Abstract
Rationale
In rodents, exposure to novel environments or psychostimulants promotes locomotion. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity-restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been examined mostly in the context of hippocampal physiology and memory.
Objective
We investigated whether RGS14 modulates novelty- and cocaine-induced locomotion (NIL and CIL, respectively) and neuronal activity.
Methods
We assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using NIL and CIL behavioral tests, followed by quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that normally express RGS14.
Results
RGS14 KO mice were less active than WT controls in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. RGS14 KO mice exhibited increased thigmotaxis, as well as greater c-fos and pERK induction in the central amygdala and dorsal hippocampus, when cocaine and novelty were paired.
Conclusions
RGS14 KO mice exhibited anti-correlated locomotor responses to novelty and cocaine, but displayed increased thigmotaxis in response to either stimuli which was augmented by their combination. Our findings also suggest RGS14 may reduce neuronal activity in limbic subregions by inhibiting ERK-dependent signaling.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alexander GM, Farris S, Pirone JR, Zheng C, Colgin LL, Dudek SM (2016) Social and novel contexts modify hippocampal CA2 representations of space. Nat Commun 7:1–14
Alexander GM, Riddick NV, McCann KE, Lustberg D, Moy SS, Dudek SM (2019) Modulation of CA2 neuronal activity increases behavioral responses to fear conditioning in female mice. Neurobiol Learn Mem 163:107044–107044. https://doi.org/10.1016/j.nlm.2019.107044
Angrini M, Leslie JC, Shephard RA (1998) Effects of propranolol, buspirone, pCPA, reserpine, and chlordiazepoxide on open-field behavior. Pharmacol Biochem Behav 59:387–397. https://doi.org/10.1016/S0091-3057(97)00457-7
Arenas MC, Daza-Losada M, Vidal-Infer A, Aguilar MA, Miñarro J, Rodríguez-Arias M (2014) Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine. Physiol Behav 133:152–160
Badiani A, Oates MM, Day HEW, Watson SJ, Akil H, Robinson TE (1998) Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty. J Neurosci 18:10579–10593
Baker DA, Cornish JL, Kalivas PW (2002) Glutamate and dopamine interactions in the motive circuit. In: Herman BH, Frankenheim J, Litten RZ, Sheridan PH, Weight FF, Zukin SR (eds) Glutamate and addiction. Humana Press, Totowa, pp 143–156. https://doi.org/10.1007/978-1-59259-306-4_9
Bardo MT, Donohew RL, Harrington NG (1996) Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res 77:23–43
Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V (2011) High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 36:569–579
Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25:515–532
Bevins RA (2001) Novelty seeking and reward: implications for the study of high-risk behaviors. Curr Dir Psychol Sci 10:189–193
Blanchard DC, Blanchard RJ (1999) Cocaine potentiates defensive behaviors related to fear and anxiety. Neurosci Biobehav Rev 23:981–991
Boulanger LM, Lombroso PJ, Raghunathan A, During MJ, Wahle P, Naegele JR (1995) Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. J Neurosci 15:1532–1544. https://doi.org/10.1523/JNEUROSCI.15-02-01532.1995
Braithwaite SP, Paul S, Nairn AC, Lombroso PJ (2006) Synaptic plasticity: one STEP at a time. Trends Neurosci 29:452–458
Brown NE, Goswami D, Branch MR, Ramineni S, Ortlund EA, Griffin PR, Hepler JR (2015) Integration of G protein α (Gα) signaling by the regulator of G protein signaling 14 (RGS14). J Biol Chem 290:9037–9049
Carey RJ, DePalma G, Damianopoulos E (2003) Response to novelty as a predictor of cocaine sensitization and conditioning in rats: a correlational analysis. Psychopharmacology 168:245–252. https://doi.org/10.1007/s00213-003-1443-9
Carmen Arenas M, Aguilar MA, Montagud-Romero S, Mateos-García A, Navarro-Francés CI, Miñarro J, Rodríguez-Arias M (2016) Influence of the novelty-seeking endophenotype on the rewarding effects of psychostimulant drugs in animal models. Curr Neuropharmacol 14:87–100
Carstens KE, Dudek SM (2019) Regulation of synaptic plasticity in hippocampal area CA2. Curr Opin Neurobiol 54:194–199. https://doi.org/10.1016/j.conb.2018.07.008
Chen R, Tilley MR, Wei H, Zhou F, Zhou F-M, Ching S, Quan N, Stephens RL, Hill ER, Nottoli T (2006) Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc Natl Acad Sci 103:9333–9338
Chen S, He L, Huang AJY, Boehringer R, Robert V, Wintzer ME, Polygalov D, Weitemier AZ, Tao Y, Gu M (2020) A hypothalamic novelty signal modulates hippocampal memory. Nature 586:270–274
Crawley JN (2007) What’s wrong with my mouse?: behavioral phenotyping of transgenic and knockout mice. John Wiley & Sons,
Cryan JF, Sweeney FF (2011) The age of anxiety: role of animal models of anxiolytic action in drug discovery. Br J Pharmacol 164:1129–1161. https://doi.org/10.1111/j.1476-5381.2011.01362.x
Datiche F, Cattarelli M (1996) Catecholamine innervation of the piriform cortex: a tracing and immunohistochemical study in the rat. Brain Res 710:69–78
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278. https://doi.org/10.1073/pnas.85.14.5274
Drouin C, Blanc G, Villégier AS, Glowinski J, Tassin JP (2002) Critical role of α1-adrenergic receptors in acute and sensitized locomotor effects of D-amphetamine, cocaine, and GBR 12783: influence of preexposure conditions and pharmacological characteristics. Synapse 43:51–61
Dudek SM, Alexander GM, Farris S (2016) Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci 17:89–102. https://doi.org/10.1038/nrn.2015.22
Evans PR, Gerber KJ, Dammer EB, Duong DM, Goswami D, Lustberg DJ, Zou J, Yang JJ, Dudek SM, Griffin PR, Seyfried NT, Hepler JR (2018a) interactome analysis reveals regulator of G protein signaling 14 (RGS14) is a novel calcium/calmodulin (Ca(2+)/CaM) and CaM kinase II (CaMKII) binding partner. J Proteome Res 17:1700–1711. https://doi.org/10.1021/acs.jproteome.8b00027
Evans PR, Lee SE, Smith Y, Hepler JR (2014) Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain. J Comp Neurol 522:186–203. https://doi.org/10.1002/cne.23395
Evans PR, Parra-Bueno P, Smirnov MS, Lustberg DJ, Dudek SM, Hepler JR, Yasuda R (2018b) RGS14 restricts plasticity in hippocampal CA2 by limiting postsynaptic calcium signaling. eNeuro 5:ENEURO.0353-0317.2018
Fadok JP, Markovic M, Tovote P, Lüthi A (2018) New perspectives on central amygdala function. Curr Opin Neurobiol 49:141–147
Fink JS, Smith GP (1980) Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats. Brain Res 199:359–384
Fraser LM, Brown RE, Hussin A, Fontana M, Whittaker A, O’Leary TP, Lederle L, Holmes A, Ramos A (2010) Measuring anxiety-and locomotion-related behaviours in mice: a new way of using old tests. Psychopharmacology 211:99–112
Fricks-Gleason AN, Marshall JF (2011) Role of dopamine D1 receptors in the activation of nucleus accumbens extracellular signal-regulated kinase (ERK) by cocaine-paired contextual cues. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36:434–444. https://doi.org/10.1038/npp.2010.174
Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG (2004) Desensitization of G protein–coupled receptors and neuronal functions. Annu Rev Neurosci 27:107–144
Gerber KJ, Dammer EB, Duong DM, Deng Q, Dudek SM, Seyfried NT, Hepler JR (2019) Specific proteomes of hippocampal regions CA2 and CA1 reveal proteins linked to the unique physiology of area CA2. J Proteome Res 18:2571–2584. https://doi.org/10.1021/acs.jproteome.9b00103
Girault JA, Valjent E, Caboche J, Hervé D (2007) ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 7(1):77–85
Goebel-Goody SM, Baum M, Paspalas CD, Fernandez SM, Carty NC, Kurup P, Lombroso PJ (2012) Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol Rev 64:65–87. https://doi.org/10.1124/pr.110.003053
Griebel G, Belzungz C, Misslin R, Vogel E (1993) The free-exploratory paradigm: an effective method for measuring neophobic behaviour in mice. Behav Pharmacol 4:637–644
He J, Yamada K, Nabeshima T (2002) A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 26:259–268. https://doi.org/10.1016/S0893-133X(01)00332-3
Hitti FL, Siegelbaum SA (2014) The hippocampal CA2 region is essential for social memory. Nature 508:88–92. https://doi.org/10.1038/nature13028
Hollinger S, Taylor J, Goldman E, Hepler J (2002) RGS14 is a bifunctional regulator of Gαi/o activity that exists in multiple populations in brain. J Neurochem 79:941–949. https://doi.org/10.0000/096381898336583
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
Hooks MS, Kalivas PW (1995) The role of mesoaccumbens-pallidal circuitry in novelty-induced behavioral activation. Neuroscience 64:587–597
Hooks SB, Martemyanov K, Zachariou V (2008) A role of RGS proteins in drug addiction. Biochem Pharmacol 75:76–84
Kabbaj M, Devine DP, Savage VR, Akil H (2000) Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. J Neurosci 20:6983–6988
Karlsson R-M, Hefner KR, Sibley DR, Holmes A (2008) Comparison of dopamine D1 and D5 receptor knockout mice for cocaine locomotor sensitization. Psychopharmacology 200:117–127
Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER (2016) Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci 113:14835–14840. https://doi.org/10.1073/pnas.1616515114
Koob GF, Simon EJ (2009) The neurobiology of addiction: where we have been and where we are going. J Drug Issues 39:115–132
Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3:760–773
Kutlu MG, Gould TJ (2016) Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction. Learn Mem 23:515–533
Laviola G, Adriani W (1998) Evaluation of unconditioned novelty-seeking and d-amphetamine–conditioned motivation in mice. Pharmacol Biochem Behav 59:1011–1020
Lee SE, Simons SB, Heldt SA, Zhao M, Schroeder JP, Vellano CP, Cowan DP, Ramineni S, Yates CK, Feng Y, Smith Y, Sweatt JD, Weinshenker D, Ressler KJ, Dudek SM, Hepler JR (2010) RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc Natl Acad Sci 107:16994–16998. https://doi.org/10.1073/pnas.1005362107
Li Y, Tang X-H, Li X-H, Dai H-J, Miao R-J, Cai J-J, Huang Z-J, Chen AF, Xing X-W, Lu Y, Yuan H (2016) Regulator of G protein signalling 14 attenuates cardiac remodelling through the MEK-ERK1/2 signalling pathway. Basic Res Cardiol 111:47–47. https://doi.org/10.1007/s00395-016-0566-1
Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212–219. https://doi.org/10.1038/nn1383
Lu L, Koya E, Zhai H, Hope BT, Shaham Y (2006) Role of ERK in cocaine addiction. Trends Neurosci 29:695–703. https://doi.org/10.1016/j.tins.2006.10.005
Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G (2011) Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science 333:353–357
Lustberg D, Tillage RP, Bai Y, Pruitt M, Liles LC, Weinshenker D (2020) Noradrenergic circuits in the forebrain control affective responses to novelty. Psychopharmacology 237:3337–3355. https://doi.org/10.1007/s00213-020-05615-8
Mankin EA, Diehl GW, Sparks FT, Leutgeb S, Leutgeb JK (2015) Hippocampal CA2 activity patterns change over time to a larger extent than between spatial contexts. Neuron 85:190–201
Manvich DF, Petko AK, Branco RC, Foster SL, Porter-Stransky KA, Stout KA, Newman AH, Miller GW, Paladini CA, Weinshenker D (2019) Selective D(2) and D(3) receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 44:1445–1455. https://doi.org/10.1038/s41386-019-0371-2
Matsubara K, Matsushita A (1982) Changes in ambulatory activities and muscle relaxation in rats after repeated doses of diazepam. Psychopharmacology 77:279–283. https://doi.org/10.1007/BF00464580
McDonald RJ, White NM. (2013). A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum.
McNamara CG, Dupret D (2017) Two sources of dopamine for the hippocampus. Trends Neurosci 40:383–384. https://doi.org/10.1016/j.tins.2017.05.005
Meira T, Leroy F, Buss EW, Oliva A, Park J, Siegelbaum SA (2018) A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics. Nat Commun 9:4163. https://doi.org/10.1038/s41467-018-06501-w
Michalak A, Wnorowski A, Berardinelli A, Zinato S, Rusinek J, Budzyńska B (2020) Diazepam and SL-327 synergistically attenuate anxiety-like behaviours in mice–possible hippocampal MAPKs specificity. Neuropharmacology 180:108302
Moreno-Castilla P, Pérez-Ortega R, Violante-Soria V, Balderas I, Bermúdez-Rattoni F (2017) Hippocampal release of dopamine and norepinephrine encodes novel contextual information. Hippocampus 27:547–557. https://doi.org/10.1002/hipo.22711
Morland RH, Novejarque A, Spicer C, Pheby T, Rice ASC (2016) Enhanced c-Fos expression in the central amygdala correlates with increased thigmotaxis in rats with peripheral nerve injury. Eur J Pain 20:1140–1154. https://doi.org/10.1002/ejp.839
Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LTL, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805
Nestler EJ (2001) Molecular neurobiology of addiction. Am J Addict 10:201–217
Paine TA, Jackman SL, Olmstead MC (2002) Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine. Behav Pharmacol 13:511–523
Papa M, Pellicano MP, Welzl H, Sadile AG (1993) Distributed changes in c-Fos and c-Jun immunoreactivity in the rat brain associated with arousal and habituation to novelty. Brain Res Bull 32:509–515
Papale A, Morella IM, Indrigo MT, Bernardi RE, Marrone L, Marchisella F, Brancale A, Spanagel R, Brambilla R, Fasano S (2016) Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors. eLife 5:e17111. https://doi.org/10.7554/eLife.17111
Pawlak CR, Ho Y-J, Schwarting RKW (2008) Animal models of human psychopathology based on individual differences in novelty-seeking and anxiety. Neurosci Biobehav Rev 32:1544–1568
Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285
Porter-Stransky KA, Centanni SW, Karne SL, Odil LM, Fekir S, Wong JC, Jerome C, Mitchell HA, Escayg A, Pedersen NP (2019) Noradrenergic transmission at alpha1-adrenergic receptors in the ventral periaqueductal gray modulates arousal. Biol Psychiatry 85:237–247
Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein MN, Choi K-H, Kovoor A, Chen C-K, DiLeone RJ, Schwarz SC, Selley DE, Sim-Selley LJ, Barrot M, Luedtke RR, Self D, Neve RL, Lester HA, Simon MI, Nestler EJ (2003) RGS9 modulates dopamine signaling in the basal ganglia. Neuron 38:941–952. https://doi.org/10.1016/S0896-6273(03)00321-0
Ross EM, Wilkie TM (2000) GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 69:795–827
Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33:267–276
Sakloth F, Polizu C, Bertherat F, Zachariou V (2020) Regulators of G protein signaling in analgesia and addiction. Mol Pharmacol 98:739–750. https://doi.org/10.1124/mol.119.119206
Sanguedo FV, Dias CVB, Dias FRC, Samuels RI, Carey RJ, Carrera MP (2016) Reciprocal activation/inactivation of ERK in the amygdala and frontal cortex is correlated with the degree of novelty of an open-field environment. Psychopharmacology 233:841–850
Schank JR, Liles LC, Weinshenker D (2008) Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety. Biol Psychiatry 63:1007–1012. https://doi.org/10.1016/j.biopsych.2007.10.018
Schmidt KT, Weinshenker D (2014) Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors. Mol Pharmacol 85:640–650. https://doi.org/10.1124/mol.113.090118
Shu F-J, Ramineni S, Amyot W, Hepler JR (2007) Selective interactions between Gi alpha1 and Gi alpha3 and the GoLoco/GPR domain of RGS14 influence its dynamic subcellular localization. Cell Signal 19:163–176. https://doi.org/10.1016/j.cellsig.2006.06.002
Shu F-J, Ramineni S, Hepler JR (2010) RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways. Cell Signal 22:366–376
Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64. https://doi.org/10.1016/0166-4328(94)90008-6
Sjögren B, Neubig RR (2010) Thinking outside of the “RGS box”: new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol 78:550–557
Squires KE, Gerber KJ, Tillman MC, Lustberg DJ, Montañez-Miranda C, Zhao M, Ramineni S, Scharer CD, Saha RN, Shu F-j, Schroeder JP, Ortlund EA, Weinshenker D, Dudek SM, Hepler JR. (2020). Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons. J Biol Chem
Squires KE, Gerber KJ, Pare J-F, Branch MR, Smith Y, Hepler JR (2018) Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain. Brain Struct Funct 223:233–253. https://doi.org/10.1007/s00429-017-1487-y
Strauch C, Manahan-Vaughan D (2020) Orchestration of hippocampal information encoding by the piriform cortex. Cereb Cortex 30:135–147
Sun W-L, Quizon PM, Zhu J (2016) Molecular mechanism: ERK signaling, drug addiction, and behavioral effects. Prog Mol Biol Transl Sci 137:1–40. https://doi.org/10.1016/bs.pmbts.2015.10.017
Sun W-L, Zhou L, Hazim R, Quinones-Jenab V, Jenab S (2008) Effects of dopamine and NMDA receptors on cocaine-induced Fos expression in the striatum of Fischer rats. Brain Res 1243:1–9
Takeuchi T, Duszkiewicz AJ, Sonneborn A, Spooner PA, Yamasaki M, Watanabe M, Smith CC, Fernández G, Deisseroth K, Greene RW, Morris RGM (2016) Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537:357–362. https://doi.org/10.1038/nature19325
Torres G, Rivier C (1993) Cocaine-induced expression of striatal c-fos in the rat is inhibited by NMDA receptor antagonists. Brain Res Bull 30:173–176
Valjent E, Corvol J-C, Pages C, Besson M-J, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701–8709
Valjent E, Corvol J-C, Trzaskos JM, Girault J-A, Hervé D (2006) Role of the ERK pathway in psychostimulant-induced locomotor sensitization. BMC Neurosci 7:20. https://doi.org/10.1186/1471-2202-7-20
Valjent E, Pagès C, Hervé D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836
Vellano CP, Brown NE, Blumer JB, Hepler JR (2013) Assembly and Function of the Regulator of G protein Signaling 14 (RGS14)·H-Ras signaling complex in live cells are regulated by Gαi1 and Gαi-linked G protein-coupled receptors. J Biol Chem 288:3620–3631
Venkitaramani DV, Paul S, Zhang Y, Kurup P, Ding L, Tressler L, Allen M, Sacca R, Picciotto MR, Lombroso PJ (2009) Knockout of striatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation. Synapse 63:69–81. https://doi.org/10.1002/syn.20608
Vidal-Infer A, Arenas MC, Daza-Losada M, Aguilar MA, Miñarro J, Rodríguez-Arias M (2012) High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine. Pharmacol Biochem Behav 102:124–132
Wagatsuma A, Okuyama T, Sun C, Smith LM, Abe K, Tonegawa S (2018) Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. Proc Natl Acad Sci 115:E310–E316. https://doi.org/10.1073/pnas.1714082115
Walker QD, Schramm-Sapyta NL, Caster JM, Waller ST, Brooks MP, Kuhn CM (2009) Novelty-induced locomotion is positively associated with cocaine ingestion in adolescent rats; anxiety is correlated in adults. Pharmacol Biochem Behav 91:398–408
Weinshenker D, Miller NS, Blizinsky K, Laughlin ML, Palmiter RD (2002) Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals. Proc Natl Acad Sci U S A 99:13873–13877. https://doi.org/10.1073/pnas.212519999
Willard FS, Willard MD, Kimple AJ, Soundararajan M, Oestreich EA, Li X, Sowa NA, Kimple RJ, Doyle DA, Der CJ, Zylka MJ, Snider WD, Siderovski DP (2009) Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector. PLoS One 4:e4884. https://doi.org/10.1371/journal.pone.0004884
Wilson DA, Best AR, Sullivan RM (2004) Plasticity in the olfactory system: lessons for the neurobiology of memory. Neuroscientist 10:513–524
Wingo T, Nesil T, Choi J-S, Li MD (2016) Novelty seeking and drug addiction in humans and animals: from behavior to molecules. J NeuroImmune Pharmacol 11:456–470
Zhao M, Choi Y-S, Obrietan K, Dudek SM (2007) Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci 27:12025–12032. https://doi.org/10.1523/JNEUROSCI.4094-07.2007
Zhao P, Nunn C, Ramineni S, Hepler JR, Chidiac P (2013) The Ras-binding domain region of RGS14 regulates its functional interactions with heterotrimeric G proteins. J Cell Biochem 114:1414–1423. https://doi.org/10.1002/jcb.24483
Acknowledgements
We thank C. Strauss for helpful editing of the manuscript.
Funding
This work was supported by the National Institutes of Health (AG061175, NS102306, DA038453, and DA049257 to DW; 2T32 NS 007480-20 to DL; F31DA044726 to SLF; R01NS037112 and 2R21NS102652 to JH).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Figure S1
Male and female RGS14 KO mice show similar locomotor phenotypes in a novel environment compared to male and female WT mice. a RGS14 KO males (n = 14) were significantly less active in the NIL test compared to WT males (n = 13). b Female RGS14 KO mice (n = 6) showed a trend towards reduced total locomotion compared to female WT mice (n = 6) which did not reach statistical significance. c RGS14 KO males demonstrated significantly reduced locomotor activity in the center of the environment compared to WT males. d RGS14 KO females demonstrated reduced locomotor activity in the center of the environment compared to WT females. e RGS14 KO males demonstrated similar levels of locomotor activity in the periphery compared to WT males. f RGS14 KO females demonstrated similar levels of locomotor activity in the periphery compared to WT females. g When the genotypes were split by sex and analyzed by two-way ANOVA (sex x genotype), there was a strong trend for a main effect of genotype on total ambulations (p = 0.051) and h a significant main effect of genotype on central ambulations. Although the experiment wasn’t powered to detect sex differences, no main effects of sex or interactions were detected for either measures; thus NIL data for both sexes were pooled. ns = not significant, *p < 0.05, ** p < 0.01. (PNG 102 kb)
Figure S2
Male and female RGS14 KO mice exhibit similar locomotor behavior in response to 20 mg/kg cocaine in a familiar environment. a RGS14 KO males (n=7) exhibited an increase in total locomotor activity that did not reach statistical significance compared to WT males. b RGS14 KO females (n=7) exhibited a slight but non-significant increase in total locomotion in comparison to WT females. c,d Neither RGS14 KO males or females differed from their same-sex WT counterparts in central ambulations. e RGS14 KO males exhibited an increase in peripheral ambulations compared to WT that did not reach statistical significance. f RGS14 KO females showed significantly more peripheral ambulations than WT. g,h Sex-specific analyses revealed no main effect of sex on total or peripheral ambulations. ns = not significant, *p < 0.05. (PNG 217 kb)
Figure S3
RGS14 deficiency does not alter induction of pERK in regions of interest in experimentally naive animals. a RGS14-ir (magenta) was evident only in WT animals with the exposure settings used to acquire epifluorescent micrographs. Overall pERK induction (green) was minimal when RGS14 KO (n = 5) and WT (n = 5) mice were rapidly euthanized compared to the levels observed following exposure to environmental novelty and cocaine, and did not significantly differ by genotype in any region examined (p > 0.05 for all comparisons). Scale bars denote 100 μm. (PNG 1622 kb)
Table S1
Summary of statistical comparisons of male and female RGS14 WT and KO mice in NIL test. a There was a strong trend (p = 0.051) for a main effect of genotype on total locomotion, with RGS14 KO mice demonstrating reduced total locomotion compared to WT controls. There was no main effect of sex (p > 0.05) and no interaction effect (p > 0.05). b There was a main effect of genotype (p < 0.01) on central locomotion, with RGS14 KO mice exhibiting fewer center ambulations. There was no main effect of sex (p > 0.05) or interaction (p > 0.05). (PNG 235 kb)
Table S2
Summary of statistical comparisons for male and female RGS14 KO and WT mice in response to 20 mg/kg cocaine in a familiar environment. a There was a strong trend (p = 0.056) for a main effect of genotype on total ambulations, where RGS14 KO mice exhibited increased total locomotion compared to WT. There was no main effect of sex (p > 0.05) and no interaction effect (p > 0.05) b Among peripheral ambulations, there was a main effect of genotype (p < 0.05) where RGS14 KO mice exhibited significantly more activity than WT, but there was no effect of sex (p > 0.05) and no interaction (p > 0.05). (PNG 108 kb)
Table S3
Summary of statistical comparisons of pERK induction within regions and between genotypes in experimentally naive RGS14 KO (n = 5) and WT (n = 5) mice. Average pERK+ cell counts were compared within regions and between genotypes using multiple t-tests adjusted for multiple comparisons, as described in the Methods section. No regional pERK+ cell counts were significantly different between genotypes in naive mice (p > 0.05 for all comparisons). (PNG 361 kb)
Rights and permissions
About this article
Cite this article
Foster, S.L., Lustberg, D.J., Harbin, N.H. et al. RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures. Psychopharmacology 238, 2755–2773 (2021). https://doi.org/10.1007/s00213-021-05892-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05892-x