Dopamine D4 Receptor Mediated Inhibition of Potassium Current in Neurohypophysial Nerve Terminals1

  1. Russell A. Wilke2,1,
  2. Shyue-Fang Hsu2 and
  3. Meyer B. Jackson3
  1. 1Department of Internal Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin (R.A.W.), 2Department of Cardiology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts (S.-F.H.) and 3Department of Physiology, University of Wisconsin School of Medicine, Madison, Wisconsin (M.B.J.)
     
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    Abstract

    Dopamine influences the release of neurohypophysial peptides in vivo. However, the extent to which this effect is caused by a direct dopaminergic action within the neurohypophysis remains unclear. With use of the patch-clamp technique on thin slices of rat posterior pituitary glands, we now provide evidence that dopaminergic agonists inhibit potassium current (IK) in neurohypophysial nerve terminals. Superfusion with the dopamine receptor agonist, (±)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin (PPHT), causes a reversible inhibition of whole-terminal IKunder voltage clamp. This effect is concentration-dependent, with a maximal inhibition of 40 ± 5% and an EC50 of 1.8 ± 1.0 μM. It can be blocked with either a nonselective D2-like antagonist (100 μM eticlopride) or with the highly selective D4 antagonist, RBI-257 (10 μM). U101958 (a derivative of RBI-257) exhibits agonist activity similar to PPHT. Neither SKF 38393 (a D1/D5 agonist) nor quinpirole (a D2/D3 agonist) had any effect on whole-terminal IK in this preparation. Kinetic analysis demonstrated that the amplitude of both the rapidly and slowly inactivating phases of neurohypophysialIK are reduced by D4 receptor activation. These two separate current components have previously been shown to represent current through two distinct potassium channels, an A-current channel and a high-conductance Ca++-activated K+ channel. Thus, both channel types can be modulated by D4 receptors. This effect is likely to enhance the release of neurohypophysial peptides in vivo.

    Antidiuretic hormone and OXT are the main hormonal secretory products of the neurohypophysis. ADH plays an integral role in the maintenance of fluid homeostasis and vascular tone; OXT is a neurohormonal mediator of various reproductive functions (Martin, 1986). It has long been known that dopamine modulates the release of these neuropeptides in vivo (Bridges et al., 1976; Moos and Richard, 1982;Melis et al., 1990). It is unclear, however, whether dopaminergic agents act directly on the neurohypophysis, or if they exert their action on neurons located more proximally within the integrative circuitry of the hypothalamus (Crowley et al., 1991). Direct electrophysiological study of the neurohypophysis should help clarify this issue.

    Animal studies suggested that the stimulatory effect of apomorphine on neurohypophysial peptide release was mediated through a D2 dopamine receptor (Amico et al., 1992). Although conflicting reports have since implicated other receptor subtypes, much of the available evidence still supports the initial claim that this effect is transduced through a dopaminergic receptor which has “D2-like” pharmacology (Parker and Crowley, 1992; Uvnas-Moberg et al., 1995). Recently, molecular cloning has revealed that the D2-like family of dopamine receptors consists of at least three distinct membrane proteins: D2, D3 and D4 (Gingrich and Caron, 1993). Great effort currently is being made in the development of selective ligands for each of these receptor subtypes. Although several highly selective D4 antagonists are now commercially available, no D4 agonist has yet been described (Strange, 1994; Kebabian, et al., 1997).

    Dopamine has been shown to modulate potassium channel function in a variety of neuronal preparations (Stack and Surprenant, 1991; Liuet al., 1996). In the past, the small size and inaccessibility of peptidergic nerve terminals has impeded progress in understanding the membrane events governing neurohypophysial hormone secretion. To overcome this problem, several approaches have been developed for making intracellular recordings in the posterior pituitary (Lemos and Nowycky, 1989; Bourque, 1990; Jackson et al., 1991). In this study we have used patch-clamp techniques to investigate the effect of dopamine receptor activation onIK in voltage-clamped nerve terminals in neurohypophysial slices.

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    Methods

    Slice preparation.

    Experiments were performed on tissue from Sprague-Dawley rats of either sex weighing 240 to 260 g. Animals were housed under constant 12/12 hr light/dark cycle with free access to water and food. After CO2-induced narcosis and decapitation, the brain was removed and discarded. The cranium was then filled with ice-cold aCSF: 115 mM NaCl, 4.0 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 2 mM CaCl2, 1 mM MgCl2, and 10 mM glucose, saturated with 95% O2/5% CO2. The neurointermediate and anterior pituitary lobes were removed from the calvarium and separated by gentle insertion of fine forceps. The neurointermediate lobe was then glued to a plastic block, submerged in ice-cold saline and sliced with a Lancer Vibratome at a thickness of 60 to 75 μm. All slices were stored at room temperature (21–24°C) in 95% O2/5% CO2-saturated aCSF and used within 3 hr (Jackson et al., 1991; Jackson, 1993).

    Patch-clamp electrophysiology.

    Patch-clamp recordings were made with an EPC-9 patch-clamp amplifier interfaced to a MacIntosh computer. Stimulus and data acquisition were carried out with the computer program Pulse (Instrutech, Great Neck, NY). Tissue slices were perfused with aCSF (as above), bubbled with 95% O2/5% CO2 at room temperature at a rate of 2 to 4 ml/min through a simple gravity feed system. Individual nerve terminals at the slice surface were located with an upright Nomarski microscope (Reichert Jung diastar) and a Zeiss 40× water immersion, long working distance objective (Jackson et al., 1991; Jackson, 1993). Patch pipettes were fabricated from thin-walled borosilicate glass, and the pipette shanks were coated with Sylgard to reduce electrode capacitance (Hamill et al., 1981).

    Whole-terminal current was recorded under voltage clamp, with patch pipettes filled with 130 mM KCl, 10 mM ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid, 2 mM MgCl2, 4 mM MgATP, 300 μM NaGTP, and 10 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) at pH 7.3. Before cell contact, pipette resistances ranged from 3 to 9 megaohm. Immediately after breaking in, cell capacitance and series resistance were determined with the transient cancellation circuitry of the EPC-9. Where the initial series resistance (Rs) was greater than 15 megaohm, an attempt was made to partially compensate this value electronically. Only cells that had a compensatedRs value less than 15 megaohm were included in the final analysis.

    Drug application.

    All dopaminergic agents used in these experiments were obtained from Research Biochemicals International (Natick, MA). These compounds were dissolved in aCSF and applied to the preparation by superfusion. Before the addition of drugs, current was recorded at 15- or 30-sec intervals for 1 to 3 min to verify the stability of the baseline. Current was also recorded after the removal of any drug(s) to demonstrate viability of the cell and recovery ofIK to the original baseline. In experiments conducted with highly lipophilic drugs like PPHT, the agent was first dissolved in dimethyl sulfoxide, then diluted into aCSF to obtain the desired final drug concentration. The final concentration never exceeded 0.1% dimethyl sulfoxide; this vehicle, without drug, was tested and had no effect on whole-terminalIK.

    Data analysis.

    Current records were analyzed on a MacIntosh computer with the computer program PulseFit (Instrutech Inc., Great Neck, NY). This program was used to fit current decays to a double-exponential function. The computer program Origin (MicroCal, Northampton, MA) was used on a personal computer to fit data to a Boltzmann function. Simple statistical analyses were performed on exported data with the program Microsoft Excel. When arithmetic means were computed, they were presented with the standard error of the mean. All null hypotheses were subjected to the appropriate ttest, and a level of P < .05 was considered statistically significant.

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    Results

    Inhibition of outward current.

    Consistent with previous studies on this preparation (Jackson et al., 1991;Bielefeldt et al., 1992), all nerve terminals in the current study displayed a prominent outward current in response to depolarizing test pulses under voltage clamp (n > 50). Pharmacological and biophysical studies have established that this is an IK (Bielefeldt et al., 1992). Voltage steps from −100 mV to +10 mV rapidly activated this current (fig. 1), which subsequently inactivated while the test potential was held constant.

    Figure 1
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    Figure 1

    Outward K+ current in voltage-clamped neurohypophysial nerve terminals. After a 250-msec prepulse at −100 mV, voltage was stepped to +10 mV for 500 msec, then returned to the holding membrane potential of −80 mV. In this representative set of tracings, a brief (<5 msec) tetrodotoxin-sensitive inward Na+ current can be seen at the beginning of each depolarizing test pulse. A prominent outward current is rapidly activated and then decays over time. When the same nerve terminal was depolarized after 5 min of exposure to 30 μM PPHT, a marked reduction in both peak and final K+ current was observed.

    Figures 1 and 2 demonstrate that superfusion of these terminals with the D2-like dopaminergic receptor agonist, PPHT, reversibly inhibited both the peak and final components of outward neurohypophysialIK. To determine the potassium channel types modulated by this agent, the current decay was fitted to a double-exponential function:FormulaEquation 1

    Figure 2
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    Figure 2

    Reversibility of the PPHT effect.IK was recorded at 30-sec intervals by the stimulation paradigm described in figure 1. Superfusion with 10 μM PPHT (indicated by the bar) reduced both peak and final components of this outward K+ current, and the effect was completely reversed when the agonist was washed from the medium. Final current represents the mean current calculated during the last 200 msec of each 500-msec depolarizing pulse (as shown in fig. 1).

    Previous work (Bielefeldt et al., 1992) showed that a rapidly inactivating component of IK (with an amplitude denoted as I1 and a time constant as τ1) reflects current through an A-current channel, and that a slowly inactivating component ofIK (with an amplitude denoted asI2 and a time constant as τ2) reflects current through a Ca++-activated K+ channel. This fitting procedure therefore provides a means of evaluating changes in each of these two K+ channel types. The time constants remain essentially unchanged after PPHT application, but the amplitudes of both the fast (I1) and slow (I2) components were reduced by PPHT. (I1 = 74 ± 11% of control andI2 = 87 ± 12% of control with 1 μM PPHT; I1 = 53 ± 9% of control andI2 = 64 ± 8% of control with 100 μM PPHT.) These results suggest that two types of K+ channel are modulated by PPHT. Furthermore, because the amplitude of I2 is altered by changes in [Ca++]i (Bielefeldtet al., 1992), we repeated these experiments in the presence of 100 μM cadmium. This compound inhibits neuronal calcium current; yet, in three separate experiments, 100 μM cadmium had no effect on the ability of PPHT to inhibit neurohypophysialIK (data not shown).

    The inhibitory effect of PPHT on neurohypophysialIK increased with increasing PPHT concentration (fig. 3). To define this relationship quantitatively, the data were fitted to the following equation:FormulaEquation 2

    Figure 3
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    Figure 3

    PPHT concentration-response curve. At each concentration, outward K+ current was recorded before and after a 5-min superfusion with the dopamine receptor agonist, PPHT. The stimulation paradigm for each voltage pulse was identical with that described in figures 1 and 2. Final current in the presence of PPHT was normalized to the predrug control response for the same individual nerve terminal. Each concentration point is a mean ± S.E.M. for three to six nerve terminals. The best curve fit (see text for equation and parameters) describing this concentration-response relationship is shown as a dotted line.

    where C is the concentration of PPHT in the superfusion medium, Emax represents the maximal inhibitory effect of PPHT and EC50 is the PPHT concentration where E/Emax = 1/2. According to this curve fit, maximal inhibition was 40 ± 5% and the EC50 was 1.8 ± 1.0 μM.

    Collectively, the results described in figures 1 to 3 show that the dopaminergic receptor agonist, PPHT, is capable of directly modulating membrane excitability within the peptidergic nerve terminals of the neurohypophysis.

    Dopamine-receptor specificity.

    Preincubation of nerve terminals with 100 μM eticlopride, a nonselective antagonist for D2-like dopamine receptors (D2, D3 and D4), completely eliminated the inhibitory effect of 10 μM PPHT (fig. 4). By itself, 100 μM eticlopride had no effect on nerve terminalIK. To address the issue of dopamine receptor subtype, we tested neurohypophysial nerve terminalIK with a panel of dopaminergic agonists (fig. 5). The agonist, SKF 38393, binds to members of the “D1-like” receptor family (D1A and D1B/D5) with an apparent affinity in the nanomolar range (Madras et al., 1990); yet 100 μM SKF had no effect on IK in our preparation.

    Figure 4
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    Figure 4

    Elimination of the PPHT effect with a D2-like receptor antagonist. FinalIK was assessed by the same pulse protocol used in figure 1. After establishing a stable current baseline (3–5 min), nerve terminals were superfused with either aCSF alone or with aCSF containing 100 μM eticlopride for a full 5 min before the addition of 10 μM PPHT. This concentration of agonist (PPHT) was chosen based on its location along the concentration-response curve just above the inflection point (fig. 3). Data represent the mean ± S.E.M. for three to six individual nerve terminals. * indicates P < .05 between columns.    

    Figure 5
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    Figure 5

    D4-type dopamine receptor selectivity. Final neurohypophysial K+ current was monitored in the presence of various dopamine receptor agonists, according to the same pulse paradigm used in figure 1. After establishing a stable base line, nerve terminals were superfused for 5 min with either SKF 38393 (D1/D5 selective), quinpirole (D2/D3 selective) or U101958 (D4selective), and then reassessed. All agonists were presented at 100 μM. Final K+ current was normalized to the predrug control response for each individual nerve terminal and averaged. Data represent the mean ± S.E.M. for three to six individual nerve terminals. The * indicates that the effect of U101958 was significantly different from that of SKF 38393 and quinpirole (P < .05).

    Although the D2-like family of dopamine receptors exhibits a considerable amount of overlap in their ability to bind various ligands, 100 μM quinpirole also had no effect onIK in our preparation (fig. 5). This dopaminergic agonist binds both D2 and D3 receptor subtypes with an affinity in the nanomolar range (Freedman et al., 1994; Sokoloff et al., 1990). Its interaction with the D4receptor subtype has been less well characterized but agonist activity of quinpirole has been reported in a cell proliferation assay (Ten Brink et al., 1996). Recently, some highly selective D4 receptor ligands have become commercially available. One of these, U101958, has been shown to bind this receptor with nanomolar affinity (Schlachter et al., 1995). Although it has been described previously as an antagonist, in our hands, U101958 reversibly inhibited neurohypophysialIK with an efficacy comparable to that of PPHT (figs. 5 and 6).

    Figure 6
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    Figure 6

    Reversible reduction ofIK by U101958. IKwas recorded at 15-sec intervals with the pulse paradigm used in figure1. The time of U101958 superfusion is indicated by the bar above. Like PPHT, 100 μM U101958 reduced both peak and final components ofIK. The effect was reversed when agonist was washed from the medium.

    As an additional test of the role of the D4dopamine receptor subtype, an attempt was made to block the PPHT response with a D4 specific antagonist (fig.7). RBI-257 is a highly selective antagonist at the D4 dopamine receptor (Kebabianet al., 1997). At a concentration of 10 μM, this compound abolished the effect of 10 μM PPHT (peakIK = 90 ± 2% of control; finalIK = 98 ± 10% of control, after 5 min; n = 4). By itself, however, RBI-257 had no effect on neurohypophysial IK (data not shown).

    Figure 7
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    Figure 7

    Blockade of the PPHT response by a D4-type dopamine receptor antagonist.IK was recorded at 15-sec intervals before, during and after challenge with agonist (pulse paradigm as in fig. 1). Both peak and final components of IK were reversibly inhibited by 10 μM PPHT (closed symbols). When a D4-selective antagonist (10 μM RBI-257) was added to the medium, the action of PPHT was blocked (open symbols). Data represent the mean of three control experiments and four blockade experiments. See text for mean normalized current values.

    Because PPHT has also been shown to interact with 5-hydroxytryptamine1A receptors (Barton et al., 1991), 100 μM 5-hydroxytryptamine was tested and did not alter neurohypophysial IK after superfusion for 5 min (peak IK = 90 ± 12% of control; final IK = 105 ± 26% of control; n = 3).

    Kinetic characterization.

    To investigate the mechanism of this alteration in neurohypophysial IK, we studied the effect of D4 receptor activation on the voltage dependence of K+ channel activation. Outward current was recorded before and after a 5-min exposure to 30 μM PPHT. By use of test pulses varying from −70 to 30 mV, current-voltage relationships were constructed for both peak and finalIK (fig. 8). At all voltages tested PPHT reduced IK by approximately proportional amounts, which indicates that D4 receptor activation does not produce its inhibitory effect by shifting the voltage dependence of these K+ channels.

    Figure 8
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    Figure 8

    Current plotted versus voltage for peak (triangles) and final (squares) K+ current. Voltage-clamped nerve terminals were held at −80 mV and interrupted at 5-sec intervals with 500-msec pulses to each of the depolarizing voltages shown (open symbols). After a 5-min exposure to 30 μM PPHT (closed symbols), the same nerve terminals were again subjected to a repeat series of voltage pulses from −70 through 30 mV. Data points (connected by solid lines) represent the mean current for six individual terminals.

    The effect of 30 μM PPHT on steady-state inactivation was also studied. After prepulses varying from −130 to −40 mV, peak outward current was monitored during depolarizing voltage steps to 10 mV. The data were then averaged from six experiments, plotted as a function of prepulse voltage (fig. 9) and fitted to the following Boltzmann function:FormulaEquation 3

    Figure 9
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    Figure 9

    Current inactivation profile. Voltage-clamped nerve terminals were held at various prepulse potentials (from −130 to −40 mV) for 500 msec, then stepped to +10 mV for an additional 500 msec. Peak current at 10 mV was then plotted as a function of prepulse voltage (open circles) to assess the voltage-dependent inactivation of these neurohypophysial K+ channels. After a 5-min exposure to 30 μM PPHT, each individual terminal was subjected to the same test series, and peak current was again plotted against prepulse voltage (closed circles). Data represent the mean values from six experiments. Best fitting Boltzmann functions are drawn as dotted lines. PPHT did not alter the voltage dependence of inactivation (see text for parameter values).

    All four parameters (Imin,Imax, κ andV½) were varied to achieve the best fit.Imin and Imaxrepresent the current asymptotes at negative and positive prepulse potentials, respectively; κ is the steepness factor;V½ is the midpoint for voltage dependence. Under control conditions (open circles), κ = 9.3 ± 0.7 mV and V½ = −79.5 ± 0.7 mV. After the 5-min exposure to 30 μM PPHT (closed circles), neither the steepness factor (κ = 8.9 ± 0.6 mV) nor the voltage midpoint (V½ = −79.9 ± 0.7 mV) of inactivation had been altered significantly.

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    Discussion

    This study has shown that activation of a dopamine receptor inhibits IK in the neurohypophysis. The nerve terminals of this preparation previously have been shown to contain three different types of K+ channels (Bielefeldt et al., 1992). One type conducts a rapidly inactivating transient outward current, IA, which shares many common properties with the transient outward current of the cell bodies within the hypothalamic nuclei from which these axons originate (Cobbett et al., 1989). A second type,IBK, is a Ca++-dependent K+ channel which differs in its kinetic profile from hypothalamic Ca++-dependent K+ channels. The data obtained from our kinetic analysis indicate that these two channel types are functionally altered by D4receptor activation. The third type of neurohypophysial K+ channel, the D channel, is slowly activating and shows no inactivation (Bielefeldt et al., 1992). Because of the small and variable contribution made by the D channel to whole terminal IK, we cannot say whetherID is also modulated by dopamine receptor activation.

    Activation of dopamine receptors expressed in a neuronal cell line increased conductance through inwardly rectifying K+ channels (Greif et al., 1995). To our knowledge, no inwardly rectifying K+ channels have been observed within the nerve terminals of the neurohypophysis. Furthermore, the dopamine response described here is an inhibition ofIK rather than an enhancement. Voltage-clamp studies in rat hippocampal pyramidal neurons (Pedarzani and Storm, 1995) have demonstrated a similar dopamine receptor-mediated reduction in a slow Ca++-dependent K+ current (IAHP). This is similar to our finding a reduction in a Ca++-dependent K+ current (IBK). However, in the neurohypophysis another IK, the A-current, was also reduced. The observation that two distinct K+channels can be modulated by the same dopamine receptor is not without precedent. With a mesencephalic neuronal preparation derived from embryonic rats, Liu et al. (1994) found that quinpirole is capable of simultaneously altering both anIA and a delayed rectifier through a common G-protein-mediated mechanism.

    A decade ago, it was widely accepted that dopamine acted through two receptor subtypes: D1 and D2 (Sokoloff and Schwartz, 1995). In this schema based on pharmacological data, butyrophenone antipsychotics (such as haloperidol) bound the D1 receptor with very low affinity and the D2 receptor with high affinity. The recent cloning and sequencing of dopamine receptors has changed this view considerably. These studies have identified six unique dopamine receptor subtypes (Sibley et al., 1993; Gingrich and Caron, 1993). However, these six are in two discrete families, now called “D1-like” and “D2-like.” Members of the D1-like family (D1A, D1B and D5 receptors) share a very high degree of sequence homology within their transmembrane domains, and they have only limited distribution within the rat central nervous system (Gingrich and Caron, 1993). The D1agonist, SKF 38393, binds all three members of this D1-like receptor family with relatively high affinity. Our finding that 100 μM SKF38393 had no effect on potassium current in peptidergic nerve terminals indicates that a D1-like receptor is not involved in this response.

    Members of the D2-like family of dopamine receptors (D2, D3 and D4) exhibit a considerable amount of overlap in their ability to bind various ligands. The nonselective D2-like dopamine receptor agonist, PPHT, reversibly inhibited neurohypophysial IK in a concentration-dependent fashion. Furthermore, the D2-like dopamine receptor antagonist eticlopride blocked the action of PPHT. These results indicate that the receptor responsible for the reduction in neurohypophysialIK is a member of the D2-like dopamine receptor family. Because the PPHT response can be blocked by the highly selective D4 dopamine receptor antagonist, RBI-257, it is likely that the PPHT response is mediated by this receptor. Quinpirole, a ligand known to exhibit nanomolar affinity at both the D2 and D3 dopamine receptors (Sokoloff et al., 1990; Levesque et al., 1992; Freedman et al., 1994) and to activate these receptors at concentrations smaller than 100 μM (Liu et al., 1996), had no effect on neurohypophysialIK at this concentration. A caveat in our identification of this receptor as a D4 subtype is the report of quinpirole activation of the human receptor (Ten Brinket al., 1996). Nevertheless, our results suggest that the only dopamine receptor with an effect on K+current in our preparation is the D4 subtype. The present study represents the first report of an in situresponse transduced by a D4 dopamine receptor. The reduction of a K+ current described here is similar to that seen in cells stably transfected with D4 receptor cDNA (Colville et al., 1994)

    We also investigated the action of U101958, a compound that binds to D4 dopamine receptors with an apparent affinity in the nanomolar range (Schlachter et al., 1995; Kebabianet al., 1997); its affinity for D2 and D3 receptors is approximately 1000-fold less (Kebabian et al., 1997). This compound was shown to antagonize responses mediated by a human D4receptor (TenBrink et al., 1996). Our observation that U101958 reduces neurohypophysial IKdemonstrates that this ligand acts as an agonist in the rat posterior pituitary, and a D4-receptor-specific agonist should be a useful experimental tool in probing the function of this receptor subtype.

    The observation that D4 receptor activation alters IK within the neurohypophysis has important implications regarding the dopaminergic modulation of neuropeptide release in vivo. An increase in the frequency of neurohypophysial impulses enhances neuropeptide release (Gaineret al., 1986; Armstrong et al., 1989), presumably through the sequence of partial IKinactivation, action potential broadening and increased calcium entry (Gainer et al., 1986; Bourque, 1990; Jacksonet al., 1991). This would suggest that D4 receptor activation, with its inhibitory effect on presynaptic IK, could enhance neurohypophysial peptide release in a similar fashion.

    The ability to secrete ADH or OXT in response to an appropriate stimulus depends on the neurohypophysis receiving information from various sensor elements. The release of ADH is affected by small (<1%) variations in plasma osmolality, a signal which is detected and integrated through hypothalamic osmoreceptors (Oliet and Bourque, 1994). Although neurohypophysial cell bodies have been shown to generate action potentials in vitro after the application of hyperosmotic solutions (Oliet and Bourque, 1993), many investigators believe that these neurons are at least one synapse away from the actual osmoreceptors (Reeves and Andreoli, 1992; Oliet and Bourque, 1994). In a recently published whole-animal study, intracerebroventricular injection of the D2-like dopamine receptor antagonist, haloperidol, was shown to attenuate the increase in circulating levels of ADH induced by intravenous infusion of hypertonic saline (Yamaguchi et al., 1996). It is possible, therefore, that dopaminergic neurotransmission within the neurohypophysis contributes to the regulation of the ADH secretory response to an osmotic load in vivo. The D4-receptor-mediated inhibition of neurohypophysial IK described above provides at least one potential mechanism whereby endogenous dopamine may mediate such an effect.

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    Footnotes

    • Send reprint requests to: Meyer B. Jackson, PhD, Department of Physiology, 121 Service Memorial Institute, University of Wisconsin School of Medicine, 1300 University Avenue, Madison, WI 53706.

    • ↵1 Support for this research was provided by National Institutes of Health grant NS30016.

    • ↵2 Trainee in the Clinical Investigator Pathway and a postdoctoral fellow in the Department of Physiology at the University of Wisconsin.

    • Abbreviations:
      aCSF
      artificial cerebrospinal fluid
      ADH
      antidiuretic hormone
      IK
      potassium current
      OXT
      oxytocin
      PPHT
      (±)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin
      • Received May 13, 1997.
      • Accepted October 27, 1997.
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