Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration

Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections co-release glutamate, no direct evidence has demonstrated a role for this specific glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Histochemical approaches and optogenetics-assisted electrophysiology were used to validate the disruption of VGLUT1 from cholinergic MHb to IPN projections. The mice displayed no gross phenotypic abnormalities and exhibited normal exploratory and locomotor behavior in the open-field assay. However, the loss of VGLUT1-mediated glutamate co-release led to increased nicotine self-administration. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine consumption and provide additional support for targeting this synapse to develop potential treatments to nicotine addiction.

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18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats

European Journal of Pharmacology ◽

10.1016/j.ejphar.2006.03.045 ◽

2006 ◽

Vol 537 (1-3) ◽

pp. 94-98 ◽

Cited By ~ 39

Author(s):

Stanley D. Glick ◽

Ruby L. Ramirez ◽

Jacklyn M. Livi ◽

Isabelle M. Maisonneuve

Keyword(s):

Self Administration ◽

Interpeduncular Nucleus ◽

Medial Habenula

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Histamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice

Nature Communications ◽

10.1038/s41467-021-21476-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Li Cheng ◽

Cenglin Xu ◽

Lu Wang ◽

Dadao An ◽

Lei Jiang ◽

...

Keyword(s):

Functional Outcomes ◽

Negative Symptoms ◽

Cholinergic Neurons ◽

Sensorimotor Gating ◽

Social Impairment ◽

H1 Receptor ◽

Behavioral Deficits ◽

Social Impairments ◽

Cholinergic Projections ◽

Functional Deficiency

AbstractNegative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.

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The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioral study

Neuroscience ◽

10.1016/s0306-4522(99)00607-7 ◽

2000 ◽

Vol 96 (4) ◽

pp. 735-742 ◽

Cited By ~ 77

Author(s):

A.J. Lança ◽

K.L. Adamson ◽

K.M. Coen ◽

B.L.C. Chow ◽

W.A. Corrigall

Keyword(s):

Cholinergic Neurons ◽

Pedunculopontine Tegmental Nucleus ◽

Behavioral Study ◽

Self Administration ◽

Tegmental Nucleus

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The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation

Journal of Neurochemistry ◽

10.1111/jnc.14008 ◽

2017 ◽

Vol 142 ◽

pp. 130-143 ◽

Cited By ~ 43

Author(s):

Ian McLaughlin ◽

John A. Dani ◽

Mariella De Biasi

Keyword(s):

Mood Regulation ◽

Interpeduncular Nucleus ◽

Medial Habenula

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Relapse-like behavior and nAChR sensitization following intermittent access nicotine self-administration

10.1101/2022.01.07.475355 ◽

2022 ◽

Author(s):

Ryan Drenan ◽

Xiao-Tao Jin ◽

Brenton Tucker ◽

Leanne Thomas ◽

Noah Walker ◽

...

Keyword(s):

Tobacco Consumption ◽

Male Rats ◽

Blood Levels ◽

Self Administration ◽

Interpeduncular Nucleus ◽

Nicotine Intake ◽

Positron Emission ◽

Intermittent Access ◽

Underlying Mechanisms ◽

Incubation Of Craving

Many tobacco smokers consume nicotine intermittently, but the underlying mechanisms and neurobiological changes associated with intermittent nicotine intake are unclear. Understanding intermittent nicotine intake is a high priority, as it could promote therapeutic strategies to attenuate tobacco consumption. We examined nicotine intake behavior and neurobiological changes in male rats that were trained to self-administer nicotine during brief (5 min) trials interspersed with longer (15 min) drug-free periods. Rats readily adapted to intermittent access (IntA) SA following acquisition on a continuous access (ContA) schedule. Probabilistic analysis of IntA nicotine SA suggested reduced nicotine loading behavior compared to ContA, and nicotine pharmacokinetic modeling revealed that rats taking nicotine intermittently may have increased intake to maintain blood levels of nicotine that are comparable to ContA SA. After IntA nicotine SA, rats exhibited an increase in unreinforced responses for nicotine-associated cues (incubation of craving) and specific alterations in the striatal proteome after 7 days without nicotine. IntA nicotine SA also induced nAChR functional upregulation in the interpeduncular nucleus (IPN), and it enhanced nicotine binding in the brain as determined via [11C]nicotine positron emission tomography. Reducing the saliency of the cue conditions during the 5 min access periods attenuated nicotine intake, but incubation of craving was preserved. Together, these results indicate that IntA conditions promote nicotine SA and nicotine seeking after a nicotine-free period.

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The Medial Habenula-Interpeduncular Nucleus Pathway in Nicotine Sensitization: The Role of α3β4 Nicotinic Acetylcholine Receptors and Substance P

Neuroscience of Nicotine ◽

10.1016/b978-0-12-813035-3.00032-0 ◽

2019 ◽

pp. 251-258

Author(s):

Branden Eggan ◽

Sarah McCallum

Keyword(s):

Substance P ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine ◽

Interpeduncular Nucleus ◽

Medial Habenula

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TMEM16A-deficient cholinergic neurons of medial habenula mediate anxiogenic behaviors

IBRO Reports ◽

10.1016/j.ibror.2019.07.854 ◽

2019 ◽

Vol 6 ◽

pp. S275

Author(s):

Ajung Kim ◽

Chang-Hoon Cho ◽

Sangjoon Lee ◽

Oleg Yarishkin ◽

Hyun-Gug Jung ◽

...

Keyword(s):

Cholinergic Neurons ◽

Medial Habenula

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Fetal Medial Habenula Transplants: Innervation of the Rat Interpeduncular Nucleus

Journal of Neural Transplantation ◽

10.1155/np.1989.57 ◽

1989 ◽

Vol 1 (2) ◽

pp. 57-62

Author(s):

Nicholas J. Lenn ◽

P. John Seeley ◽

Pauline M. Field ◽

Geoffrey Raisman

Keyword(s):

Colloidal Gold ◽

Third Ventricle ◽

Donor Age ◽

Adult Rats ◽

Interpeduncular Nucleus ◽

The Third ◽

Medial Dorsal ◽

Medial Habenula ◽

The Difference

The effects of donor age and site of placement on the survival of fetal medial habenula (MH) transplants into adult rats hosts were examined. The innervation of the interpeduncular nucleus (IPN) in such cases was also examined. Explants of MH consisting of the medial-dorsal lip of the third ventricle were heldin vitrofor 1—2 days. Colloidal gold conjugated to wheat germ agglutinin was added for the last 18 hours to label the cells. Four of 16 cases with E19 derived transplants contained donor neurons. Markedly larger transplants were present in 95% of 20 cases with E16 derived transplants. Sites in the ventral midbrain were successful, while limited or no survival occurred at sites more remote from IPN. Retrograde labeling of transplant neurons was present in each case studied with HRP injection into host IPN. Colloidal gold-labeled macrophages, some oriented capillaries and GFAP-positive processes marked the donor-host interface. In EM the interface was evident only by the difference in tissue elements in the transplant versus host. Numerous synapses of Gray types I and II were present in the transplant. Excellent survival of MH neurons, donor/host interfaces, innervation of IPN by the transplant and fine structure in and around the transplants, all suggest that such preparations are suitable for further experimental analysis of the habenulo-interpeduncular system.

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