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Preparations Used in Electrophysiological Research

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FIGURE 5–7. Determining the effects of systemic and direct drug administration on neuronal activity.There are several means of applying drugs to a neuron to examine their actions. During in vivo recording, drugs may be administered systemically (i.e., intravenously, intraperitoneally, subcutaneously, intraventricularly, intramuscularly) or directly to the neuron by microiontophoresis or pressure ejection. (A) Systemic administration of a drug is useful for determining how a drug affects neurons in the intact organism, regardless of whether the action is direct or indirect. In this case, intravenous administration of the -aminobutyric acid (GABA) agonist muscimol (solid arrows) causes a dose-dependent increase in the firing rate of this dopamine-containing neuron. (B) In contrast, direct administration of a drug to a neuron will provide information about the site of action of the drug, at least as it concerns the discharge of the neuron under study. In this case, GABA is administered directly to a dopamine neuron by microiontophoresis. In this technique, several drug-containing pipettes are attached to the recording electrode. The pH of the drug solutions is adjusted to ensure that the drug molecules are in a charged state (e.g., GABA is used at pH = 4.0 to give it a positive charge), and the drug is ejected from the pipette tip by applying very small currents to the drug-containing pipette. Because the total diameter of the microiontophoretic pipette tip is only about 5 m, the drugs ejected typically affect only the cell being recorded. In this case, GABA is applied to a dopamine neuron by microiontophoresis; the horizontal bars show the time during which the current is applied to the drug-containing pipette, and the amplitude of the current (indicated in nA) is listed above each bar. Note that, unlike the excitatory effects produced by a systemically administered GABA agonist in (A), direct application of GABA will inhibit dopamine neurons. This has been shown to be caused by inhibition of a much more GABA-sensitive inhibitory interneuron by the systemically administered drug and illustrates the need to compare systemic drug administration with direct drug administration to ascertain the site of action of the drug of interest.Source. Adapted from Grace AA, Bunney BS: "Opposing Effects of Striatonigral Feedback Pathways on Midbrain Dopamine Cell Activity." Brain Research 333:271–284, 1985. Copyright 1985, Elsevier. Used with permission.

FIGURE 5–8. Use of a microdialysis probe for delivering drugs locally during in vivo recordings to affect local circuits.(A) In this schematic diagram, the relationship between the microdialysis probe and the intracellular recording electrode is depicted. In this case, the neuron recorded is in the striatum. The active surface of the microdialysis probe is shown in gray; this is the area through which the compound is delivered. The probe is implanted very slowly so as not to disrupt the tissue (i.e., 3–6 m per second) and is perfused with artificial cerebrospinal fluid for 2–4 hours to allow equilibration and settling of the tissue prior to recording. The intracellular recording electrode is then advanced, and a neuron is impaled. After recording baseline activity for 10 minutes, the perfusate is changed to a drug-containing solution to examine the effects on the neuron. (B) The histology taken after the recording shows the track of the microdialysis probe; the termination site of the probe tip is indicated by a dashed arrow. To confirm that the neuron recorded was near the probe, the neuron is filled with a stain (in this case, biocytin) so as to allow visualization of the neuron. In this case, the neuron was confirmed to be a medium spiny striatal neuron (magnified in insert). ac = anterior commissure. (C) Recordings taken from the neuron labeled in B. The top trace shows the activity of the neuron while the microdialysis probe is being perfused with artificial cerebrospinal fluid. The neuron demonstrates a healthy resting membrane potential, and spontaneously occurring postsynaptic potentials are evident. The lower trace shows the same neuron 15 minutes after switching to a perfusate containing the dopamine D2 antagonist eticlopride. The neuron shows a strong depolarization of the resting potential (by 12 mV) as well as increased postsynaptic potential activity and spontaneous spike firing. Since the eticlopride is blocking the effects of dopamine that is being released spontaneously from dopamine terminals in this region, we can conclude that basal levels of dopamine D2 receptor stimulation cause a tonic hyperpolarization of the neuronal membrane and suppress spontaneous excitatory postsynaptic potentials.Source. Adapted from West AR, Grace AA "Opposite Influences of Endogenous Dopamine D1 and D2 Receptor Activation on Activity States and Electrophysiological Properties of Striatal Neurons: Studies Combining In Vivo Intracellular Recordings and Reverse Microdialysis." Journal of Neuroscience 22:294–304, 2002. Copyright 2002, Society for Neuroscience. Used with permission.

FIGURE 5–9. Variation (sometimes substantial) in patterns of activity of a neuron type, depending on the preparation in which it is recorded.(A) Extracellular recordings of a dopamine neuron in an intact anesthetized rat (i.e., in vivo) illustrate the typical irregular firing pattern of the cell, with single spikes occurring intermixed with bursts of action potentials. (B) In contrast, intracellular recordings of a dopamine neuron in an isolated brain slice preparation (i.e., in vitro) illustrate the pacemaker pattern that occurs exclusively in identified dopamine neurons in this preparation. For dopamine neurons, a pacemaker firing pattern is rarely observed in vivo, and burst firing has never been observed in the in vitro preparation. However, although the activity recorded in vitro is obviously an abstraction compared with the firing pattern of this neuron in vivo, a comparative study in each preparation does provide the opportunity to examine factors that may underlie the modulation of firing pattern in this neuronal type.Source. Adapted from Grace AA: "The Regulation of Dopamine Neuron Activity as Determined by In Vivo and In Vitro Intracellular Recordings," in The Neurophysiology of Dopamine Systems. Edited by Chiodo LA, Freeman AS. Detroit, MI, Lake Shore Publications, 1987, pp. 1–67 (Copyright 1987, Lake Shore Publications. Used with permission); and Grace AA, Bunney BS: "Intracellular and Extracellular Electrophysiology of Nigral Dopaminergic Neurons, I: Identification and Characterization." Neuroscience 10:301–315, 1983. Copyright 1983, International Brain Research Organization. Used with permission.

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