Abstract
Rationale
Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA.
Objective
We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later.
Results
The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice.
Conclusions
These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs.
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References
Alderson HL, Latimer P, Winn P (2005) Involvement of the laterodorsal tegmental nucleus in the locomotor response to repeated nicotine administration. Neurosci Lett 380:335–339. https://doi.org/10.1016/j.neulet.2005.01.067
Argilli E, Sibley DR, Malenka RC, England PM, Bonci A (2008) Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J Neurosci 28:9092–10000. https://doi.org/10.1523/JNEUROSCI.1001-08.2008
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
Calu DJ, Kawa AB, Marchant NJ, Navarre BM, Henderson MJ, Chen B, Yau HJ, Bossert JM, Schoenbaum G, Deisseroth K, Harvey BK, Hope BT, Shaham Y (2013) Optogenetic inhibition of dorsal medial prefrontal cortex attenuates stress-induced reinstatement of palatable food seeking in female rats. J Neurosci 33:214–226. https://doi.org/10.1523/JNEUROSCI.2016-12.2013
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
Carr CC, Ferrario CR, Robinson TE (2020) Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization. Psychopharmacology 237:1795–1812. https://doi.org/10.1007/s00213-020-05500-4
Chandra R, Lenz JD, Gancarz AM, Chaudhury D, Schroeder GL, Han MH, Cheer JF, Dietz DM, Lobo MK (2013) Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1. Front Mol Neurosci 6:13. https://doi.org/10.3389/fnmol.2013.00013
Churchill L, Swanson CJ, Urbina M, Kalivas PW (1999) Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J Neurochem 72:2397–2403. https://doi.org/10.1046/j.1471-4159.1999.0722397.x
Cornwall J, Cooper JD, Phillipson OT (1990) Afferent and efferent connections of the laterodorsal tegmental nucleus in the rat. Brain Res Bull 25:271–284. https://doi.org/10.1016/0361-9230(90)90072-8
Danjo T, Yoshimi K, Funabiki K, Yawata S, Nakanishi S (2014) Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens. Proc Natl Acad Sci USA 111:6455–6460. https://doi.org/10.1073/pnas.1404323111
Dautan D, Huerta-Ocampo I, Witten IB, Deisseroth K, Bolam JP, Gerdjikov T, Mena-Segovia J (2014) A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem. J Neurosci 34:4509–4518. https://doi.org/10.1523/JNEUROSCI.5071-13.2014
Dautan D, Souza AS, Huerta-Ocampo I, Valencia M, Assous M, Witten IB, Deisseroth K, Tepper JM, Bolam JP, Gerdjikov TV, Mena-Segovia J (2016) Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits. Nat Neurosci 39:1025–1033. https://doi.org/10.1038/nn.4335
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 USA 85:5274–5278. https://doi.org/10.1073/pnas.85.14.5274
Dunn JM, Inderwies BR, Licata SC, Pierce RC (2005) Repeated administration of AMPA or a metabotropic glutamate receptor agonist into the rat ventral tegmental area augments the subsequent behavioral hyperactivity induced by cocaine. Psychopharmacology 179:172–180. https://doi.org/10.1007/s00213-004-2054-9
Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J Neurosci 16:274–282. https://doi.org/10.1523/JNEUROSCI.16-01-00274.1996
Forster GL, Blaha CD (2000) Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur J Neurosci 23:3596–3604. https://doi.org/10.1046/j.1460-9568.2000.00250.x
Forster GL, Yeomans JS, Takeuchi J, Blaha CD (2002) M5 muscarinic receptors are required for prolonged accumbal dopamine release after electrical stimulation of the pons in mice. J Neurosci 22:RC190. https://doi.org/10.1523/JNEUROSCI.22-01-j0001.2002
Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates. Elsevier Academic Press, San Diego, CA
Geisler S, Wise RA (2008) Functional implications of glutamatergic projections to the ventral tegmental area. Rev Neurosci 19:227–244. https://doi.org/10.1515/REVNEURO.2008.19.4-5.227
Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743. https://doi.org/10.1523/JNEUROSCI.0012-07.2007
Glick SD, Hinds PA (1984) Sex differences in sensitization to cocaine-induced rotation. Eur J Pharmacol 99:119–121. https://doi.org/10.1016/0014-2999(84)90442-4
Good CH, Lupica CR (2010) Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs. J Neurosci 30:7900–7909. https://doi.org/10.1523/JNEUROSCI.1507-10.2010
Harrod SB, Booze RM, Welch M, Browning CE, Mactutus CF (2005) Acute and repeated intravenous cocaine-induced locomotor activity is altered as a function of sex and gonadectomy. Pharmacol Biochem Behav 82:170–181. https://doi.org/10.1016/j.pbb.2005.08.005
Henry DJ, Hu XT, White FJ (1998) Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization. Psychopharmacology 140:233–242. https://doi.org/10.1007/s002130050762
Hu M, Becker JB (2003) Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23:693–699. https://doi.org/10.1523/JNEUROSCI.23-02-00693.2003
Kalivas PW, Duffy P (1995) D1 receptors modulate glutamate transmission in the ventral tegmental area. J Neurosci 15:5379–5388. https://doi.org/10.1523/JNEUROSCI.15-07-05379.1995
Kalivas PW, Pierce RC, Cornish J, Sorg BA (1998) A role for sensitization in craving and relapse in cocaine addiction. J Psychopharmacol 12:49–53. https://doi.org/10.1177/026988119801200107
Kawa AB, Bentzley BS, Robinson TE (2016) Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior. Psychopharmacology 233:3587–3602. https://doi.org/10.1007/s00213-016-4393-8
Kawa AB, Valenta AC, Kennedy RT, Robinson TE (2019) Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration. Eur J Neurosci 50:2663–2682. https://doi.org/10.1111/ejn.14418
Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212–217. https://doi.org/10.1038/nature11527
Li Y, Hu XT, Berney TG, Vartanian AJ, Stine CD, Wolf ME, White FJ (1999) Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations. Synapse 34:169–180. https://doi.org/10.1002/(SICI)1098-2396(19991201)34:3%3c169::AID-SYN1%3e3.0.CO;2-C
Lodge DJ, Grace AA (2006) The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons. Proc Natl Acad Sci USA 103:5167–5172. https://doi.org/10.1073/pnas.0510715103
Mahn M, Prigge M, Ron S, Levy R, Yizhar O (2016) Biophysical constraints of optogenetic inhibition at presynaptic terminals. Nat Neurosci 19:554–556. https://doi.org/10.1038/nn.4266
McCutcheon JE, Cone JC, Sinon CG, Fortin SM, Kantak PA, Witten IB, Deisseroth K, Stuber GD, Roitman MF (2014) Optical suppression of drug-evoked phasic dopamine release. Front Neural Circuits 8:114. https://doi.org/10.3389/fncir.2014.00114
Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201. https://doi.org/10.1016/0306-4522(83)90108-2
Nelson CL, Wetter JB, Milovanovic M, Wolf ME (2007) The laterodorsal tegmentum contributes to behavioral sensitization to amphetamine. Neuroscience 146:41–49. https://doi.org/10.1016/j.neuroscience.2007.01.027
Oakman S, Faris PL, Kerr PE, Cozzari C, Hartman BK (1995) Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area. J Neurosci 15:5859–5869. https://doi.org/10.1523/JNEUROSCI.15-09-05859.1995
Omelchenko N, Sesack SR (2005) Laterodorsal tegmental projections to identified cell populations in the rat ventral tegmental area. J Comp Neurol 483:217–235. https://doi.org/10.1002/cne.20417
Omelchenko N, Sesack SR (2007) Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources. Neuroscience 146:1259–1274. https://doi.org/10.1016/j.neuroscience.2007.02.016
Pierce RC, Born B, Adams M, Kalivas PW (1996) Repeated intra-ventral tegmental area administration of SKF-38393 induces behavioral and neurochemical sensitization to a subsequent cocaine challenge. J Pharmacol Exp Ther 278:384–392
Qi J, Zhang S, Wang HL, Wang H, de Jesus Aceves Buendia J, Hoffman AF, Lupica CR, Seal RP, Morales M (2014) A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons. Nat Commun 5:5390. https://doi.org/10.1038/ncomms6390
Robinson TE (1984) Behavioral sensitization: characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats. Psychopharmacology 84:466–475. https://doi.org/10.1007/BF00431451
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
Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582. https://doi.org/10.1016/s0896-6273(03)00021-7
Satoh K, Fibiger HC (1986) Cholinergic neurons of the laterodorsal tegmental nucleus: efferent and afferent connections. J Comp Neurol 253:277–302. https://doi.org/10.1002/cne.902530302
Semba K, Fibiger HC (1992) Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study. J Comp Neurol 323:387–410. https://doi.org/10.1002/cne.903230307
Sesack SR, Deutch AY, Roth RH, Bunney BS (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242. https://doi.org/10.1002/cne.902900205
Stefanik M, Moussawi K, Kupchik YM, Smith KC, Miller RL, Huff ML, Deisseroth K, Kalivas PW, LaLumiere RT (2013) Optogenetic inhibition of cocaine seeking in rats. Addict Biol 18:50–53. https://doi.org/10.1111/j.1369-1600.2012.00479.x
Steidl S, Veverka K (2015) Optogenetic excitation of LDTg axons in the VTA reinforces operant responding in rats. Brain Res 1614:86–93. https://doi.org/10.1016/j.brainres.2015.04.021
Steidl S, O’Sullivan S, Pilat D, Bubula N, Brown J, Vezina P (2017) Operant responding for optogenetic excitation of LDTg inputs to the VTA requires D1 and D2 dopamine receptor activation in the NAcc. Behav Brain Res 333:161–170. https://doi.org/10.1016/j.bbr.2017.06.045
Steidl S, Wang HL, Ordonez M, Zhang S, Morales M (2017) Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. Eur J Neurosci 45:559–571. https://doi.org/10.1111/ejn.13436
Steketee JD (2005) Cortical mechanisms of cocaine sensitization. Crit Rev Neurobiol 17:69–86. https://doi.org/10.1615/CritRevNeurobiol.v17.i2.20
Suto N, Austin JD, Tanabe LM, Kramer MK, Wright DA, Vezina P (2002) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner. Neuropsychopharmacology 27:970–979. https://doi.org/10.1016/S0893-133X(02)00379-2
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. https://doi.org/10.1038/sj.npp.1300075
Suto N, Tanabe LM, Austin JD, Creekmore E, Chauchau TP, Vezina P (2004) Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacology 29:2149–2159. https://doi.org/10.1038/sj.npp.1300533
Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K (2011) Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471:358–362. https://doi.org/10.1038/nature09820
Tzschentke TM, Schmidt WJ (1998) The development of cocaine-induced behavioral sensitization is affected by discrete quinolinic acid lesions of the prelimbic medial prefrontal cortex. Brain Res 795:71–76. https://doi.org/10.1016/S0006-8993(98)00254-6
Tzschentke TM, Schmidt WJ (1999) Functional heterogeneity of the rat medial prefrontal cortex: effects of discrete subarea-specific lesions on drug-induced conditioned place preference and behavioural sensitization. Eur J Neurosci 11:4099–4109. https://doi.org/10.1046/j.1460-9568.1999.00834.x
Tzschentke TM, Schmidt WJ (2000) Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization. Cereb Cortex 10:488–498. https://doi.org/10.1093/cercor/10.5.488
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 31:583–587. https://doi.org/10.1038/35079077
Van Haaren F, Meyer ME (1991) Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav 39:923–927. https://doi.org/10.1016/0091-3057(91)90054-6
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
Vezina P (1996) D1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area. J Neurosci 16:2411–2420. https://doi.org/10.1523/JNEUROSCI.16-07-02411.1996
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, Lorrain DS, Arnold GM, Austin JD, Suto N (2002) Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine. J Neurosci 22:4654–4662. https://doi.org/10.1523/JNEUROSCI.22-11-04654.2002
Wang HL, Morales M (2009) Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in rats. Eur J Neurosci 29:340–358. https://doi.org/10.1111/j.1460-9568.2008.06576.x
Wang X, Yang H, Pan L, Hao S, Wu X, Zhan L, Liu Y, Meng F, Lou H, Shen Y, Duan S, Wang H (2019) Brain-wide mapping of mono-synaptic afferents to different cell types in the laterodorsal tegmentum. Neurosci Bull 35:781–790. https://doi.org/10.1007/s12264-019-00397-2
Wang HL, Chakraborti T, Ng T, Yamaguchi T, Morales M (2010) Ventral tegmental input from the pedunculopontine and laterodorsal tegmental nuclei is dominated by glutamatergic and GABAergic, rather than cholinergic neurons. Program No. 366.22. 2010 Neuroscience Meeting Planner. Society for Neuroscience, San Diego
White FJ, Hu XT, Zhang XF, Wolf ME (1995) Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 273:445–454
Wise RA (2005) Forebrain substrates of reward and motivation. J Comp Neurol 493:115–121. https://doi.org/10.1002/cne.20689
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
Woolf NJ (1991) Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol 37:475–524. https://doi.org/10.1016/0301-0082(91)90006-M
Woolf NJ, Butcher LL (1986) Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain. Brain Res Bull 16:603–637. https://doi.org/10.1016/0361-9230(86)90134-6
Xiao C, Cho JR, Zhou C, Treweek JB, Chan K, McKinney SL, Yang B, Gradinaru V (2016) Cholinergic mesopontine signals govern locomotion and reward through dissociable midbrain pathways. Neuron 90:333–347. https://doi.org/10.1016/j.neuron.2016.03.028
Yeomans JS, Mathur A, Tampakeras M (1993) Rewarding brain stimulation: role of tegmental cholinergic neurons that activate dopamine neurons. Behav Neurosci 107:1077–1087. https://doi.org/10.1037/0735-7044.107.6.1077
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
Acknowledgements
We thank Dr. Karl Deisseroth for making viral vector constructs AAV5-EF1α-DIO-NpHR3.0-eYFP and AAV5-EF1a-DIO-eYFP available to us.
Funding
This work was funded by the US National Institutes of Health (NIH) Grants R15 DA041694-01 to SS and R01 DA09397 to PV.
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Puranik, A., Buie, N., Arizanovska, D. et al. Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice. Psychopharmacology 239, 3263–3276 (2022). https://doi.org/10.1007/s00213-022-06209-2
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DOI: https://doi.org/10.1007/s00213-022-06209-2