Cholinergic modulation of mesolimbic dopamine function and reward.

paper Cited Public

Authors: Mark, Gregory P; Shabani, Shkelzen; Dobbs, Lauren K; Hansen, Stephen T
Year: 2011
Journal: Physiology & behavior
PMID: 21549724
DOI: 10.1016/j.physbeh.2011.04.052
PMCID: PMC4495915

Figure 1

ACh fibers (green) innervate key components of the mesolimbic system, including projections from nucleus basalis (NB) to sub-cortical areas (Hipp & Amygdala). ACh interneurons reside in the NAc and striatum. Another ACh projection system from the lateral dorsal tegmental nucleus (LDTg) projects to the DA cell body region of the ventral tegmental area (VTA).

LLM interpretation

This is a schematic diagram illustrating neurotransmitter projections within the mesolimbic system of a brain. Color-coded lines represent different neurotransmitters: dopamine (grey), GABA (blue), glutamate (pink), and acetylcholine (green). The diagram shows connectivity between key regions, including the prefrontal cortex (PFC), nucleus accumbens (NAc), amygdala, ventral tegmental area (VTA), and the LDTg and PBTg nuclei.

Figure 2

Bilateral microdialysis probes were implanted into the NAc of rats and probes were perfused with a standard Ringer’s solution over the course of 8 hr during dark cycle in non-food deprived rats (N=10). Food intake was measured hourly for three hr, at which point half of the rats had the dialysis perfusion medium switched to a Ringer solution plus the cholinesterase inhibitor, neostigmine (100 µM). The remaining rats were maintained on the standard Ringer perfusion medium. Addition of neostigmine to the perfusion Ringer caused a cessation of eating in free-feeding rats.

LLM interpretation

This line graph shows cumulative food intake (gm) over a period of 7 hours for two groups of rats. Both groups show similar food intake for the first 3 hours, after which the "Ringer" control group continues to increase intake linearly while the "Ringer + Neostig." group plateaus. A gray bar indicates the period of perfusion starting at hour 3, coinciding with the cessation of eating in the neostigmine-treated group.

Figure 3

Lever pressing for 45 mg food pellets was measured for 10 min daily in non-food-deprived rats (N=8). Bilateral NAc injection of AF64A, a cholinergic cell toxin, caused a substantial increase in bar pressing for food on the first test day after the lesion and persisted for up to one week (P1–P7).

LLM interpretation

This bar chart shows the number of bar presses for food over several test days in rats. The x-axis labels baseline days (1–3) and post-lesion days (P1–P7), while the y-axis measures bar presses over 10 minutes. Following the AF64A lesion, there is a visible increase in bar pressing behavior compared to the baseline period, with values remaining elevated through day P7.

Figure 4

Systemic injections of cocaine increase ACh and dendritic DA in VTA. Intraperitoneal injections of cocaine caused a robust increase in DA released from dendrites in the VTA (Top panel). Measured simultaneously, ACh levels in the VTA also increased dramatically (Bottom panel). The time courses of the ACh and DA responses differed; there was a sharp, phasic spike in DA compared to a slower, tonic ACh response.

LLM interpretation

This figure consists of two line graphs showing intra-VTA microdialysis measurements of Dopamine (top) and Acetylcholine (bottom) over 14 consecutive 15-minute samples. Following a cocaine injection (20 mg/kg) at sample 4, dopamine shows a sharp, phasic spike peaking at sample 5, while acetylcholine exhibits a slower, tonic increase peaking at sample 6. In both graphs, the saline IP control group remains stable near the baseline throughout the duration of the experiment.

Figure 5

Perfusion of the non-specific nicotinic receptor antagonist mecamylamine into the VTA blocks DA response to systemic injection of cocaine. The DA response was measured by microdialysis in the VTA. Systemic cocaine (20 mg/kg IP) caused an increase in VTA DA levels under normal perfusion conditions (Ringer: Blue line) but cocaine did not increase DA levels when mecamylamine was perfused through the VTA by reverse dialysis (Red line). This strongly suggests that the ability of cocaine to increase DA in VTA is dependent on the functional mecamylamine-sensitive nicotinic ACh receptors. Note also that perfusion of VTA with mecamylamine caused a moderate reduction in the amount of DA recovered before the cocaine injection (samples 5 & 6). This suggests that nicotinic cholinergic receptors have an effect on basal DA release from dendrites in the VTA.

LLM interpretation

This line graph shows VTA dopamine levels over 15-minute sample intervals for two conditions: Ringer perfusion (blue dashed line) and mecamylamine (MEC) perfusion (red solid line). Following a systemic injection of cocaine (20 mg/kg), the Ringer group shows a sharp increase in dopamine levels peaking at sample 7, while the MEC group shows no such increase. The x-axis represents 15-minute samples and the y-axis represents the percentage of baseline dopamine levels.

Figure 6

Intra-LDTg injection of the ACh autoreceptor agonist OXO-SQ reduced VTA ACh output. Top panel: Intra-LDTg injection of oxotremorine-sesquifumerate (OXO-SQ: an M2 cholinergic autoreceptor agonist) decreased the level of ACh measured in the VTA by microdialysis. Artificial cerebrospinal fluid (aCSF) did not have this effect (N=4/group). These results show the feasibility of inducing an ACh “deficit” in the VTA using microinjections in the LDTg. The histological slice shows the site of a thionin injection that was infused immediately after the conclusion of the microdialysis. Bottom panel: Coronal section of unstained (and unfixed) section from a rat that received an injection of OXO-SQ into the LDTg. Thionin stain was injected immediately after the conclusion of the microdialysis experiment. The red arrow shows the injection site, here compared to a plate taken from the atlas of Paxinos & Watson, (Bregma −8.72).

LLM interpretation

The figure consists of a line graph (top) and a histological comparison (bottom). The graph shows that intra-LDTg injection of 10 nmol OXO-SQ (red line) significantly decreased ACh levels in the VTA compared to aCSF (blue dashed line) between samples 3 and 5, with values returning toward baseline by sample 7. The bottom panel displays a coronal brain section and an atlas diagram, with a red arrow indicating the specific injection site within the LDTg.

Figure 7

The graph shows the number of cocaine infusions (normalized to baseline; 0.75 mg/kg/infusion) rats took in the first hr when access was limited to 1-hr (Days 1–4) or increased to 6-hr per day (Days 5–8). Rats tended to escalate cocaine intake with 6-hr access time (upper line) but if mecamylamine (MEC; 20 µg/kg/infusion) was added to the cocaine solution, escalation in cocaine intake did not occur. Note that MEC did not completely eliminate cocaine self-administration but prevented the expression of high-level (i.e. escalated) intake. Adapted from Hansen & Mark, (2007).

LLM interpretation

This line graph shows the percentage of baseline cocaine infusions over 15 days, comparing a control group (No MEC, red line) to a group receiving mecamylamine (MEC, blue dashed line). During the 1-hour access period (Days 1–5), both groups show similar intake levels around 100% of baseline. Upon switching to 6-hour access (Days 6–10), the "No MEC" group shows a steady escalation in intake, while the "MEC" group remains near baseline levels until Day 11, after which both groups converge at a higher intake level.

Figure 8

Intra VTA injection of mecamylamine (MEC; 60 µg/side) reduced cocaine self-administration in rats that had established escalated cocaine intake on a 6 hr schedule. Dotted line indicates the average pre-escalation cocaine intake. Note that MEC reduced escalated intake but did not reduce cocaine self-administration below pre-escalation levels. Baclofen was used as a positive control to show that VTA injections could reduce cocaine self-administration below pre-escalation levels, whereas MEC only reduced escalated intake. (N=5–6 per group; # P<0.05; ** P<0.01).

LLM interpretation

This bar chart shows the effect of intra-VTA microinjections of mecamylamine (at doses of 3, 10, 30, and 60 µg) and baclofen (25 ng) on cocaine infusions as a percentage of pre-injection baseline. A dose-dependent decrease in cocaine infusions is observed for mecamylamine, with the 60 µg dose significantly reducing intake (# P<0.05) toward the pre-escalation baseline (dotted line). Baclofen significantly reduced cocaine infusions well below the pre-escalation baseline (** P<0.01) compared to the aCSF control.

#	Section	Preview
0	Introduction	More than three decades of research into the neurobiological substrates of reward have focused…
1	Introduction	Of the many perspectives Hoebel brought to the study of neurochemical modulation of motivated…
2	Introduction	large, aspiny acetylcholine (ACh) -containing interneurons in the NAc [14]. Cholinergic interneurons…
3	Introduction	Cholinergic cells in the laterodorsal tegmental nucleus (LDTg) and the posterior component of the…
4	Introduction	Several lines of evidence suggest that stimulation of both nicotinic and muscarinic cholinergic…
5	Introduction	In comparison to the rather clear-cut situation for nicotinic activation, the effect of muscarinic…
6	Introduction	Identifying the precise location of cholinergic effects on psychostimulant reward has been difficult…
7	Introduction — Acetylcholine-Dopamine Interactions and Ingestive Behavior	Seminal studies by Hernandez & Hoebel (1988) demonstrated that food reward increased DA in the NAc…
8	Introduction — Acetylcholine-Dopamine Interactions and Ingestive Behavior	saccharin in rats that had developed an aversion [45]. A complementary study was performed in rats…
9	Introduction — Acetylcholine-Dopamine Interactions and Ingestive Behavior	The fact that mesolimbic DA plays a major role in modulating ingestive related behavior is now well…
10	Introduction — Acetylcholine-Dopamine Interactions and Ingestive Behavior	Evidence from the Hoebel laboratory has suggested that a particular balance between DA and ACh may…
11	Introduction — Acetylcholine-Dopamine Interactions and Ingestive Behavior	their night cycle. Probes implanted in control animals were perfused throughout the night with a…
12	Introduction — Cholinergic interactions with mesencephalic dopamine systems and drug reward	Work done in the Hoebel laboratory over a decade ago was some of the first to demonstrate a relevant…
13	Introduction — Cholinergic interactions with mesencephalic dopamine systems and drug reward	In a separate set of experiments, we measured the response to systemic injections of cocaine of DA…
14	Introduction — Cholinergic interactions with mesencephalic dopamine systems and drug reward	Another proposal we tested was whether inactivation of ACh would reduce the behavioral reinforcing…
15	Introduction — Cholinergic antagonist prevents escalation of cocaine self-administration in rats	When rats are allowed increased access time to cocaine for self-administration (from 1-hr/day to…
16	Introduction — Cholinergic antagonist prevents escalation of cocaine self-administration in rats	We examined whether a nicotinic receptor antagonist, mecamylamine (MEC) would affect escalation…
17	Introduction — Intra-VTA Injection of Mecamylamine reduces high-level cocaine intake	A key goal was to identify whether inactivation of cholinergic input to VTA can reduce expression of…
18	Introduction — Intra-VTA Injection of Mecamylamine reduces high-level cocaine intake	These findings have strong implications for the role of cholinergic systems in controlling drug…

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Muscarinic receptors mediate motivation via preparatory neural activity in humans	Grogan JP et al.	—	2021	—
Mutual assistance of nucleus accumbens cannabinoid receptor-1 and orexin receptor-2 in response to nicotine: a single-unit study.	Fartootzadeh R et al.	—	2021	→
Neural Substrates and Circuits of Drug Addiction.	Feltenstein MW et al.	—	2021	→
The role of acetylcholine in negative encoding bias: Too much of a good thing?	Mineur YS et al.	—	2021	→
Understanding the genetics and neurobiological pathways behind addiction (Review).	Popescu A et al.	—	2021	→
Activity-Dependent Epigenetic Remodeling in Cocaine Use Disorder.	López AJ et al.	—	2020	→
Dopamine beta-hydroxylase and its genetic variants in human health and disease.	Gonzalez-Lopez E et al.	—	2020	→
Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an <i>alpha-1 adrenoreceptor subtype D</i> genetic variant.	Shorter DI et al.	—	2020	→
Muscarinic receptors in energy homeostasis: Physiology and pharmacology.	Falk S et al.	—	2020	→
Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence.	Xiao C et al.	—	2020	→
A Mini-Review of the Role of Glutamate Transporter in Drug Addiction.	Wang W et al.	—	2019	→
Cholinergic system in sleep regulation of emotion and motivation.	Mu P et al.	—	2019	→
Functional crosstalk of nucleus accumbens CB1 and OX2 receptors in response to nicotine-induced place preference.	Fartootzadeh R et al.	—	2019	→
NMDA Receptor-Dependent Cholinergic Modulation of Mesolimbic Dopamine Cell Bodies: Neurochemical and Behavioral Studies.	Spanos M et al.	—	2019	→
Opioid addiction and the cerebellum.	Moreno-Rius J	—	2019	→
Orexin type-2 receptor blockade prevents the nicotine-induced excitation of nucleus accumbens core neurons in rats: An electrophysiological perspective.	Fartootzadeh R et al.	—	2019	→
Pharmacogenetics of Dopamine β-Hydroxylase in cocaine dependence therapy with doxazosin.	Zhang X et al.	—	2019	→
Effects of systemic cholinergic antagonism on reinforcer devaluation in macaques.	Waguespack HF et al.	—	2018	→
Galantamine and Computerized Cognitive Behavioral Therapy for Cocaine Dependence: A Randomized Clinical Trial.	Carroll KM et al.	—	2018	→
Neuropharmacology of compulsive eating.	Moore CF et al.	—	2018	→
Self-administration of the synthetic cathinone MDPV enhances reward function via a nicotinic receptor dependent mechanism.	Geste JR et al.	—	2018	→
Sugar Addiction: From Evolution to Revolution.	Wiss DA et al.	—	2018	→
Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling.	Aitta-Aho T et al.	—	2017	→
Effects of nicotine on homeostatic and hedonic components of food intake.	Stojakovic A et al.	—	2017	→
Unravelling the Link Between Prenatal Stress, Dopamine and Substance Use Disorder.	Pastor V et al.	—	2017	→
Acquisition and reinstatement of ethanol-induced conditioned place preference in rats: Effects of the cholinesterase inhibitors donepezil and rivastigmine.	Gawel K et al.	—	2016	→
A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders.	Grasing K	—	2016	→
Cognitive Function as a Transdiagnostic Treatment Target in Stimulant Use Disorders.	Sofuoglu M et al.	—	2016	→
Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain.	Kashem MA et al.	—	2016	→
Modulatory effects of the basolateral amygdala α2-adrenoceptors on nicotine-induced anxiogenic-like behaviours of rats in the elevated plus maze.	Bashiri H et al.	—	2016	→
Neurochemical modulation of repetition suppression and novelty signals in the human brain.	Bunzeck N et al.	—	2016	→
Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake.	Shariff M et al.	—	2016	→
Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions.	Gonzales KK et al.	—	2015	→
Early Life Stress, Nicotinic Acetylcholine Receptors and Alcohol Use Disorders.	Holgate JY et al.	—	2015	→
Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.	Sagheddu C et al.	—	2015	→
Endogenous cholinergic neurotransmission contributes to behavioral sensitization to morphine.	Bajic D et al.	—	2015	→
High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.	Khroyan TV et al.	—	2015	→
Identification and characterization of ML352: a novel, noncompetitive inhibitor of the presynaptic choline transporter.	Ennis EA et al.	—	2015	→
Regulation of the mesolimbic dopamine circuit by feeding peptides.	Liu S et al.	—	2015	→
The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited.	van Enkhuizen J et al.	—	2015	→
Basolateral amygdala CB1 cannabinoid receptors mediate nicotine-induced place preference.	Hashemizadeh S et al.	—	2014	→
Citicoline in addictive disorders: a review of the literature.	Wignall ND et al.	—	2014	→
Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei.	Vélez-Hernández ME et al.	—	2014	→
Effects of biperiden on the treatment of cocaine/crack addiction: a randomised, double-blind, placebo-controlled trial.	Dieckmann LH et al.	—	2014	→
Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.	Gawel K et al.	—	2014	→
Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum.	Knapp CM et al.	—	2014	→
Optogenetic studies of nicotinic contributions to cholinergic signaling in the central nervous system.	Jiang L et al.	—	2014	→
Pharmacological dissociation of novelty responses in the human brain.	Bunzeck N et al.	—	2014	→
Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens.	Salamone A et al.	—	2014	→
Resting state functional connectivity of the basal nucleus of Meynert in humans: in comparison to the ventral striatum and the effects of age.	Li CS et al.	—	2014	→
The evidence for the contribution of the autism susceptibility candidate 2 (AUTS2) gene in heroin dependence susceptibility.	Dang W et al.	—	2014	→
5-HT1A receptor antagonists reduce food intake and body weight by reducing total meals with no conditioned taste aversion.	Dill MJ et al.	—	2013	→
Acute NK₁ receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers.	Saji K et al.	—	2013	→
A Methanol Extract of Brugmansia arborea Affects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice.	Bracci A et al.	—	2013	→
Differential effects of natural rewards and pain on vesicular glutamate transporter expression in the nucleus accumbens.	Tukey DS et al.	—	2013	→
Dopamine D₂ and acetylcholine α7 nicotinic receptors have subcellular distributions favoring mediation of convergent signaling in the mouse ventral tegmental area.	Garzón M et al.	—	2013	→
Effects of cocaine and withdrawal on the mouse nucleus accumbens transcriptome.	Eipper-Mains JE et al.	—	2013	→
Evaluation of acetylcholinesterase in an animal model of mania induced by D-amphetamine.	Varela RB et al.	—	2013	→
Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.	Chorlian DB et al.	—	2013	→
Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle.	Guzman MS et al.	—	2013	→
PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors.	Melis M et al.	—	2013	→
Somatodendritic targeting of M5 muscarinic receptor in the rat ventral tegmental area: implications for mesolimbic dopamine transmission.	Garzón M et al.	—	2013	→
Systems level neuroplasticity in drug addiction.	Feltenstein MW et al.	—	2013	→
Acetylcholine, drug reward and substance use disorder treatment: intra- and interindividual striatal and accumbal neuron ensemble heterogeneity may explain apparent discrepant findings.	Prast JM et al.	—	2012	→
Cholinergic modulation of food and drug satiety and withdrawal.	Avena NM et al.	—	2012	→
L-tyrosine administration increases acetylcholinesterase activity in rats.	Ferreira GK et al.	—	2012	→
Neurocircuitry for modeling drug effects.	Noori HR et al.	—	2012	→
Periaqueductal gray neuroplasticity following chronic morphine varies with age: role of oxidative stress.	Bajic D et al.	—	2012	→