The contributions of midbrain dopamine (DA) systems to drug reward and to drug sensitization are clear. It is not clear which brain circuits most importantly contribute to changes in DA neurons following drug exposure. The laterodorsal tegmental nucleus (LDTg) provides parallel cholinergic (ACh) and glutamatergic (GLU) inputs to ventral tegmental area (VTA) DA neurons that importantly control the activity of midbrain DA systems. In rats and mice ACh and GLU inputs to the VTA modulate the rewarding effects of cocaine and of opiates. Understanding the contributions of LDTg ACh or GLU inputs to the VTA to drug reward and addiction requires a means of selectively targeting these inputs. Preliminary results in Cre transgenic mice indicate that selective optogenetic excitation (via channelrhodopsin 2) of LDTg ACh but not GLU axons in the VTA is rewarding. Selective optogenetic inhibition of LDTg GLU cells (via halorhodopsin) reduces the induction of cocaine locomotor sensitization (an established model that quantifies behavioral adaptations induced by repeated drug exposure thought to reflect underlying neural changes important for drug addiction) but does not affect the acquisition of cocaine conditioned place preference (CPP - an established model that tests primary drug reward). This suggests that these LDTg GLU afferents to the VTA may be a site at which GLU plasticity is important for addictive behaviors to occur. Considering the above, this project will test the hypothesis that LDTg ACh afferents to the VTA are important for reinforcement and for drug reward, and that LDTg GLU afferents to the VTA are important for the induction of sensitization following repeated drug exposure.
Aim 1 focuses on establishing that excitation of LDTg ACh but not GLU axons to the VTA is rewarding.
Aim 2 focuses on determining the contributions of LDTg ACh afferents to the VTA to cocaine (typical stimulant drug) and to morphine (typical opiate drug) CPP, by optogenetically inhibiting LDTg ACh or GLU axons in the VTA during drug conditioning.
Aim 3 focuses on establishing the importance of LDTg GLU inputs to the VTA in the induction of drug sensitization by inhibiting LDTg GLU axons in the VTA during repeated cocaine- or morphine-induced locomotion testing. The critical contribution of the proposed research will be to define, for the first time, the sourc of VTA glutamate and acetylcholine that are important for drug reward and for sensitization. Characterizing the role of select LDTg inputs to the VTA in drug reward and locomotor sensitization will inform future studies aimed at developing mechanistically based interventions, targeting a specific neural circuit, seeking to prevent the long-lasting adaptations in DA neuron function that underlie addictive behaviors. In line with the goals of the R15 funding mechanism these experiments will continue to expose several Loyola University Chicago (a primary educational institution) undergraduate students to research in Behavioral Neuroscience.

Public Health Relevance

It is known that the brain chemicals acetylcholine and glutamate each interact with the brain dopamine system (critically implicated in drug addiction) and that these interactions are important for the rewarding effects of drugs of abuse or for the behavioral changes that result from repeated drug exposure, but the critical brain sources that provide acetylcholine and glutamate input to the dopamine system are not known. This grant will use optogenetic techniques to selectively target acetylcholine and glutamate inputs to the dopamine system that originate from a particular brain source and define their contributions to drug reward and to the behavioral changes that result from repeated drug exposure. The expected results will define a brain circuit important for drug reward and addiction and this will guide the development of mechanistically based interventions designed to prevent dopamine neural adaptations that underlie addictive behaviors.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Sorensen, Roger
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Loyola University Chicago
Schools of Arts and Sciences
United States
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Steidl, Stephan; Wasserman, David I; Blaha, Charles D et al. (2017) Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons. Neurosci Biobehav Rev 83:72-82
Steidl, Stephan; Dhillon, Ekamjeet S; Sharma, Natasha et al. (2017) Muscarinic cholinergic receptor antagonists in the VTA and RMTg have opposite effects on morphine-induced locomotion in mice. Behav Brain Res 323:111-116
Steidl, Stephan; O'Sullivan, Shannon; Pilat, Dustin et al. (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