Excitability properties of medial forebrain bundle axons of A9 and A10 dopamine cells

A9 and A10 units identified as dopaminergic were recorded with extracellular micropipettes. The units were antidromically activated by electrical stimulation at the level of the preoptic area. The absolute refractory periods ranged from 1.2 to 2.5 ms. During the 2–8 ms of the relative refractory period, conduction was slower than normal by up to 1.5 ms. The time constant, C, of the strength-duration curve ranged from 0.4 to 0.6 ms. The current (I)-distance (D) relationship, tested by moving the stimulating electrode past the axon, was approximately parabolic (I = K D exp 2), with the constant of the equation, K, ranging from 900 to 2000 μA/mm exp 2, for 0.5 ms pulses. This relationship allows calculation of the radius of the field of dopamine axon excitation at any current. These high K values show that axons of dopamine cells cannot be activated unless high current densities are derivered, even when electrodes are placed near the axons. These data allow determination of the extent to which dopamine axons can be the directly activated substrates for behaviors, such as self-stimulation and circling, which are evoked by electrical stimulation of the medial forebrain bundle or internal capsule.     

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

Presynaptic dopamine receptors: Insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol

Summary The effects of kainic acid lesions and chronic haloperidol treatment on rat striatal dopaminergic presynaptic receptors were studied. Following the -butyrolactone-induced inhibition of dopaminergic impulse flow, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists was measured in vivo.³H-apomorphine (a dopamine receptor ligand with purported presynaptic specificity) was used for in vitro binding experiments. Presynaptic dopamine receptors, as assessed by both methods, were unaffected by intrastriatal kainic acid injection 5–6 days before sacrifice. Seven days after termination of chronic haloperidol treatment (28 days, 0.5 mg/kg/day s.c.) both an increased apomorphine response using the dopa accumulation method and an increase in³H-apomorphine binding were observed, indicating the development of presynaptic dopamine receptor supersensitivity.