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FIGURE 5–2. Detection of changes in firing rates and pattern of spike discharge by extracellular recording measurements.

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FIGURE 5–2. Detection of changes in firing rates and pattern of spike discharge by extracellular recording measurements.Extracellular recording techniques are an effective means of assessing the effects of afferent pathway stimulation or drug administration on neuron activity. On the other hand, the measurements that can be made are typically restricted to changes in firing rates or in the pattern of spike discharge. (A) This firing rate histogram illustrates the response of a substantia nigra–zona reticulata neuron to stimulation of the -aminobutyric acid (GABA)ergic striatonigral pathway. A common method for illustrating how a manipulation affects the firing rate of a neuron is by constructing a firing rate histogram. This is typically done by using some type of electronic discriminator and counter to count the number of spikes that a cell fires in a given time. In this example, the counter counts spikes over a 10-second interval and converts this number to a voltage, which is then plotted on a chart recorder. The counter then resets to zero and begins counting spikes over the next 10-second interval. Therefore, in this firing rate histogram, the height of each vertical line is proportional to the number of spikes that the cell fires during each 10-second interval, with the calibration bar on the left showing the equivalent firing frequency in spikes per second. During the period at which the striatonigral pathway is stimulated (horizontal bars above trace marked "STIM"), the cell is inhibited, as reflected by the decrease in the height of the vertical lines. When the stimulation is terminated, a rebound activation of cell firing is observed. (B) In this figure, a similar histogram is used to illustrate the effects of a drug on the firing of a neuron. (B1) This figure shows the well-known inhibition of dopamine neuron firing rate on administration of the dopamine agonist apomorphine (APO). Each of the filled arrows represents the intravenous administration of a dose of APO. After the cell is completely inhibited, the specificity of the response is tested by examining the ability of the dopamine antagonist haloperidol (HAL [open arrow]) to reverse this response. Typically, drug sensitivity is determined by administering the drug in a dose–response fashion. This is done by giving an initial drug dose that is subthreshold for altering the firing rate of the cell. The first dose is then repeated, with each subsequent dose given being twice that of the previous dose. This is continued until a plateau response is achieved (in this case, a complete inhibition of cell discharge). (B2) The drug is administered in a dose–response manner to facilitate the plotting of a cumulative dose–response curve, with drug doses plotted on a logarithmic scale (i.e., a log dose–response curve). To compare the potency of two drugs or the sensitivity of two cells to the same drug, a point on the curve is chosen during which the fastest rate of change of the response is obtained. The point usually chosen is that at which the drug dose administered causes 50% of the maximal change obtained (i.e., the ED50). As is shown in this example, the dopamine neurons recorded after a partial dopamine depletion (dashed line) are substantially more sensitive to inhibition by APO than the dopamine neurons recorded in control (solid line) rats. (C) In addition to determining the firing rate of a neuron, extracellular recording techniques may be used to assess the effects of drugs on the pattern of spike discharge. This is typically done by plotting an interspike interval histogram. In this paradigm, a computer is connected to a spike discriminator, and a train of about 500 spikes is analyzed. The computer is used to time the delay between subsequent spikes in the train (i.e., the time interval between spikes) and plots this in the form of a histogram, in which the x-axis represents time between subsequent spikes and the y-axis shows the number of interspike intervals that had a specific delay (bin = range of time; e.g., for 1-msec bins, all intervals between 200.0 and 200.99 msec). (C1) The cell is firing irregularly (as shown by the primarily normal distribution of intervals around 200 msec), with some spikes occurring after longer-than-average delays (i.e., bins greater than 400 msec, probably caused by spontaneous inhibitory postsynaptic potentials [IPSPs] delaying spike occurrence). (C2) In contrast, this cell is firing in bursts, which consist of a series of 3–10 spikes with comparatively short interspike intervals (i.e., approximately 70 msec) separated by long delays between bursts (i.e., events occurring at greater than 150-msec intervals). The computer determined that in this case, the cell was discharging 79% of its spikes in bursts, compared with 0% in (C1).Source. (A) 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. (B) Adapted from Pucak ML, Grace AA: "Partial Dopamine Depletions Result in an Enhanced Sensitivity of Residual Dopamine Neurons to Apomorphine." Synapse 9:144–155, 1991. Copyright 1991, Wiley. Used with permission. (C) Adapted from Grace AA, Bunney BS: "The Control of Firing Pattern in Nigral Dopamine Neurons: Single Spike Firing." Journal of Neuroscience 4:2866–2876, 1984a. Copyright 1984, Society for Neuroscience. Used with permission.

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