Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons

Kohlmeier, Kristi A.; Christensen, Mark H.; Kristensen, Morten P.; Kristiansen, Uffe

doi:10.1016/j.neuropharm.2012.02.016

Cited by 18 publications

(11 citation statements)

References 92 publications

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“…Therefore, ontogenetic differences in kinetics of voltage dependent sodium channels may also play a role in the functional outcome of nicotine effects on AHP minimums. The AHP minimum is greatly dependent upon the initial fast AHP, which has been found to be mediated by a large conductance calcium-activated potassium (BK) channel in the LDT (Kohlmeier et al, 2013) and shown in other cells types to be affected by nicotine (Kuhlmann et al, 2005). If similar actions on BK channels are present in the LDT, nicotinic inhibition of BK channels could subsequently underlie the nicotine-induced depolarization of the AHP minimum.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: Implications for the heightened adolescent susceptibility to nicotine addiction

et al. 2014

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The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on several parameters affecting LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7-P15), nicotine was found to induce larger intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15-P34). Nicotine increased neuronal firing of cholinergic cells to a greater degree in younger animals, possibly linked to development associated differences found in nicotinic effects on action potential shape and afterhyperpolarization. We conclude that in addition to age-associated alterations of several properties expected to affect resting cell excitability, parameters affecting cell excitability are altered by nicotine differentially across ontogeny. Taken together, our data suggest that nicotine induces a larger excitatory response in cholinergic LDT neurons from the youngest animals, which could result in a greater excitatory output from these cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across age.

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Section: Discussionmentioning

confidence: 99%

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: Implications for the heightened adolescent susceptibility to nicotine addiction

et al. 2014

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“…67 In cholinergic cells of the LDT, BKchannels have also been shown to mediate the initial fast part of the AHP. 27 Therefore, in order to determine whether PNE affects this channel in LDT neurons, we measured the amplitude of the AHP and the AHP minimum. In cells from PNE animals the amplitude of the AHP was significantly larger in the population of cells from the youngest PNE group when compared with the amplitude in group I controls (14.7% larger).…”

Section: Pne Changes the Spike Shape And Afterhyperpolarizationmentioning

confidence: 99%

Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse

Christensen

Nielsen

Kohlmeier

2014

J Dev Orig Health Dis

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Prenatal nicotine exposure (PNE) is a risk factor for developing an addiction to nicotine at a later stage in life. Understanding the neurobiological changes in reward related circuitry induced by exposure to nicotine prenatally is vital if we are to combat the heightened addiction liability in these vulnerable individuals. The laterodorsal tegmental nucleus (LDT), which is comprised of cholinergic, GABAergic and glutamatergic neurons, is importantly involved in reward mediation via demonstrated excitatory projections to dopamine-containing ventral tegmental neurons. PNE could lead to alterations in LDT neurons that would be expected to alter responses to later-life nicotine exposure. To examine this issue, we monitored nicotine-induced responses of LDT neurons in brain slices of PNE and drug naive mice using calcium imaging and whole-cell patch clamping. Nicotine was found to induce rises in calcium in a smaller proportion of LDT cells in PNE mice aged 7-15 days and smaller rises in calcium in PNE animals from postnatal ages 11-21 days when compared with age-matched control animals. While inward currents induced by nicotine were not found to be different, nicotine did induce larger amplitude excitatory postsynaptic currents in PNE animals in the oldest age group when compared with amplitudes induced in similar-aged control animals. Immunohistochemically identified cholinergic LDT cells from PNE animals exhibited slower spike rise and decay slopes, which likely contributed to the wider action potential observed. Further, PNE was associated with a more negative action potential afterhyperpolarization in cholinergic cells. Interestingly, the changes found in these parameters in animals exposed prenatally to nicotine were age related, in that they were not apparent in animals from the oldest age group examined. Taken together, our data suggest that PNE induces changes in cholinergic LDT cells that would be expected to alter cellular excitability. As the changes are age related, these PNE-associated alterations could contribute differentially across ontogeny to nicotine-mediated reward and may contribute to the particular susceptibility of in utero nicotine exposed individuals to addict to nicotine upon nicotine exposure in the juvenile period.

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“…Another neurotransmitter that may exert an inhibition of cholinergic neurons was found surprisingly to be glutamate. Although glutamate is the major excitatory neurotransmitter in the brain when acting at ionotropic glutamate receptors, activation of metabotropic glutamate receptors (mGluRs) of the Group I, type 5, and Group 2 (type 2/3) elicited a relatively long-lived membrane hyperpolarization in cholinergic LDT cells [148]. These data suggested a dual polarity action of this classic excitatory neurotransmitter with final actions likely dependent on receptor distribution at the target site.…”

Section: Actions Of Neuroactive Substances On Ldt Neuronsmentioning

confidence: 99%

“…In brain slices, endogenous release of glutamate onto cholinergic neurons is apparent, indicating a high level of ongoing glutamate tone directed to these cells remaining intact in this reduced preparation [152, 153]. In addition to glutamate-induced excitatory actions mediated by ionotropic receptors, glutamate can excite cholinergic neurons directly via activation of mGluRs of the Group I, type 1 [148, 154]. Based on in vitro findings within the PPT and in vivo extracellular recordings in cat, histamine is presumed to excite cholinergic LDT neurons via an H 1 receptor mediated increase in membrane resistance [149, 155].…”

Section: Actions Of Neuroactive Substances On Ldt Neuronsmentioning

confidence: 99%

Off the Beaten Path: Drug Addiction and the Pontine Laterodorsal Tegmentum

Kohlmeier

2013

ISRN Neuroscience

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Drug addiction is a multileveled behavior controlled by interactions among many diverse neuronal groups involving several neurotransmitter systems. The involvement of brainstem-sourced, cholinergic neurotransmission in the development of addiction and in the persistent physiological processes that drive this maladaptive behavior has not been widely investigated. The major cholinergic input to neurons in the midbrain which are instrumental in assessment of reward and assignment of salience to stimuli, including drugs of abuse, sources from acetylcholine- (ACh-) containing pontine neurons of the laterodorsal tegmentum (LDT). Excitatory LDT input, likely cholinergic, is critical in allowing behaviorally relevant neuronal firing patterns within midbrain reward circuitry. Via this control, the LDT is positioned to be importantly involved in development of compulsive, addictive patterns of behavior. The goal of this review is to present the anatomical, physiological, and behavioral evidence suggesting a role of the LDT in the neurobiology underlying addiction to drugs of abuse. Although focus is directed on the evidence supporting a vital participation of the cholinergic neurons of the LDT, data indicating a contribution of noncholinergic LDT neurons to processes underlying addiction are also reviewed. While sparse, available information of actions of drugs of abuse on LDT cells and the output of these neurons as well as their influence on addiction-related behavior are also presented. Taken together, data from studies presented in this review strongly support the position that the LDT is a major player in the neurobiology of drug addiction. Accordingly, the LDT may serve as a future treatment target for efficacious pharmaceutical combat of drug addiction.

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Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons

Cited by 18 publications

References 92 publications

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: Implications for the heightened adolescent susceptibility to nicotine addiction

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: Implications for the heightened adolescent susceptibility to nicotine addiction

Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse

Off the Beaten Path: Drug Addiction and the Pontine Laterodorsal Tegmentum

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