Abstract
Rationale
Repeated chemogenetic stimulation is often employed to study circuit function and behavior. Chronic or repeated agonist administration can result in homeostatic changes, but this has not been extensively studied with designer receptors exclusively activated by designer drugs (DREADDs).
Objectives
We sought to evaluate the impact of repeated DREADD activation of dopaminergic (DA) neurons on basal behavior, amphetamine response, and spike firing. We hypothesized that repeated DREADD activation would mimic compensatory effects that we observed with genetic manipulations of DA neurons.
Methods
Excitatory hM3D(Gq) DREADDs were virally expressed in adult TH-Cre and WT mice. In a longitudinal design, clozapine N-oxide (CNO, 1.0 mg/kg) was administered repeatedly. We evaluated basal and CNO- or amphetamine (AMPH)-induced locomotion and stereotypy. DA neuronal activity was assessed using in vivo single-unit recordings.
Results
Acute CNO administration increased locomotion, but basal locomotion decreased after repeated CNO exposure in TH-CrehM3Dq mice relative to littermate controls. Further, after repeated CNO administration, AMPH-induced hyperlocomotion and stereotypy were diminished in TH-CrehM3Dq mice relative to controls. Repeated CNO administration reduced DA neuronal firing in TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the decreases in basal locomotion and AMPH response.
Conclusions
We found that repeated DREADD activation of DA neurons evokes homeostatic changes that should be factored into the interpretation of chronic DREADD applications and their impact on circuit function and behavior. These effects are likely to also be seen in other neuronal systems and underscore the importance of studying neuroadaptive changes with chronic or repeated DREADD activation.
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Data Availability
Data will be made available upon reasonable request.
References
Ackerman JM, White FJ (1990) A10 somatodendritic dopamine autoreceptor sensitivity following withdrawal from repeated cocaine treatment. Neurosci Lett 117:181–187. https://doi.org/10.1016/0304-3940(90)90141-u
Alam MR (1981) Enhancement of motor-accelerating effect induced by repeated administration of methamphetamine in mice: involvement of environmental factors. Jpn J Pharmacol 31:897–904. https://doi.org/10.1254/jjp.31.897
Anagnostaras SG, Robinson TE (1996) Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning. Behav Neurosci 110:1397–1414. https://doi.org/10.1037//0735-7044.110.6.1397
Antelman SM, Eichler AJ, Black CA, Kocan D (1980) Interchangeability of stress and amphetamine in sensitization. Science 207:329–331. https://doi.org/10.1126/science.7188649
Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 104:5163–5168. https://doi.org/10.1073/pnas.0700293104
Ashok AH, Mizuno Y, Volkow ND, Howes OD (2017) Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-analysis JAMA. Psychiatry 74:511–519. https://doi.org/10.1001/jamapsychiatry.2017.0135
Avelar AJ, Juliano SA, Garris PA (2013) Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem 125:373–385. https://doi.org/10.1111/jnc.12197
Baldan LC et al (2014) Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron 81:77–90. https://doi.org/10.1016/j.neuron.2013.10.052
Beutler LR, Wanat MJ, Quintana A, Sanz E, Bamford NS, Zweifel LS, Palmiter RD (2011) Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization. Proc Natl Acad Sci U S A 108:4206–4211. https://doi.org/10.1073/pnas.1101424108
Bevins RA, Peterson JL (2004) Individual differences in rats’ reactivity to novelty and the unconditioned and conditioned locomotor effects of methamphetamine. Pharmacol Biochem Behav 79:65–74. https://doi.org/10.1016/j.pbb.2004.06.002
Bian WJ, Brewer CL, Kauer JA, de Lecea L (2022) Adolescent sleep shapes social novelty preference in mice. Nat Neurosci 25:912–923. https://doi.org/10.1038/s41593-022-01076-8
Bloomfield MA, Ashok AH, Volkow ND, Howes OD (2016) The effects of Delta(9)-tetrahydrocannabinol on the dopamine system. Nature 539:369–377. https://doi.org/10.1038/nature20153
Bonate PL, Swann A, Silverman PB (1997) Context-dependent cross-sensitization between cocaine and amphetamine. Life Sci 60:PL1–7. https://doi.org/10.1016/s0024-3205(96)00591-7
Borgkvist A, Valjent E, Santini E, Herve D, Girault JA, Fisone G (2008) Delayed, context- and dopamine D1 receptor-dependent activation of ERK in morphine-sensitized mice. Neuropharmacology 55:230–237. https://doi.org/10.1016/j.neuropharm.2008.05.028
Borgland SL, Malenka RC, Bonci A (2004) Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J Neurosci 24:7482–7490. https://doi.org/10.1523/JNEUROSCI.1312-04.2004
Brabant C, Tambour S, Tirelli E (2003) Quasi-asymptotic development of conditioned hyperactivity induced by intermittent injections of cocaine in C57BL/6J mice. Pharmacol Biochem Behav 75:273–280. https://doi.org/10.1016/s0091-3057(03)00083-2
Browman KE, Badiani A, Robinson TE (1998) Modulatory effect of environmental stimuli on the susceptibility to amphetamine sensitization: a dose-effect study in rats. J Pharmacol Exp Ther 287:1007–1014
Burnett CJ, Krashes MJ (2016) Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs. J Neurosci 36:9268–9282. https://doi.org/10.1523/JNEUROSCI.1333-16.2016
Carlezon WA Jr, Nestler EJ (2002) Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse? Trends Neurosci 25:610–615. https://doi.org/10.1016/s0166-2236(02)02289-0
CarvalhoPoyraz F et al (2016) Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action. J Neurosci 36:5988–6001. https://doi.org/10.1523/JNEUROSCI.0444-16.2016
Chohan MO et al (2022a) Developmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior. Mol Psychiatry. https://doi.org/10.1038/s41380-021-01424-3
Chohan MO, Yueh H, Fein H, Kopelman JM, Ahmari SE, Veenstra-VanderWeele J (2022) Intact amphetamine-induced behavioral sensitization in mice with increased or decreased neuronal glutamate transporter SLC1A1/EAAT3. Neurochem Int 160:105418. https://doi.org/10.1016/j.neuint.2022.105418
Chohan MO, Esses S, Haft J, Ahmari S, Veenstra-VanderWeele J (2020) Altered baseline and amphetamine-mediated behavioral profiles in dopamine transporter Cre (DAT-Ires-Cre) mice compared to tyrosine hydroxylase Cre (TH-Cre) mice. Psychopharmacology (Berl). https://doi.org/10.1007/s00213-020-05635-4
Clark D, Overton PG (1998) Alterations in excitatory amino acid-mediated regulation of midbrain dopaminergic neurones induced by chronic psychostimulant administration and stress: relevance to behavioural sensitization and drug addiction. Addict Biol 3:109–135. https://doi.org/10.1080/13556219872191
National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. The National Academies Press, Washington, DC. https://doi.org/10.17226/12910
Covey DP, Bunner KD, Schuweiler DR, Cheer JF, Garris PA (2016) Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids. Eur J Neurosci 43:1661–1673. https://doi.org/10.1111/ejn.13248
Daberkow DP et al (2013) Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. J Neurosci 33:452–463. https://doi.org/10.1523/JNEUROSCI.2136-12.2013
Damianopoulos EN, Carey RJ (1992) Conditioning, habituation and behavioral reorganization factors in chronic cocaine effects. Behav Brain Res 49:149–157. https://doi.org/10.1016/s0166-4328(05)80159-7
Drew KL, Glick SD (1988) Characterization of the associative nature of sensitization to amphetamine-induced circling behavior and of the environment dependent placebo-like response. Psychopharmacology 95:482–487. https://doi.org/10.1007/BF00172959
Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320. https://doi.org/10.1523/JNEUROSCI.22-09-03312.2002
Ferrario CR, Robinson TE (2007) Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsychopharmacol 17:352–357. https://doi.org/10.1016/j.euroneuro.2006.08.005
Fourgeaud L, Mato S, Bouchet D, Hemar A, Worley PF, Manzoni OJ (2004) A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens. J Neurosci 24:6939–6945. https://doi.org/10.1523/JNEUROSCI.0671-04.2004
Freyberg Z et al (2016) Mechanisms of Amphetamine Action Illuminated through Optical Monitoring of Dopamine Synaptic Vesicles in Drosophila. Brain Nat Commun 7:10652. https://doi.org/10.1038/ncomms10652
Gilani AI et al (2014) Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci U S A 111:7450–7455. https://doi.org/10.1073/pnas.1316488111
Gilman S et al (1998) Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]dihydrotetrabenazine and positron emission tomography. Ann Neurol 44:326–333. https://doi.org/10.1002/ana.410440307
Gold LH, Koob GF (1989) MDMA produces stimulant-like conditioned locomotor activity. Psychopharmacology 99:352–356. https://doi.org/10.1007/BF00445556
Gold LH, Swerdlow NR, Koob GF (1988) The role of mesolimbic dopamine in conditioned locomotion produced by amphetamine. Behav Neurosci 102:544–552. https://doi.org/10.1037//0735-7044.102.4.544
Gomes FV, Zhu X, Grace AA (2020) The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability. Mol Psychiatry 25:3278–3291. https://doi.org/10.1038/s41380-019-0514-1
Grace AA, Bunney BS (1984) The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci 4:2877–2890
Guan LC, Robinson TE, Becker JB (1985) Sensitization of rotational behavior produced by a single exposure to cocaine. Pharmacol Biochem Behav 22:901–903. https://doi.org/10.1016/0091-3057(85)90545-3
Hall DA, Stanis JJ, Marquez Avila H, Gulley JM (2008) A comparison of amphetamine- and methamphetamine-induced locomotor activity in rats: evidence for qualitative differences in behavior. Psychopharmacology 195:469–478. https://doi.org/10.1007/s00213-007-0923-8
Henry DJ, Greene MA, White FJ (1989) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration. J Pharmacol Exp Ther 251:833–839
Herman JP, Stinus L, Le Moal M (1984) Repeated stress increases locomotor response to amphetamine. Psychopharmacology 84:431–435. https://doi.org/10.1007/BF00555227
Heusner CL, Palmiter RD (2005) Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference. J Neurosci 25:6651–6657. https://doi.org/10.1523/JNEUROSCI.1474-05.2005
Holly EN, Shimamoto A, Debold JF, Miczek KA (2012) Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats. Psychopharmacology 224:179–188. https://doi.org/10.1007/s00213-012-2846-2
Ingram SL, Prasad BM, Amara SG (2002) Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci 5:971–978. https://doi.org/10.1038/nn920
Itzhak Y (1997) Modulation of cocaine- and methamphetamine-induced behavioral sensitization by inhibition of brain nitric oxide synthase. J Pharmacol Exp Ther 282:521–527
Itzhak Y, Martin JL (1999) Effects of cocaine, nicotine, dizocipline and alcohol on mice locomotor activity: cocaine-alcohol cross-sensitization involves upregulation of striatal dopamine transporter binding sites. Brain Res 818:204–211. https://doi.org/10.1016/s0006-8993(98)01260-8
Jackson HC, Nutt DJ (1993) A single preexposure produces sensitization to the locomotor effects of cocaine in mice. Pharmacol Biochem Behav 45:733–735. https://doi.org/10.1016/0091-3057(93)90533-y
Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18:1979–1986
Jones S, Kornblum JL, Kauer JA (2000) Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J Neurosci 20:5575–5580. https://doi.org/10.1523/JNEUROSCI.20-15-05575.2000
Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A (2005) Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A 102:3495–3500. https://doi.org/10.1073/pnas.0407737102
Kalivas PW, Duffy P (1990) Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 5:48–58. https://doi.org/10.1002/syn.890050104
Kalivas PW, Duffy P (1993) Time course of extracellular dopamine and behavioral sensitization to cocaine. II Dopamine Perikarya J Neurosci 13:276–284. https://doi.org/10.1523/JNEUROSCI.13-01-00276.1993
Krashes MJ et al (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121:1424–1428. https://doi.org/10.1172/JCI46229
Lee KW, Kim Y, Kim AM, Helmin K, Nairn AC, Greengard P (2006) Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc Natl Acad Sci U S A 103:3399–3404. https://doi.org/10.1073/pnas.0511244103
Li MH, Underhill SM, Reed C, Phillips TJ, Amara SG, Ingram SL (2017) Amphetamine and Methamphetamine Increase NMDAR-GluN2B Synaptic Currents in Midbrain Dopamine Neurons. Neuropsychopharmacology 42:1539–1547. https://doi.org/10.1038/npp.2016.278
Little KY, Krolewski DM, Zhang L, Cassin BJ (2003) Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users. Am J Psychiatry 160:47–55. https://doi.org/10.1176/appi.ajp.160.1.47
Liu Y, Morgan D, Roberts DC (2007) Cross-sensitization of the reinforcing effects of cocaine and amphetamine in rats. Psychopharmacology 195:369–375. https://doi.org/10.1007/s00213-007-0909-6
Lodge DJ, Grace AA (2008) Amphetamine activation of hippocampal drive of mesolimbic dopamine neurons: a mechanism of behavioral sensitization. J Neurosci 28:7876–7882. https://doi.org/10.1523/JNEUROSCI.1582-08.2008
Ma ST, Maier EY, Ahrens AM, Schallert T, Duvauchelle CL (2010) Repeated intravenous cocaine experience: development and escalation of pre-drug anticipatory 50-kHz ultrasonic vocalizations in rats. Behav Brain Res 212:109–114. https://doi.org/10.1016/j.bbr.2010.04.001
Martinez D et al (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779–786. https://doi.org/10.1016/j.biopsych.2005.04.044
Martinez D et al (2007) Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry 164:622–629. https://doi.org/10.1176/ajp.2007.164.4.622
Martinez D et al (2012) Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: commonalities and differences with other types of addiction. Biol Psychiatry 71:192–198. https://doi.org/10.1016/j.biopsych.2011.08.024
Mazurski EJ, Beninger RJ (1987) Environment-specific conditioning and sensitization with (+)-amphetamine. Pharmacol Biochem Behav 27:61–65. https://doi.org/10.1016/0091-3057(87)90477-1
Michel A, Tambour S, Tirelli E (2003) The magnitude and the extinction duration of the cocaine-induced conditioned locomotion-activated response are related to the number of cocaine injections paired with the testing context in C57BL/6J mice. Behav Brain Res 145:113–123. https://doi.org/10.1016/s0166-4328(03)00106-2
Mohawk JA, Pezuk P, Menaker M (2013) Methamphetamine and dopamine receptor D1 regulate entrainment of murine circadian oscillators. PLoS One 8:e62463. https://doi.org/10.1371/journal.pone.0062463
Moore H, Rose HJ, Grace AA (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 24:410–419. https://doi.org/10.1016/S0893-133X(00)00188-3
Morikawa H, Morrisett RA (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235–288. https://doi.org/10.1016/S0074-7742(10)91008-8
Narendran R et al (2012) In vivo evidence for low striatal vesicular monoamine transporter 2 (VMAT2) availability in cocaine abusers. Am J Psychiatry 169:55–63. https://doi.org/10.1176/appi.ajp.2011.11010126
Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449. https://doi.org/10.1038/nn1578
Piantadosi SC, Chamberlain BL, Glausier JR, Lewis DA, Ahmari SE (2019) Lower excitatory synaptic gene expression in orbitofrontal cortex and striatum in an initial study of subjects with obsessive compulsive disorder. Mol Psychiatry. https://doi.org/10.1038/s41380-019-0431-3
Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192–216. https://doi.org/10.1016/s0165-0173(97)00021-0
Ramsson ES, Covey DP, Daberkow DP, Litherland MT, Juliano SA, Garris PA (2011) Amphetamine augments action potential-dependent dopaminergic signaling in the striatum in vivo. J Neurochem 117:937–948. https://doi.org/10.1111/j.1471-4159.2011.07258.x
Rauhut AS, Bialecki V (2011) Development and persistence of methamphetamine-conditioned hyperactivity in Swiss-Webster mice. Behav Pharmacol 22:228–238. https://doi.org/10.1097/FBP.0b013e328345f741
Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198. https://doi.org/10.1016/s0006-8993(86)80193-7
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291. https://doi.org/10.1016/0165-0173(93)90013-p
Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497. https://doi.org/10.1523/JNEUROSCI.17-21-08491.1997
Robinson TE, Becker JB, Presty SK (1982) Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences. Brain Res 253:231–241. https://doi.org/10.1016/0006-8993(82)90690-4
Roth BL (2016) DREADDS for Neuroscientists. Neuron 89:683–694. https://doi.org/10.1016/j.neuron.2016.01.040
Runegaard AH, Dencker D, Wortwein G, Gether U (2019) G protein-coupled receptor signaling in VTA dopaminergic neurons bidirectionally regulates the acute locomotor response to amphetamine but does not affect behavioral sensitization. Neuropharmacology 161:107663. https://doi.org/10.1016/j.neuropharm.2019.06.002
Salesse C, Charest J, Doucet-Beaupre H, Castonguay AM, Labrecque S, De Koninck P, Levesque M (2020) Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior. Cell Rep 30:2374-2386.e2375. https://doi.org/10.1016/j.celrep.2020.01.084
Savitt JM, Jang SS, Mu W, Dawson VL, Dawson TM (2005) Bcl-x is required for proper development of the mouse substantia nigra. J Neurosci 25:6721–6728. https://doi.org/10.1523/JNEUROSCI.0760-05.2005
Schenk S, Snow S, Horger BA (1991) Pre-exposure to amphetamine but not nicotine sensitizes rats to the motor activating effect of cocaine. Psychopharmacology 103:62–66. https://doi.org/10.1007/BF02244075
Schiff SR (1982) Conditioned dopaminergic activity. Biol Psychiatry 17:135–154
Segal DS, Mandell AJ (1974) Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255. https://doi.org/10.1016/0091-3057(74)90060-4
Sequeira-Cordero A, Brenes JC (2021) Time-dependent changes in striatal monoamine levels and gene expression following single and repeated amphetamine administration in rats. Eur J Pharmacol 904:174148. https://doi.org/10.1016/j.ejphar.2021.174148
Shi WX, Pun CL, Zhang XX, Jones MD, Bunney BS (2000) Dual effects of D-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors. J Neurosci 20:3504–3511. https://doi.org/10.1523/JNEUROSCI.20-09-03504.2000
Shibata S, Minamoto Y, Ono M, Watanabe S (1994) Aging impairs methamphetamine-induced free-running and anticipatory locomotor activity rhythms in rats. Neurosci Lett 172:107–110. https://doi.org/10.1016/0304-3940(94)90673-4
Shibata S, Ono M, Fukuhara N, Watanabe S (1995) Involvement of dopamine, N-methyl-D-aspartate and sigma receptor mechanisms in methamphetamine-induced anticipatory activity rhythm in rats. J Pharmacol Exp Ther 274:688–694
Shuster L, Yu G, Bates A (1977) Sensitization to cocaine stimulation in mice. Psychopharmacology 52:185–190. https://doi.org/10.1007/BF00439108
Smith KS, Bucci DJ, Luikart BW, Mahler SV (2016) DREADDS: Use and application in behavioral neuroscience. Behav Neurosci 130:137–155. https://doi.org/10.1037/bne0000135
Soumier A, Sibille E (2014) Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice. Neuropsychopharmacology 39:2252–2262. https://doi.org/10.1038/npp.2014.76
Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365. https://doi.org/10.1124/pr.109.001933
Sternson SM, Roth BL (2014) Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci 37:387–407. https://doi.org/10.1146/annurev-neuro-071013-014048
Stewart J, Badiani A (1993) Tolerance and sensitization to the behavioral effects of drugs. Behav Pharmacol 4:289–312
Subramaniyan M, Dani JA (2015) Dopaminergic and cholinergic learning mechanisms in nicotine addiction. Ann N Y Acad Sci 1349:46–63. https://doi.org/10.1111/nyas.12871
Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108
Taylor JR, Jentsch JD (2001) Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3,4- methylenedioxymethamphetamine (“Ecstasy”). Biol Psychiatry 50:137–143. https://doi.org/10.1016/s0006-3223(01)01106-4
Tilson HA, Rech RH (1973) Conditioned drug effects and absence of tolerance to d-amphetamine induced motor activity. Pharmacol Biochem Behav 1:149–153. https://doi.org/10.1016/0091-3057(73)90091-9
Tirelli E, Terry P (1998) Amphetamine-induced conditioned activity and sensitization: the role of habituation to the test context and the involvement of Pavlovian processes. Behav Pharmacol 9:409–419. https://doi.org/10.1097/00008877-199809000-00004
Torre-Muruzabal T, Devoght J, Van den Haute C, Brone B, Van der Perren A, Baekelandt V (2019) Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an alpha-synuclein based rat model for Parkinson’s Disease Acta. Neuropathol Commun 7:160. https://doi.org/10.1186/s40478-019-0814-3
Tsai HC, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L, Deisseroth K (2009) Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324:1080–1084. https://doi.org/10.1126/science.1168878
Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (2014) Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. Neuron 83:404–416. https://doi.org/10.1016/j.neuron.2014.05.043
Ungless MA, Grace AA (2012) Are you or aren’t you? Challenges associated with physiologically identifying dopamine neurons. Trends Neurosci 35:422–430. https://doi.org/10.1016/j.tins.2012.02.003
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587. https://doi.org/10.1038/35079077
Ungless MA, Magill PJ, Bolam JP (2004) Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 303:2040–2042. https://doi.org/10.1126/science.1093360
Urban DJ et al (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404–1415. https://doi.org/10.1038/npp.2015.293
Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120. https://doi.org/10.1007/s002130000493
Vanderschuren LJ, Schmidt ED, De Vries TJ, Van Moorsel CA, Tilders FJ, Schoffelmeer AN (1999) A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J Neurosci 19:9579–9586. https://doi.org/10.1523/JNEUROSCI.19-21-09579.1999
Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839. https://doi.org/10.1016/j.neubiorev.2003.11.001
Vezina P, Leyton M (2009) Conditioned cues and the expression of stimulant sensitization in animals and humans. Neuropharmacology 56(Suppl 1):160–168. https://doi.org/10.1016/j.neuropharm.2008.06.070
Volkow ND et al (1997) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830–833. https://doi.org/10.1038/386830a0
Volkow ND et al (2007) Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 27:12700–12706. https://doi.org/10.1523/JNEUROSCI.3371-07.2007
Volkow ND et al (2014) Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Mol Psychiatry 19:1037–1043. https://doi.org/10.1038/mp.2014.58
Wang GJ et al (2012) Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry 17:918–925. https://doi.org/10.1038/mp.2011.86
Weiss F, Hurd YL, Ungerstedt U, Markou A, Plotsky PM, Koob GF (1992) Neurochemical correlates of cocaine and ethanol self-administration. Ann N Y Acad Sci 654:220–241. https://doi.org/10.1111/j.1749-6632.1992.tb25970.x
White FJ, Wang RY (1984) Electrophysiological evidence for A10 dopamine autoreceptor subsensitivity following chronic D-amphetamine treatment. Brain Res 309:283–292. https://doi.org/10.1016/0006-8993(84)90594-8
Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720. https://doi.org/10.1016/s0301-0082(97)00090-7
Wyvell CL, Berridge KC (2000) Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J Neurosci 20:8122–8130. https://doi.org/10.1523/JNEUROSCI.20-21-08122.2000
Xue J et al (2022) Midbrain dopamine neurons arbiter OCD-like behavior. Proc Natl Acad Sci U S A 119:e2207545119. https://doi.org/10.1073/pnas.2207545119
Yang PB, Swann AC, Dafny N (2003) Chronic pretreatment with methylphenidate induces cross-sensitization with amphetamine. Life Sci 73:2899–2911. https://doi.org/10.1016/s0024-3205(03)00673-8
Yates JW, Meij JT, Sullivan JR, Richtand NM, Yu L (2007) Bimodal effect of amphetamine on motor behaviors in C57BL/6 mice. Neurosci Lett 427:66–70. https://doi.org/10.1016/j.neulet.2007.09.011
Yun S et al (2018) Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat Med 24:658–666. https://doi.org/10.1038/s41591-018-0002-1
Zhang XF, Hu XT, White FJ, Wolf ME (1997) Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J Pharmacol Exp Ther 281:699–706
Zhang M, Balmadrid C, Kelley AE (2003) Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat. Behav Neurosci 117:202–211. https://doi.org/10.1037/0735-7044.117.2.202
Zike ID et al (2017) OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. Proc Natl Acad Sci U S A 114:5719–5724. https://doi.org/10.1073/pnas.1701736114
Zweifel LS, Argilli E, Bonci A, Palmiter RD (2008) Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Neuron 59:486–496. https://doi.org/10.1016/j.neuron.2008.05.028
Zweifel LS et al (2009) Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc Natl Acad Sci U S A 106:7281–7288. https://doi.org/10.1073/pnas.0813415106
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This work was funded by NIH Grant MH114296.
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JV has served on advisory boards for Roche, Novartis, and SynapDx; has received research funding from NIH, Simon’s Foundation, Roche, Novartis, SynapDx, Forest, Janssen, Yamo, MapLight, Seaside Therapeutics, and Acadia Pharmaceuticals; and has received editorial stipends from Wiley and Springer. The remaining authors declare no competing interests.
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Chohan, M.O., Fein, H., Mirro, S. et al. Repeated chemogenetic activation of dopaminergic neurons induces reversible changes in baseline and amphetamine-induced behaviors. Psychopharmacology 240, 2545–2560 (2023). https://doi.org/10.1007/s00213-023-06448-x
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DOI: https://doi.org/10.1007/s00213-023-06448-x