Biphasic stimulation

Nicotine is a cholinergic agonist that has biphasic (stimulant and depressant) action. 

In the preceding section, I have made the argument for biphasic stimulation. The first, usually... 

With stainless steel, we know that imbalanced biphasic stimulation of muscle cells is a safe way to avoid corrosion and more than triple charge injection limits imposed by balanced charge stimulation. There is no obvious reason to think imbalanced biphasic stimulation shouldn t be safe with electrodes in the brain, cells are cells, and it appears that the corrosiOTi products are the culprits, which occur during the anodic phase. If a reference electrode could be developed for implantable pulse generator, IPG, closed-loop control could be used to eliminate electrode potentials that push the metal into regions where metal loss occurs. 

Wang G, Liu W, Sivaprakasam M, Humayun MS, Weiland JD (2005) Power supply topologies for biphasic stimulation in inductively powered implants. IEEE ISCAS 3 2743-2746. 

Patel, J. et al., Biphasic inhibition of stimulated endogenous dopamine release by 7-Oh-Dpat in slices of rat nucleus-accumbens, Brit. J. Pharmacol., 115, 421, 1995. 

Because electrode measurements of O2 uptake can detect intra- and extracellular oxidase activity, this assay can be used to measure the respiratory burst elicited by soluble and particulate stimuli. What is somewhat surprising is that, during stimulation of neutrophils with agonists such as fMet-Leu-Phe, the activated O2 uptake profile is biphasic (Fig. 5.11c). A rapid burst of O2 uptake (which coincides with measurements of cytochrome c reduction) is followed by a more sustained activity of lower magnitude. 

Several indirect neurochemical effects of methyixanthines contribute to their effects. Micromolar concentrations of caffeine enhance release of acetylcholine (Pedata et al. 1984). However, this effect is biphasic, augmenting release at 50 pM, but decreasing it at 0.5 pM. This effect is also modulatory, affecting stimulated, but not basal, release. Caffeine enhances acetylcholine release in the hippocampus, which is due to adenosine Al receptor subtypes (Carter et al. 1995). Conversely, chronic caffeine reduces the excitatory effect of acetylcholine in the cerebral cortex (Lin and Phillis... 

Intracellular messengers A biphasic effect of ginkgo extract is seen on cAMP phosphodiesterase under in vitro and ex vivo conditions (Saponara and Bosisio 1998 Macovschi et al. 1987). Whereas low concentrations (0.25-4.0 mg/L) activate the enzyme, higher concentrations (5-250 mg/L), dose-dependently inhibit it. However, tolerance develops to this effect because it is undetectable after daily administration for 4 days. Thus, ginkgo may initially produce effects by inhibiting enzymatic breakdown of cAMP. This mechanism is similar to the stimulant caffeine, but it is not likely to explain any long-term effects of ginkgo because it disappears after chronic daily treatment. The responsible constituent for this effect has not been identified. 

Paradoxically, catnip fed to mice had stimulant effects, with increased rearing, locomotion, and stereotypical behavior, increased susceptibility to chemically induced (picrotoxin and strychnine) seizures, and decreased sleeping time after barbiturate administration (Massoco et al. 1995). The LD50 for nepetalactone in mice was reported to be quite high at 1300 mg/kg (Harney et al. 1978). In chicks, an a cohol extract of catnip had biphasic effects, where low to moderate doses (25-1800 mg/kg) produced sedative effects, while higher doses (>2 g/kg) had less sedative and perhaps stimulant effects (Sherry and Hunter 1979). Humans have reported sedative effects of catnip, and one accidental ingestion by a young child reportedly produced sedative effects (Osterhoudt et al. 1997). 

Pedata F, Pepeu G, Spignoli G. (1984). Biphasic effect of methyixanthines on acetylcholine release from electrically-stimulated brain slices. Br J Pharmacol. 83(1) 69-73. 

Marks MJ, Meinerz NM, Drago J, Collins AC (2007) Gene targeting demonstrates that a4 nicotinic acetylcholine receptor subunits contribute to expression of diverse [ H]epibatidine binding sites and components of biphasic Rb+ efflux with high and low sensitivity to stimulation by acetylcholine. Neuropharmacol 53 390-405... 

---