Skip to main content
SpringerLink
Log in

Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats

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

Abstract

The subthalamic nucleus (STN) is a key node in cortico-basal-ganglia thalamic circuits, guiding behavioral output through its position as an excitatory relay of the striatal indirect pathway and its direct connections with the cortex. There have been conflicting results regarding the role of the STN in addiction-related behavior to psychostimulants, and little is known with respect to the role of STN afferents. To address this, we used viral vectors to express DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in the STN of rats in order to bidirectionally manipulate STN activity during the induction of amphetamine sensitization. In addition, we used a Cre-recombinase dependent Gi/o-coupled DREADD approach to transiently inhibit afferents from ventral pallidum (a subcomponent of the striatal indirect pathway) or the prelimbic cortex (a subcomponent of the cortico-STN hyperdirect pathway). Despite inducing mild hyperactivity in non-drug controls, stimulation of STN neurons with Gq-DREADDs blocked the development and persistence of amphetamine sensitization as well as conditioned responding. In contrast, inhibition of STN neurons with Gi/o-DREADDs enhanced the induction of sensitization without altering its persistence or conditioned responding. Chemogenetic inhibition of afferents from ventral pallidum had no effect on amphetamine sensitization but blocked conditioned responding whereas chemogenetic inhibition of afferents from prelimbic cortex attenuated the persistence of sensitization as well as conditioned responding. These results suggest the STN and its afferents play complex roles in the regulation of amphetamine sensitization and highlight the need for further characterization of how integration of inputs within STN guide behavior.

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
Fig. 4

Similar content being viewed by others

References

  • Alkemade A (2013) Subdivisions and anatomical boundaries of the subthalamic nucleus. J Neurosci 33:9233–9234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allain F, Samaha AN (2019) Revisiting long-access versus short-access cocaine self-administration in rats: intermittent intake promotes addiction symptoms independent of length. Addict Biol 24:641–651

    Article  CAS  PubMed  Google Scholar 

  • Anagnostaras SG, Robinson TE (1996) Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning. Behav Neurosci 110:1397–1414

    Article  CAS  PubMed  Google Scholar 

  • Andrén PE, Levin ED, Liminga U, Gunne L (1995) Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset. Brain Res Bull 36:301–307

    Article  PubMed  Google Scholar 

  • 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 104:5163–5168

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baunez C, Dias C, Cador M, Amalric M (2005) The subthalamic nucleus exerts opposite control on cocaine and “natural” rewards. Nat Neurosci 8:484–489

    Article  CAS  PubMed  Google Scholar 

  • Bentzley BS, Aston-Jones G (2016) Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. Addict Biol

  • Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25:515–532

    Article  CAS  PubMed  Google Scholar 

  • Bosch C, Mailly P, Degos B, Deniau JM, Venance L (2012) Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice. Neuroscience 215:31–41

    Article  CAS  PubMed  Google Scholar 

  • Burnett CJ, Krashes MJ (2016) Resolving behavioral output via chemogenetic designer receptors exclusively activated by designer drugs. J Neurosci 36:9268–9282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA (1990) Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat. Brain Res

  • Castro-Alamancos MA, Borrel J (1995) Functional recovery of forelimb response capacity after forelimb primary motor cortex damage in the rat is due to the reorganization of adjacent areas of cortex. Neuroscience 68:793–805

    Article  CAS  PubMed  Google Scholar 

  • Chu H-Y, Atherton JF, Wokosin D, Surmeier DJ, Bevan MD (2015) Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron 85:364–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delfs JM, Ciaramitaro VM, Parry TJ, Chesselet MF (1995) Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats. J Neurosci 15:6562–6575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferguson SM, Neumaier JF (2012) Grateful DREADDs: engineered receptors reveal how neural circuits regulate behavior. Neuropsychopharmacology 37:296–297

    Article  PubMed  Google Scholar 

  • Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PEM, Dong Y, Roth BL, Neumaier JF (2011) Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 14:22–24

    Article  CAS  PubMed  Google Scholar 

  • Ferguson SM, Phillips PEM, Roth BL, Wess J, Neumaier JF (2013) Direct-pathway striatal neurons regulate the retention of decision-making strategies. J Neurosci 33:11668–11676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia AF, Webb IG, Yager LM, Seo MB, Ferguson SM (2020) Intermittent but not continuous access to cocaine produces individual variability in addiction susceptibility in rats. Psychopharmacology 237:2929–2941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Groenewegen HJ, Berendse HW (1990) Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat. J Comp Neurol 294:607–622

    Article  CAS  PubMed  Google Scholar 

  • Haynes WIA, Haber SN (2013) The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation. J Neurosci 33:4804–4814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantak KM, Yager LM, Brisotti MF (2013) Impact of medial orbital cortex and medial subthalamic nucleus inactivation, individually and together, on the maintenance of cocaine self-administration behavior in rats. Behav Brain Res 238:1–9

    Article  CAS  PubMed  Google Scholar 

  • Kerstetter KA, Wunsch AM, Nakata KG, Donckels E, Neumaier JF, Ferguson SM (2015) Corticostriatal afferents modulate responsiveness to psychostimulant drugs and drug-associated stimuli. Neuropsychopharmacology

  • Kita H, Kitai ST (1987) Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method. J Comp Neurol 260:435–452

    Article  CAS  PubMed  Google Scholar 

  • Kita T, Osten P, Kita H (2014) Rat subthalamic nucleus and zona incerta share extensively overlapped representations of cortical functional territories. J Comp Neurol 522:4043–4056

    Article  PubMed  PubMed Central  Google Scholar 

  • Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3:760–773

    Article  PubMed  PubMed Central  Google Scholar 

  • Kremer EJ, Boutin S, Chillon M, Danos O (2000) Canine adenovirus vectors: an alternative for adenovirus-mediated gene transfer. J Virol 74:505–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lévesque J-C, Parent A (2005) GABAergic interneurons in human subthalamic nucleus. Mov Disord 20:574–584

    Article  PubMed  Google Scholar 

  • Lobo MK, Nestler EJ (2011) The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Front Neuroanat 5:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Luigjes J, van den Brink W, Feenstra M, van den Munckhof P, Schuurman PR, Schippers R, Mazaheri A, De Vries TJ, Denys D (2012) Deep brain stimulation in addiction: a review of potential brain targets. Mol Psychiatry 17:572–583

    Article  CAS  PubMed  Google Scholar 

  • Lüscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69:650–663

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nambu A, Takada M, Inase M, Tokuno H (1996) Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. J Neurosci 16:2671–2683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  CAS  PubMed  Google Scholar 

  • Paulson PE, Robinson TE (1991) Sensitization to systemic amphetamine produces an enhanced locomotor response to a subsequent intra-accumbens amphetamine challenge in rats. Psychopharmacology 104:140–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pelloux Y, Baunez C (2013) Deep brain stimulation for addiction: why the subthalamic nucleus should be favored. Curr Opin Neurobiol 23:713–720

    Article  CAS  PubMed  Google Scholar 

  • Pelloux Y, Baunez C (2017) Targeting the subthalamic nucleus in a preclinical model of alcohol use disorder. Psychopharmacology 234:2127–2137

    Article  CAS  PubMed  Google Scholar 

  • Pelloux Y, Degoulet M, Tiran-Cappello A, Cohen C, Lardeux S, George O, Koob GF, Ahmed SH, Baunez C (2018) Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use. Mol Psychiatry 23:2266–2276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierce RC, Vassoler FM (2013) Deep brain stimulation for the treatment of addiction: basic and clinical studies and potential mechanisms of action. Psychopharmacology 229:487–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prasad AA, McNally GP (2016) Ventral pallidum output pathways in context-induced reinstatement of alcohol seeking. J Neurosci 36:11716–11726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95(Suppl 2):S91-117

    PubMed  Google Scholar 

  • Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Philos. Trans. R. Soc. Lond., B. Biol Sci 363:3137–3146

    Article  Google Scholar 

  • Romansky KV, Usunoff KG, Ivanov DP, Galabov GP (1979) Corticosubthalamic projection in the cat: an electron microscopic study. Brain Res 163:319–322

    Article  CAS  PubMed  Google Scholar 

  • Roth BL (2016) DREADDs for neuroscientists. Neuron 89:683–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C (2010) Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proc Natl Acad Sci USA 107:1196–1200

    Article  CAS  PubMed  Google Scholar 

  • Segal DS, Mandell AJ (1974) Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255

    Article  CAS  PubMed  Google Scholar 

  • Smith KS, Bucci DJ, Luikart BW, Mahler SV (2016) DREADDS: use and application in behavioral neuroscience. Behav Neurosci 130:137–155

    Article  PubMed  PubMed Central  Google Scholar 

  • Temel Y, Blokland A, Steinbusch HWM, Visser-Vandewalle V (2005) The functional role of the subthalamic nucleus in cognitive and limbic circuits. Prog Neurobiol 76:393–413

    Article  CAS  PubMed  Google Scholar 

  • Uslaner JM, Yang P, Robinson TE (2005) Subthalamic nucleus lesions enhance the psychomotor-activating, incentive motivational, and neurobiological effects of cocaine. J Neurosci 25:8407–8415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wade CL, Kallupi M, Hernandez DO, Breysse E, de Guglielmo G, Crawford E, Koob GF, Schweitzer P, Baunez C, George O (2017) High-frequency stimulation of the subthalamic nucleus blocks compulsive-like re-escalation of heroin taking in rats. Neuropsychopharmacology 42:1850–1859

    Article  PubMed  PubMed Central  Google Scholar 

  • Wall NR, Parra La, De M, Callaway EM, Kreitzer AC (2013) Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron 79:347–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    Article  CAS  PubMed  Google Scholar 

  • Wunsch AM, Yager LM, Donckels EA, Le CT, Neumaier JF, Ferguson SM (2017) Chemogenetic inhibition reveals midline thalamic nuclei and thalamo-accumbens projections mediate cocaine-seeking in rats. Eur J Neurosci 46:1850–1862

    Article  PubMed  PubMed Central  Google Scholar 

  • Yager LM, Garcia AF, Wunsch AM, Ferguson SM (2015) The ins and outs of the striatum: role in drug addiction. Neuroscience 301:529–541

    Article  CAS  PubMed  Google Scholar 

  • Yager LM, Garcia AF, Donckels EA, Ferguson SM (2019) Chemogenetic inhibition of direct pathway striatal neurons normalizes pathological, cue-induced reinstatement of drug-seeking in rats. Addict Biol 24:251–264

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. John Neumaier and Dr. Michelle Kelly for providing the CAV2-Cre virus.

Funding

This work was supported by grants from the National Institute on Drug Abuse (R01DA036582 and R01DA036582-S1 to SMF).

Author information

Authors and Affiliations

  1. Graduate Program in Neuroscience, University of Washington, Seattle, WA, 98195, USA

    K. G. Nakata & Susan M. Ferguson

  2. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, 98101, USA

    K. G. Nakata, E. Yin, E. Sutlief & Susan M. Ferguson

  3. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA

    Susan M. Ferguson

  4. Addictions, Drug & Alcohol Insitute, University of Washington, Seattle, WA, 98195, USA

    Susan M. Ferguson

Authors
  1. K. G. Nakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Sutlief
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan M. Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KGN, EY, and ES performed the behavioral and immunohistochemical experiments. KGN and SMF designed the experiments and wrote the manuscript.

Corresponding author

Correspondence to Susan M. Ferguson.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakata, K.G., Yin, E., Sutlief, E. et al. Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats. Psychopharmacology 239, 353–364 (2022). https://doi.org/10.1007/s00213-021-05985-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-021-05985-7

Keywords

Search

Navigation