Muscarinic and NMDA Receptors in the Substantia Nigra Play a Role in Reward-Related Learning

Overview

Journal Int J Neuropsychopharmacol

Publisher Oxford University Press

Specialty Psychiatry

Date 2022 Nov 19

PMID 36402549

Authors

Ewa Galaj

Eddy D Barrera

Olivia L Lynch

Rachel Diodati

Ashley Thomas

Piper Schneider

Hayley Lenhard

Apoorva Vashisht

Robert Ranaldi

Affiliations

Soon will be listed here.

Abstract

Background: Reward-related learning, where animals form associations between rewards and stimuli (i.e., conditioned stimuli [CS]) that predict or accompany those rewards, is an essential adaptive function for survival.

Methods: In this study, we investigated the mechanisms underlying the acquisition and performance of conditioned approach learning with a focus on the role of muscarinic acetylcholine (mACh) and NMDA glutamate receptors in the substantia nigra (SN), a brain region implicated in reward and motor processes.

Results: Using RNAscope in situ hybridization assays, we found that dopamine neurons of the SN express muscarinic (mACh5), NMDA2a, NMDA2b, and NMDA2d receptor mRNA but not mACh4. NMDA, but not mACh5, receptor mRNA was also found on SN GABA neurons. In a conditioned approach paradigm, rats were exposed to 3 or 7 conditioning sessions during which light/tone (CS) presentations were paired with delivery of food pellets, followed by a test session with CS-only presentations. Intra-SN microinjections of scopolamine (a mACh receptor antagonist) or AP-5 (a NMDA receptor antagonist) were made either prior to each conditioning session (to test their effects on acquisition) or prior to the CS-only test (to test their effects on expression of the learned response). Scopolamine and AP-5 produced dose-dependent significant reductions in the acquisition, but not performance, of conditioned approach.

Conclusions: These results suggest that SN mACh and NMDA receptors are key players in the acquisition, but not the expression, of reward-related learning. Importantly, these findings redefine the role of the SN, which has traditionally been known for its involvement in motor processes, and suggest that the SN possesses attributes consistent with a function as a hub of integration of primary reward and CS signals.

References

Sharf R, Ranaldi R . Blockade of muscarinic acetylcholine receptors in the ventral tegmental area disrupts food-related learning in rats. Psychopharmacology (Berl). 2005; 184(1):87-94. DOI: 10.1007/s00213-005-0235-9. View

Beninger R, DAmico C, Ranaldi R . Microinjections of flupenthixol into the caudate putamen of rats produce intrasession declines in food-rewarded operant responding. Pharmacol Biochem Behav. 1993; 45(2):343-50. DOI: 10.1016/0091-3057(93)90249-s. View

Levey A, Kitt C, Simonds W, Price D, Brann M . Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci. 1991; 11(10):3218-26. PMC: 6575445. View

Stuber G, Klanker M, de Ridder B, Bowers M, Joosten R, Feenstra M . Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons. Science. 2008; 321(5896):1690-2. PMC: 2613864. DOI: 10.1126/science.1160873. View

Renner U, Oertel R, Kirch W . Pharmacokinetics and pharmacodynamics in clinical use of scopolamine. Ther Drug Monit. 2005; 27(5):655-65. DOI: 10.1097/01.ftd.0000168293.48226.57. View

Windels F, Bruet N, Poupard A, Urbain N, Chouvet G, Feuerstein C . Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci. 2000; 12(11):4141-6. DOI: 10.1046/j.1460-9568.2000.00296.x. View

Moehle M, Pancani T, Byun N, Yohn S, Wilson 3rd G, Dickerson J . Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M Muscarinic Receptor. Neuron. 2017; 96(6):1358-1372.e4. PMC: 5753765. DOI: 10.1016/j.neuron.2017.12.008. View

Galaj E, Ananthan S, Saliba M, Ranaldi R . The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats. Psychopharmacology (Berl). 2013; 231(3):501-10. DOI: 10.1007/s00213-013-3254-y. View

Watabe-Uchida M, Zhu L, Ogawa S, Vamanrao A, Uchida N . Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron. 2012; 74(5):858-73. DOI: 10.1016/j.neuron.2012.03.017. View

10.

Zellner M, Ranaldi R . How conditioned stimuli acquire the ability to activate VTA dopamine cells: a proposed neurobiological component of reward-related learning. Neurosci Biobehav Rev. 2009; 34(5):769-80. DOI: 10.1016/j.neubiorev.2009.11.011. View

11.

Yun I, Nicola S, Fields H . Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior. Eur J Neurosci. 2004; 20(1):249-63. DOI: 10.1111/j.1460-9568.2004.03476.x. View

12.

Galaj E, Han X, Shen H, Jordan C, He Y, Humburg B . Dissecting the Role of GABA Neurons in the VTA SNr in Opioid Reward. J Neurosci. 2020; 40(46):8853-8869. PMC: 7659457. DOI: 10.1523/JNEUROSCI.0988-20.2020. View

13.

Buller A, Larson H, Schneider B, Beaton J, Morrisett R, Monaghan D . The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. J Neurosci. 1994; 14(9):5471-84. PMC: 6577092. View

14.

Saunders B, Richard J, Margolis E, Janak P . Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties. Nat Neurosci. 2018; 21(8):1072-1083. PMC: 6082399. DOI: 10.1038/s41593-018-0191-4. View

15.

Kayadjanian N, Gioanni H, Menetrey A, Besson M . Muscarinic receptor stimulation increases the spontaneous [3H]GABA release in the rat substantia nigra through muscarinic receptors localized on striatonigral terminals. Neuroscience. 1994; 63(4):989-1002. DOI: 10.1016/0306-4522(94)90567-3. View

16.

Ranaldi R . Dopamine and reward seeking: the role of ventral tegmental area. Rev Neurosci. 2014; 25(5):621-30. DOI: 10.1515/revneuro-2014-0019. View

17.

CLARKE P, Hommer D, Pert A, Skirboll L . Innervation of substantia nigra neurons by cholinergic afferents from pedunculopontine nucleus in the rat: neuroanatomical and electrophysiological evidence. Neuroscience. 1987; 23(3):1011-9. DOI: 10.1016/0306-4522(87)90176-x. View

18.

Quinlan M, Sharf R, Lee D, Wise R, Ranaldi R . Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats. Psychopharmacology (Berl). 2004; 175(1):53-9. DOI: 10.1007/s00213-003-1771-9. View

19.

Crocker A . The regulation of motor control: an evaluation of the role of dopamine receptors in the substantia nigra. Rev Neurosci. 1997; 8(1):55-76. DOI: 10.1515/revneuro.1997.8.1.55. View

20.

Zellner M, Kest K, Ranaldi R . NMDA receptor antagonism in the ventral tegmental area impairs acquisition of reward-related learning. Behav Brain Res. 2008; 197(2):442-9. DOI: 10.1016/j.bbr.2008.10.013. View