Effects of ethylcholine mustard azirinium ion (AF64A) on the choline acetyltransferase and nitric oxide synthase activities in mesopontine cholinergic neurons of the rat

Rodrı́guez, Manuel; Mantolán-Sarmiento, Beatriz; González‐Hernández, Tomás

doi:10.1016/s0306-4522(97)00293-5

Cited by 6 publications

(2 citation statements)

References 45 publications

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“…In addition, although Lança et al . (2000a) report selective damage to cholinergic neurons, our own observations, and those of others (Rodríguez et al ., 1998) suggest that this toxin produces nonspecific damage in the form of cavitation at the site of injection. This is in contrast to the fibre‐sparing nature of excitotoxin lesions, such as those in the present study.…”

Section: Discussionmentioning

confidence: 78%

Intravenous self‐administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus

Alderson

Latimer

Winn

2006

Eur J of Neuroscience

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The reinforcing properties of nicotine involve actions at nicotinic acetylcholine receptors located on dopamine (DA) neurons in the ventral tegmental area (VTA). The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of these DA neurons, and those of the substantia nigra pars compacta (SNc). The PPTg can be subdivided into anterior (aPPTg) and posterior (pPPTg) regions on the basis of its innervation of midbrain DA neurons - the pPPTg innervates both VTA and SNc while the aPPTg innervates SNc. As the reinforcing actions of nicotine depend on its actions in the VTA more than SNc, it was hypothesized that excitotoxic lesions of pPPTg would alter nicotine reinforcement, measured by intravenous self-administration, while lesions of aPPTg would not. Rats were given ibotenate lesions of pPPTg or aPPTg, followed by intravenous catheterization. Intravenous self-administration (IVSA) of nicotine (0.03 mg/kg/inf) was carried out until a stable response baseline was reached. A dose-response function for nicotine was then established. There was no significant effect of aPPTg lesions on nicotine IVSA, while IVSA was significantly elevated following pPPTg lesions, compared with both sham lesioned controls and aPPTg excitotoxin lesioned rats. This was found across all doses, including saline, of the dose-response function. The differential effect of aPPTg lesions and pPPTg lesions suggests that disruption of regulatory innervation from pPPTg results in altered regulation of VTA DA neurons. The resulting change in nicotine self-administration behaviour was hypothesized to reflect either a reduction in intrinsic nicotine reward value, or enhancement of associative incentive salience.

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Section: Discussionmentioning

confidence: 78%

Intravenous self‐administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus

Alderson

Latimer

Winn

2006

Eur J of Neuroscience

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“…Ethylcholine mustard aziridium ion, which targets choline uptake processes, was a candidate (Hanin 1990), and indeed has been used in the PPTg (Lanca et al. 2000), but it in fact produces non‐specific lesions (Rodriguez et al. 1998).…”

Section: Discussionmentioning

confidence: 99%

Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum

Clark

Alderson

Winn

et al. 2007

Journal of Neurochemistry

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Urotensin II is a neuropeptide first isolated from fish and later found in mammals: where it has potent cardiovascular, endocrine and behavioral effects. In rat brain the urotensin II receptor (UII-R) is predominately expressed in the cholinergic neurons of the pedunculopontine (PPTg) and laterodorsal tegmental nuclei. Typically, the function of the PPTg has been examined using excitotoxins, destroying both cholinergic and non-cholinergic neurons, which confounds interpretation. We took advantage of UII-R's unique expression profile, by combining UII with diphtheria toxin, to engineer a toxin specific for cholinergic neurons of the PPTg. In vitro, two different toxin constructs were shown to selectively activate UII-R (average EC50 30 nmol/L; calcium mobility assay) and to be 10 000-fold more toxic to UII-R expressing CHO cells, than wildtype cells (average LD50 2 nmol/L; cell viability). In vivo, pressure injection into the PPTg of rats, resulted in specific loss of choline transporter and NADPH diaphorase positive neurons known to express the UII-R. The lesions developed over time, resulting in the loss of over 80% of cholinergic neurons at 21 days, with little damage to surrounding neurons. This is the first highly selective molecular tool for the depletion of mesopontine cholinergic neurons. The toxin will help to functionally dissect the pedunculopontine and laterodorsal tegmental nuclei, and advance the understanding of the functions of these structures.

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The Role of the Pedunculopontine Tegmental Nucleus in Motor Disorders

Gut

Winn

2011

Neuromethods

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Effects of ethylcholine mustard azirinium ion (AF64A) on the choline acetyltransferase and nitric oxide synthase activities in mesopontine cholinergic neurons of the rat

Cited by 6 publications

References 45 publications

Intravenous self‐administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus

Intravenous self‐administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus

Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum

The Role of the Pedunculopontine Tegmental Nucleus in Motor Disorders

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