CAS  PubMed  Google Scholar 

  • Broekkamp CLE, Pijnenburg AJJ, Cools AR, Van Rossum JM (1975) The effect of microinjections of amphetamine into the neostriatum and the nucleus accumbens on self-stimulation behavior. Psychopharmacologia 42:179–183

    CAS  PubMed  Google Scholar 

  • Cador M, Bjijou Y, Cailhol S, Stinus L (1999) d-Amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation. Neuroscience 94:705–721

    Article  CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Devine DP, Wise RA (1995) Habit-forming actions of nomifensine in nucleus accumbens. Psychopharmacology 122:194–197

    Google Scholar 

  • Carlezon WA Jr, Haile CN, Coppersmith R, Hayashi Y, Malinow R, Neve RL, Nestler EJ (2000) Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1. J Neurosci 20:RC62

    PubMed  Google Scholar 

  • Chergui K, Charlety PJ, Akaoka H, Saunier CF, Brunet J-L, Buda M, Svensson TH, Chouvet G (1993) Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci 5:137–144

    CAS  PubMed  Google Scholar 

  • Colle LM, Wise RA (1988) Effects of nucleus accumbens amphetamine on lateral hypothalamic brain stimulation reward. Brain Res 459:361–368

    Article  CAS  PubMed  Google Scholar 

  • David V, Durkin TP, Cazala P (1997) Self-administration of the GABAA antagonist bicuculline into the ventral tegmental area in mice: dependence on D2 dopaminergic mechanisms. Psychopharmacology 130:85–90

    CAS  PubMed  Google Scholar 

  • Fedele E, Bisaglia M, Raiteri M (1997) d-serine modulates the NMDA receptor/nitric oxide/cGMP pathway in the rat cerebellum during in vivo microdialysis. Naunyn-Schmiedeberg’s Arch Pharmacol 355:43–47

    Google Scholar 

  • Fink JS, Smith GP (1980) Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats. Brain Res 199:359–384

    CAS  PubMed  Google Scholar 

  • Glimcher PW, Giovino AA, Hoebel BG (1987) Neurotensin self-injection in the ventral tegmental area. Brain Res 403:147–150

    Article  CAS  PubMed  Google Scholar 

  • Harris GC, Aston-Jones G (2003) Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28:73–76

    Article  CAS  PubMed  Google Scholar 

  • Herberg LJ, Rose IC (1990) Excitatory amino acid pathways in brain-stimulation reward. Behav Brain Res 39:230–239

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ikemoto S (2002) Ventral striatal anatomy of locomotor activity induced by cocaine, d-amphetamine, dopamine and D1/D2 agonists. Neuroscience 113:939–955

    Article  CAS  PubMed  Google Scholar 

  • Ikemoto S, Panksepp J (1996) Dissociations between appetitive and consummatory responses by pharmacological manipulations of reward-relevant brain regions. Behav Neurosci 110:331–345

    CAS  PubMed  Google Scholar 

  • Ikemoto S, Sharpe LG (2001) A head-attachable device for injecting nanoliter volumes of drug solutions into brain sites of freely moving rats. J Neurosci Meth 110:135–140

    Article  CAS  Google Scholar 

  • Ikemoto S, Wise RA (2002) Rewarding effects of the cholinergic agents carbachol and neostigmine in the posterior ventral tegmental area. J Neurosci 22:9895–9904

    CAS  PubMed  Google Scholar 

  • Ikemoto S, Glazier BS, Murphy JM, McBride WJ (1997a) Role of D1 and D2 receptors in the nucleus accumbens in mediating reward. J Neurosci 17:8580–8587

    CAS  PubMed  Google Scholar 

  • Ikemoto S, Murphy JM, McBride WJ (1997b) Self-infusion of GABAA antagonists directly into the ventral tegmental area and adjacent regions. Behav Neurosci 111:369–380

    CAS  PubMed  Google Scholar 

  • Ikemoto S, Murphy JM, McBride WJ (1998) Regional differences within the rat ventral tegmental area for muscimol self-infusions. Pharmacol Biochem Behav 61:87–92

    Article  CAS  PubMed  Google Scholar 

  • Ikemoto S, Witkin BM, Wise RA (2002) Rats self-administer the glutamate agonist AMPA directly into the posterior hypothalamic area but not the ventral tegmental area. 2002 Abstracts Viewer/Itinerary Planner. Society for Neuroscience, Program No. 876.9, Washington D.C.

  • Ikemoto S, Witkin BM, Morales M (2003) Rewarding injections of the cholinergic agonist carbachol into the ventral tegmental area induce locomotion and c-Fos expression in the retrosplenial area and supramammillary nucleus. Brain Res 969:78–87

    Article  CAS  PubMed  Google Scholar 

  • Johnson SW, Seutin V, North RA (1992) Burst firing in dopamine neurons induced by N-methyl-d-aspartate—role of electrogenic sodium-pump. Science 258:665–667

    PubMed  Google Scholar 

  • Joyce EM, Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neurosci Lett 14:207–12

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW, Alesdatter JE (1993) Involvement of N-methyl-d-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine. J Pharmacol Exp Ther 267:486–495

    CAS  PubMed  Google Scholar 

  • Kalivas PW, Weber B (1988) Amphetamine injection into the ventral mesencephalon sensitizes rats to peripheral amphetamine and cocaine. J Pharmacol Exp Ther 245:1095–102

    CAS  PubMed  Google Scholar 

  • Kalivas PW, Burgess SK, Nemeroff CB, Prange AJ Jr (1983) Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat. Neuroscience 8:495–505

    CAS  PubMed  Google Scholar 

  • Kalivas PW, Duffy P, Barrow J (1989) Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes. J Pharmacol Exp Ther 251:378–387.

    CAS  PubMed  Google Scholar 

  • Kemp JA, Leeson PD (1993) The glycine site of the NMDA receptor--five years on. Trends Pharmacol Sci 14:20–25

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Riley SJ, Smith SC, Robbins TW (1978) Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi and olfactory tubercle on feeding, locomotor activity, and amphetamine anorexia in the rat. J Comp Physiol Psychol 92:917–927

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Mogenson GJ (1987) Limbic-motor integration. In: Epstein A, Morrison AR (eds) Progress in psychobiology and physiological psychology. Academic Press, New York, pp 117–170

  • Museo E, Wise RA (1994) Place preference conditioning with ventral tegmental injections of cytisine. Life Sci 55:1179–1186

    CAS  PubMed  Google Scholar 

  • Panagis G, Kastellakis A (2002) The effects of ventral tegmental administration of GABA(A), GABA(B), NMDA and AMPA receptor agonists on ventral pallidum self-stimulation. Behav Brain Res 131:115–123

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic Press, New York

  • Pijnenburg AJJ, Van Rossum JM (1973) Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens. J Pharm Pharmacol 25:1003–1005

    CAS  PubMed  Google Scholar 

  • Pycock CJ, Dawbarn D (1980) Acute motor effects of N-methyl-d-aspartic acid and kainic acid applied focally to mesencephalic dopamine cell body regions in the rat. Neurosci Lett 18:85–90

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, McKinzie DL, Crile RS, Murphy JM, McBride WJ (2000) Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats. Psychopharmacology 149:217–224

    Google Scholar 

  • Schenk S, Partridge B (1997) Effects of acute and repeated administration of N-methyl-d-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine. Brain Res 769:225–232

    CAS  PubMed  Google Scholar 

  • Stellar JR, Corbett D (1989) Regional neuroleptic microinjections indicate a role for nucleus accumbens in lateral hypothalamic self-stimulation reward. Brain Res 477:126-143

    CAS  PubMed  Google Scholar 

  • Suaud-Chagny MF, Chergui K, Chouvet G, Gonon F (1992) Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area. Neuroscience 49:63–72

    CAS  PubMed  Google Scholar 

  • Suto N, Tanabe LM, Austin JD, Creekmore E, Vezina P (2003) Previous Exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner. Neuropsychopharmacology 28:629–639

    Article  PubMed  Google Scholar 

  • Vezina P (1993) Amphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine: an in vivo microdialysis study in the rat. Brain Res 605: 332–337

    CAS  PubMed  Google Scholar 

  • Vezina P, Queen AL (2000) Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area. Psychopharmacology 151:184–191

    Google Scholar 

  • Wang T, French ED (1993) l-Glutamate excitation of A10 dopamine neurons is preferentially mediated by activation of NMDA receptors: extra- and intracellular electrophysiological studies in brain slices. Brain Res 627:299–306

    Article  CAS  PubMed  Google Scholar 

  • Wang T, O’Connor WT, Ungerstedt U, French ED (1994) N-Methyl-d-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666:255–262

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Willick ML, Kokkinidis L (1995) The effects of ventral tegmental administration of GABAA, GABAB and NMDA receptor agonists on medial forebrain bundle self-stimulation. Behav Brain Res 70:31–36

    CAS  PubMed  Google Scholar 

  • Zangen A, Ikemoto S, Zadina JE, Wise RA (2002) Rewarding and psychomotor stimulant effects of endomorphin—1: anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens. J Neurosci 22:7225–7233

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The present work was supported by the NIDA Intramural Research Program.

Author information

Authors and Affiliations

  1. Behavioral Neuroscience Branch, National Institute on Drug Abuse, Department of Health and Human Services, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD, 21224, USA

    Satoshi Ikemoto

Authors
  1. Satoshi Ikemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoshi Ikemoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ikemoto, S. Unconditional hyperactivity and transient reinforcing effects of NMDA administration into the ventral tegmental area in rats. Psychopharmacology 172, 202–210 (2004). https://doi.org/10.1007/s00213-003-1651-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1651-3

Keywords

Search

Navigation