PubMed · 4400993
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R Werman. 1972. CNS cellular level: membranes.. https://doi.org/10.1146/annurev.ph.34.030172.002005
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The effects of Pa-1G, a phospholipase A(2) (PLA(2)) from the venom of the Australian king brown snake (Pseudechis australis) were determined on the release of acetylcholine, muscle resting membrane potential and motor nerve terminal action potential at mouse neuromuscular junction. Intracellular recording from endplate regions of mouse triangularis sterni nerve-muscle preparations revealed that Pa-1G (800 nM) significantly reduced the amplitude of endplate potentials within 10 min exposure. The quantal content of endplate potentials was decreased to 58+/-6% of control after 30 min exposure to 800 nM Pa-1G. The toxin also caused a partial depolarisation of mouse muscle fibres within 60 min exposure. Extracellular recording of action potentials at motor nerve terminals showed that Pa-1G reduced the waveforms associated with both sodium and potassium conductances. To investigate whether this was a direct or indirect effect of the toxin on these ionic currents, whole cell patch clamp experiments were performed using human neuroblastoma (SK-N-SH) cells and B82 mouse fibroblasts stably transfected with rKv1.2. Patch clamp recording experiments confirmed that potassium currents sensitive to alpha-dendrotoxin recorded from B82 cells and sodium currents in SK-N-SH cells were not affected by the toxin. Since neither facilitation of acetylcholine release at mouse neuromuscular junction nor depression of potassium currents in B82 cells has been observed, the apparent blockade of potassium currents at mouse motor nerve endings induced by the toxin is unlikely to be due to a selective block of potassium channels.
Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (NAc), which receives dopaminergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxin-mediated cell targeting and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. Acute exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice. This abnormal turning was enhanced by repeated exposure of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine.
The effects of changes in regional cerebral blood flow (rCBF) with aging on muscarinic cholinergic receptor binding were evaluated with [15O]H(2)O and N-[11C]methyl-4-piperidyl benzilate (4-MPB) in the living brains of young (5.9+/-1.8 years old) and aged (19.0+/-3.3 years old) monkeys (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of receptor binding in vivo with [11C]4-MPB, metabolite-corrected arterial plasma radioactivity curves were obtained as an input function into the brain, and graphical Patlak plot analysis was applied. In addition, two-compartment model analysis using the radioactivity curve in the cerebellum as an input function (reference analysis) was also applied to determine the distribution volume (DV=K(1)/k(2)') for [11C]4-MPB. With metabolite-corrected arterial input, Patlak plot analysis of [11C]4-MPB indicated a regionally specific decrease in muscarinic cholinergic receptor binding in vivo in the frontal and temporal cortices as well as the striatum in aged compared with young animals, showing no correlation with the degree of reduced rCBF. In contrast, on the reference analysis with cerebellar input of [11C]4-MPB, all regions assayed except the pons showed a significant age-related decrease of DV, and the degree of reduction of DV was correlated with that of rCBF. These results demonstrated the usefulness of kinetic analysis of [11C]4-MPB with metabolite-corrected arterial input, not with reference region's input, as an indicator of the aging process of cortical muscarinic cholinergic receptors in vivo measured by PET with less blood flow dependency.