Determination of neurotensin projections to the ventral tegmental area in mice

Woodworth, Hillary L.; Brown, Juliette A.; Batchelor, Hannah M; Bugescu, Raluca; Leinninger, Gina M.

doi:10.1016/j.npep.2018.02.003

Cited by 32 publications

(14 citation statements)

References 113 publications

(174 reference statements)

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“…Hypothalamic nuclei in the forebrain, as we have briefly discussed, consist of classic homeostatic neural regulators. In parallel with hindbrain and midbrain pathways, hypothalamic brain regions, in particular the lateral hypothalamic area (LHA), send direct and reciprocal projections to the VTA and NAc ( 3 , 201 – 207 ) and provide another set of circuits through which homeostatic signals can be relayed to the mesolimbic dopamine system. Several studies have delved into the role of LHA-VTA pathways in reward related behaviors, while others have assessed the relationship between homeostatic LHA signaling and the VTA.…”

Section: Neuronal Inputs To Mesolimbic Pathways That Regulate Homeostmentioning

confidence: 99%

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

2018

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Motivated behaviors are often initiated in response to perturbations of homeostasis. Indeed, animals and humans have fundamental drives to procure (appetitive behaviors) and eventually ingest (consummatory behaviors) substances based on deficits in body fluid (e.g., thirst) and energy balance (e.g., hunger). Consumption, in turn, reinforces motivated behavior and is therefore considered rewarding. Over the years, the constructs of homeostatic (within the purview of the hypothalamus) and reward (within the purview of mesolimbic circuitry) have been used to describe need-based vs. need-free consumption. However, many experiments have demonstrated that mesolimbic circuits and “higher-order” brain regions are also profoundly influenced by changes to physiological state, which in turn generate behaviors that are poised to maintain homeostasis. Mesolimbic pathways, particularly dopamine neurons of the ventral tegmental area (VTA) and their projections to nucleus accumbens (NAc), can be robustly modulated by a variety of energy balance signals, including post-ingestive feedback relaying nutrient content and hormonal signals reflecting hunger and satiety. Moreover, physiological states can also impact VTA-NAc responses to non-nutritive rewards, such as drugs of abuse. Coupled with recent evidence showing hypothalamic structures are modulated in anticipation of replenished need, classic boundaries between circuits that convey perturbations in homeostasis and those that drive motivated behavior are being questioned. In the current review, we examine data that have revealed the importance of mesolimbic dopamine neurons and their downstream pathways as a dynamic neurobiological mechanism that provides an interface between physiological state, perturbations to homeostasis, and reward-seeking behaviors.

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Section: Neuronal Inputs To Mesolimbic Pathways That Regulate Homeostmentioning

confidence: 99%

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

2018

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“…6 The VTA receives dense neurotensinergic innervation from the lateral hypothalamus, the preoptic area, and the nucleus accumbens. 8 The overlap between the mesolimbic dopamine and neurotensin systems is a strong indication of a functional interaction controlling motivated behavior, from feeding to the reinforcing properties of psychostimulants such as methamphetamine (METH). 1,7,[9][10][11] Considerable evidence supports a functional synergism of the central effects of neurotensin and METH reinforcing efficacy.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, while NtsR2 is expressed in some dopamine neurons, their predominant localization in the VTA is thought to be glial 6 . The VTA receives dense neurotensinergic innervation from the lateral hypothalamus, the preoptic area, and the nucleus accumbens 8 . The overlap between the mesolimbic dopamine and neurotensin systems is a strong indication of a functional interaction controlling motivated behavior, from feeding to the reinforcing properties of psychostimulants such as methamphetamine (METH) 1,7,9–11 …”

Section: Introductionmentioning

confidence: 99%

Neurotensin receptor 1 deletion decreases methamphetamine self‐administration and the associated reduction in dopamine cell firing

2019

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We previously reported that a non-selective pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here, we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) on METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired self-administration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. Non-bursting dopamine neurons from KO mice fired at slower rates than those from WT mice, supporting an excitatory role for NtsR1 on VTA dopamine neuronal activity. In WT mice, a history of METH self-administration decreased dopamine cell firing frequency compared with cells from drug-naïve controls. NtsR1 KO and HET mice did not exhibit this decline in dopamine cell firing activity after METH experience. We also observed an increase in population activity following METH self-administration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior and indicate that ablation of NtsR1 prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.

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“…NtsR1 is highly expressed in the dopamine neurons that are located in the rostral aspect of the VTA with well-defined mesolimbic projections [7,8]. Furthermore, the VTA receives dense neurotensinergic innervation from the lateral hypothalamus, the preoptic area, and the nucleus accumbens [9]. The overlap between the dopamine and the neurotensin systems in the mesolimbic pathway is a strong indication of a functional interaction controlling motivated behavior, including the reinforcing properties of psychostimulants such as methamphetamine (METH) [1,10,11].…”

Section: Introductionmentioning

confidence: 99%

Neurotensin receptor 1 deletion suppresses methamphetamine self-administration and the associated reduction in dopamine cell firing

Lopez

Sharma

Beckstead

2019

Preprint

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We previously reported that pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) in METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired selfadministration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. In WT METH-experienced mice, dopamine cell firing frequency dramatically decreases compared to WT drug-naïve mice. NtsR1 KO and HET mice did not exhibit this decline of dopamine cell firing activity after prolonged METH selfadministration. We also observed an increase in population activity following METH selfadministration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior, and ablation of NtsR1 receptors prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.Here we combined METH self-administration in mice with a genetic deletion of NtsR1 with in vivo single unit recordings of VTA dopamine neurons. We observed a decrease in METH self-administration and drug-seeking behavior in NtsR1 heterozygotes (HET) and knockouts (KO) versus wild type (WT) littermates. We also observed that METH self-administration increased the number of low firing rate dopamine neurons in vivo, an effect that was eliminated in mice lacking NtsR1. MATERIALS AND METHODSAnimals: Ntsr1 tm1Dgen mice (Jackson Stock #005826, Bar Harbor, ME) were generously provided by Dr. Gina M. Leinninger and were bred with C57Bl/6J mice, also from Jackson. A total of 36 adult male littermates were used, aged 6-8 months (KO, n= 10; HET, n=13; WT, n=13). Mice were group housed (3-5 per cage) in polycarbonate boxes with rodent bedding and shredding material and kept on a 12/12-hour reverse light-dark cycle (lights off at 0900 h) with ad libitum access to food and water. All procedures were approved by the Institutional Animal Care and Use Committee at the Oklahoma Medical Research Foundation.Genotyping: DNA from offspring was extracted from mouse ear punches using Extract-N-Amp® kit (Sigma, St. Louis, MO) and genotyped using a multiplex PCR reaction; primers at 1 µM final concentration used were: 5' CTC TAA TGT GCC ACA GCT CAG AGA G 3`, 5' CAG CAA CCT GGA CGT GAA CAC TGA C 3' and 5' CCA AGC GGC TTC GGC CAG TAA CGT T 3'. PCR conditions used were: 94ºC for 30 sec, 60ºC for 30 sec, and 72ºC for 2 min, for 35 cycles followed by a final amplif...

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Determination of neurotensin projections to the ventral tegmental area in mice

Cited by 32 publications

References 113 publications

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

Neurotensin receptor 1 deletion decreases methamphetamine self‐administration and the associated reduction in dopamine cell firing

Neurotensin receptor 1 deletion suppresses methamphetamine self-administration and the associated reduction in dopamine cell firing

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