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1Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville; and 2Department of Neurology and Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, California
Submitted 18 August 2004; accepted in final form 17 December 2004
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ABSTRACT |
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INTRODUCTION |
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opioid receptors (KOP-R) (Arvidsson et al. 1995
; Mansour et al. 1996) and µ opioid receptors (MOP-R) (Garzon and Pickel 2001; Svingos et al. 2001) are present in significant density in the VTA. Furthermore, microinjections of both KOP-R and MOP-R agonists directly into the VTA produce robust behavioral responses. The KOP-R agonist U50488H produces conditioned place aversion (Bals-Kubik et al. 1993). In contrast, the MOP-R agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-Enkephalin (DAMGO) produces conditioned place preference (Bals-Kubik et al. 1993; Nader and van der Kooy 1997; Phillips and LePiane 1980).
Glutamate transmission within the VTA is required for the motivational properties of opioids (e.g., Cornish et al. 2001; Harris and Aston-Jones 2003; Xi and Stein 2002). In the VTA, glutamatergic inputs are derived from neurons in the medial prefrontal cortex (mPFC), subthalamic nucleus (STN), and the pedunculopontine nucleus (PPN) (Charara et al. 1996; Christie et al. 1985; Groenewegen and Berendse 1990; Sesack and Pickel 1992). There is also indirect evidence that lateral hypothalamic projections to the VTA contain glutamate (Chou et al. 2001; Rosin et al. 2003). Under physiological conditions, glutamate can induce phasic firing in dopaminergic neurons through the activation of N-methyl-D-aspartate (NMDA) receptors (Chergui et al. 1993; Johnson et al. 1992; Overton and Clark 1997), and this effect is facilitated by group 1 metabotropic glutamate receptor activation (Zheng and Johnson 2002). There is also evidence that glutamate activation of 2-amino-3(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptors in the VTA can increase extracellular dopamine (DA) in the nucleus accumbens (NAc) (Karreman et al. 1996; Schilstrom et al. 1998).
Essential to determining how KOP and MOP receptor agonists in the VTA produce their behavioral actions is elucidating their synaptic effects at the cellular level in all VTA cell types. VTA neurons are classified as principal, secondary, or tertiary according to their electrophysiological and pharmacological properties (Cameron et al. 1997). Both principal and tertiary neurons exhibit the hyperpolarization-activated nonspecific cation current (Ih) and have relatively long duration action potentials. Secondary cells lack an Ih and have shorter duration action potentials. They are directly hyperpolarized by MOP-R agonists and are GABA neurons. Secondary cell inhibition by MOP-R agonists has been proposed to disinhibit principal neurons through local circuitry (Johnson and North 1992; Margolis et al. 2003). Tertiary neurons differ from principal cells in that they are directly hyperpolarized by MOP-R agonists and serotonin. While most principal neurons are dopaminergic (
80%), <40% of tertiary neurons are dopaminergic. KOP-R agonists postsynaptically inhibit a subset of both principal and tertiary neurons, an effect limited to dopaminergic neurons of each class (Margolis et al. 2003).
Despite the evidence that VTA glutamatergic transmission is critical for reward and motivation, our understanding of presynaptic control of glutamate release by opioids is incomplete. We therefore examined the effects of both KOP and MOP receptor agonists on glutamate release onto each VTA cell type. We directly compared KOP and MOP effects within and across individual neurons and neuron types. Because both KOP and MOP effects were observed, we addressed the issue of whether KOP and MOP receptor agonists act on the same terminals by testing whether the effects of the two agonists occluded.
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METHODS |
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1 h.
Individual slices were visualized under a Zeiss Axioskop with differential interference contrast optics and infrared illumination. Whole cell patch-clamp recordings were made at 31°C using 2.5- to 4-M
pipettes containing (in mM) 123 K-gluconate, 10 HEPES, 0.2 EGTA, 8 NaCl, 2 MgATP, and 0.3 Na3GTP (pH 7.2, osmolarity adjusted to 275).
Recordings were made using an Axopatch 1-D, filtered at 2 kHz, and collected at 5 kHz using IGOR Pro (Wavemetrics, Lake Oswego, OR). Ih was recorded by voltage clamping cells and stepping from –60 to –120 mV. Series resistance and input resistance were sampled throughout voltage-clamp experiments with 4-mV, 200-ms depolarizing steps once every 10 s. For purposes of classification, every neuron was tested for postsynaptic actions of either the MOP-R selective agonist DAMGO (3 µM) or the 5-HT1 agonist 5-carboxamidotryptamine (5-CT; 500 nM) in current clamp following the voltage-clamp experiment. Cells were recorded in voltage-clamp mode (V = –70 mV) while measuring excitatory postsynaptic currents (EPSCs). All EPSCs were measured in the presence of picrotoxin (100 µM). Stimulating electrodes were placed 60–150 µm rostral to the patched cell. In neurons where paired pulses were administered, two pulses 50 ms apart were delivered once every 10 s. The EPSC amplitude was calculated by comparing a 2-ms period around the peak to a 2-ms interval just before stimulation. The paired-pulse ratio (PPR) was calculated by dividing the amplitude of the second EPSC by that of the first, trial by trial, and averaging across trials. Spontaneous events were identified in a subset of experiments by searching the smoothed first derivative of the data trace for values that exceeded a set threshold, and these events were visually confirmed. Experiments with baseline sEPSC frequencies <0.25 Hz were excluded from drug effect analyses because too few events were detected to reliably measure changes in frequency.
Results are presented as means ± SE where appropriate. Summary comparisons were made between the average of the 4 min of baseline just preceding each respective drug application to 4 min of stable drug effect. The significance of drug effects was tested across all VTA neurons and within individual cell types using the two-way repeated-measures ANOVA followed by the Student-Newman-Keuls (SNK) method for multiple comparisons. Differences in effect sizes between neuron populations were tested with one-way ANOVA and the SNK method where appropriate. The significance of effects within individual neurons was tested with the Student's t-test, comparing the last 4 min of baseline to the last 4 min of drug application. Significance was defined at P < 0.05. In the case of postsynaptic drug effects, recovery during drug washout was also required.
All drugs were applied by bath perfusion. Stock solutions were made and diluted in Ringer immediately before application. (trans)-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593 [GenBank] ) was diluted in 50% EtOH to a concentration of 1 mM; nor-binaltorphimine (nor-BNI; 1 mM), 5-CT (1 mM), CTAP (1 mM), and DAMGO (1 mM) were diluted in H2O. Picrotoxin was diluted in DMSO (100 mM). All chemicals were obtained from Sigma Chemical (St. Louis, MO) or Tocris (Ballwin, MO).
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RESULTS |
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To address the question of whether opioids differentially alter glutamatergic transmission onto different cell types in the VTA, we classified neurons by their electrophysiological and pharmacological properties as principal, secondary, or tertiary (Margolis et al. 2003). In most neurons, the changes in stimulated EPSC amplitude following bath application of both the KOP-R selective agonist U69593
[GenBank]
(1 µM) and the MOP-R selective agonist DAMGO (3 µM) were measured (Fig. 1). U69593
[GenBank]
produced a modest reduction in EPSC amplitude in principal neurons (14 ± 4%), significantly smaller than the DAMGO effect in the same neurons (42 ± 8%, n = 11, ANOVA: P < 0.01). In contrast, in secondary cells, EPSCs were inhibited to a similar degree by both U69593
[GenBank]
(47 ± 10%) and DAMGO (45 ± 10%, n = 10). EPSCs in tertiary neurons were also inhibited by both U69593
[GenBank]
(33 ± 6%) and DAMGO (35 ± 6%, n = 9). Because inhibition by the KOP-R agonist U69593
[GenBank]
persisted for 15 min after washout commenced (1 µM, n = 6, data not shown), we used the KOP-R selective antagonist nor-BNI (100 nM) to reverse the KOP-mediated inhibition. Application of nor-BNI before U69593
[GenBank]
completely blocked the KOP-R agonist effect (2 ± 2%, n = 3, 1 cell of each type). Because DAMGO was applied a second time to identify the cell type while recording in current-clamp mode, in most experiments no antagonist was used to reverse the prolonged presynaptic MOP-R activation response. However, in a separate set of cells, the application of the MOP-R selective antagonist D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2 (CTAP; 500 nM) reversed the DAMGO (3 µM) effect (n = 4, data not shown).
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To provide evidence that the observed EPSC inhibitions were presynaptic, we examined changes in the PPR for each drug. A drug-induced decrease in the probability of release is typically correlated with an increase in the PPR (Manabe et al. 1993). We found no significant differences between the baseline PPRs of the different cell types (principal: 0.9 ± 0.1, n = 12; secondary: 1.2 ± 0.2, n = 9; tertiary: 0.93 ± 0.06 Hz, n = 8; ANOVA: P > 0.05).
Although opioid-induced changes in PPR for both U69593 [GenBank] and DAMGO varied greatly across cells and cell types, enhancement of PPR was observed for both receptor types. Figure 2A shows examples comparing baseline evoked EPSCs to those recorded in the presence of either U69593 [GenBank] or DAMGO and the time courses of the EPSC amplitude and PPR. This principal neuron exhibited a significant increase in PPR with both drugs. Overall, VTA neurons showed a significant facilitation of PPR in the presence of U69593 [GenBank] (n = 29, ANOVA: P < 0.05, Fig. 2B) and DAMGO (n = 28, ANOVA: P < 0.05, Fig. 2C). However, when broken down by cell type, the only significant effect observed was that produced by DAMGO in secondary neurons. Individually, less than one-third of all neurons (8/30) showed a significant increase in PPR with U69593 [GenBank] (Student's t-test, P < 0.05), and these neurons were distributed across all three cell types. A slightly higher proportion of neurons showed a significant increase in PPR with DAMGO (11/29), and these also included neurons of each type. There was overall a significant linear correlation between the magnitude of EPSC inhibition and the change in PPR for both U69593 [GenBank] (Fig. 2D; principal, n = 12; secondary, n = 9; tertiary, n = 8; r2 = 0.67, P < 0.05) and DAMGO (Fig. 2E; principal, n = 11; secondary, n = 8; tertiary, n = 8; r2 = 0.22, P < 0.05), but these relationships did not hold for individual neuron types.
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In the presence of TTX, there was a significant inhibition of mEPSC frequency by U69593 [GenBank] (1 µM) among pooled VTA neurons (n = 10, ANOVA: P < 0.001), with the largest effect occurring in tertiary neurons (Fig. 4A). There was no change in mEPSC amplitude observed during U69593 [GenBank] application (n = 10, ANOVA: P > 0.05, Fig. 4B). In separate experiments, DAMGO (3 µM) also inhibited the frequency of mEPSCs in pooled VTA neurons (n = 15, ANOVA: P < 0.005, Fig. 4A). While as a group VTA neurons did show a significant decrease in mEPSC amplitude in the presence of DAMGO (n = 15, ANOVA: P < 0.05), no individual cell type showed a significant change (Fig. 4B). That the frequency of mEPSCs decreases with both U69593 [GenBank] and DAMGO further supports a presynaptic mechanism for the observed effects.
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). To confirm that this postsynaptic effect was not contributing to our evoked presynaptic observations, we compared the evoked presynaptic effects of U69593
[GenBank]
in Ih expressing (principal and tertiary) neurons in which the KOP-R agonist induced a positive change in the holding current (n = 6) to those recorded in neurons that exhibited no change in holding current with U69593
[GenBank]
(n = 13, Fig. 5A). There was no difference between the KOP-R agonist-mediated presynaptic inhibitions of EPSCs for these two groups (ANOVA: P > 0.05). Interestingly, there was a significant difference in the MOP-R agonist DAMGO inhibition of evoked EPSCs in these two groups: Ih neurons that were postsynaptically hyperpolarized by the KOP-R agonist showed a significantly greater EPSC inhibition during a separate application of DAMGO (ANOVA: P < 0.01). Conversely, Ih neurons that were postsynaptically inhibited by the MOP-R agonist DAMGO (i.e., tertiary neurons, n = 9) showed a greater EPSC inhibition by U69593
[GenBank]
than those that were not (i.e., principal neurons, n = 12, ANOVA: P < 0.05, Fig. 5B). There was no difference in the presynaptic DAMGO effect for neurons postsynaptically inhibited by MOP-R agonists compared with those that were not (Fig. 5B).
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DISCUSSION |
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Our results confirm and extend previous findings on opioid modulation of glutamate release in the VTA. The results presented here are in agreement with earlier observations of presynaptic inhibition of glutamate release by MOP-R agonists in Ih and non–Ih-expressing VTA neurons (Bonci and Malenka 1999; Manzoni and Williams 1999). However, the presynaptic KOP effect showed here was not observed in a previous investigation of glutamate release onto Ih-expressing neurons in the VTA (Manzoni and Williams 1999). Given the large variability reported for the seven neurons tested with U69593
[GenBank]
in that study, an EPSC inhibition is likely to have occurred in a subset of those neurons. The variability of KOP inhibition across all Ih neurons reported here may have led to an average effect that was not significantly different from zero in their study when principal and tertiary neurons were not distinguished. The small but significant U69593
[GenBank]
effect we observed in principal neurons was not only confirmed by sEPSC and mEPSC measurements, but was reversed by nor-BNI, confirming its KOP-R selectivity.
We observed a previously unreported and significant relationship between the pre- and postsynaptic effects of KOP and MOP receptor agonists in Ih neurons. The EPSC inhibition by KOP-R agonists was larger among neurons postsynaptically hyperpolarized by MOP-R agonists (i.e., tertiary neurons), and MOP-mediated EPSC inhibition was larger in neurons postsynaptically inhibited by KOP-R agonists. Interestingly, while about 70% of Ih-expressing neurons in the VTA are dopaminergic, all neurons hyperpolarized by KOP are dopaminergic (Margolis et al. 2003). Although there are also DA neurons that are not inhibited by KOP-R agonists, the data reported here suggest that glutamatergic inputs to DA neurons are more sensitive to MOP-R agonists than those onto non-DA, Ih-expressing neurons. This conclusion will need to be confirmed in future experiments.
The inhibition of excitatory input to DA neurons by MOP-R agonists seems counter to the observation that MOP-R agonists in the VTA excite DA neurons. However, it is possible that the function of MOP-R activation in the VTA is to increase firing rate without producing bursting in DA neurons. Glutamate input to DA neurons tends to shift the tonic, spontaneous activity of DA neurons to a bursting pattern, often without changing the overall firing rate of the neuron (Chergui et al. 1993; Connelly and Shepard 1997; Floresco et al. 2003; Johnson et al. 1992; Overton and Clark 1992). The combination of indirect disinhibition of DA neurons by MOP-R agonists (through the inhibition of local GABAergic neurons) with presynaptic EPSC inhibition could produce greater neuron activity without shifting the firing pattern to bursting. Such a change could increase a temporally broad DA signal, which is likely to carry very different information from the pulsed release associated with bursting of VTA DA neurons (Phillips et al. 2003).
Presynaptic inhibition of glutamate release in the VTA provides an important mechanism by which inputs to the VTA can be differentially controlled by KOP and MOP receptor agonists. The occlusion experiments reported here provide evidence that MOP-Rs and KOP-Rs differentially regulate glutamatergic inputs onto both principal and tertiary neurons. The lack of a difference among principal neurons in EPSC inhibition by U69593
[GenBank]
applied in the presence of DAMGO compared with that observed in ACSF is consistent with KOP-Rs and MOP-Rs being segregated to separate terminals. However, secondary and tertiary neurons must have at least partial overlap of receptor expression on individual glutamatergic terminals. In tertiary neurons, this conclusion is supported by the finding that the KOP-R agonist mediated EPSC inhibition was diminished in the presence of the MOP-R agonist. In many secondary cells, U69593
[GenBank]
and DAMGO each inhibited EPSC amplitude by >50%. Together with the correlation between U69593
[GenBank]
and DAMGO EPSC inhibitions in these neurons, these data support the hypothesis that KOP-Rs and MOP-Rs are on the same glutamatergic terminals synapsing onto secondary neurons. Interestingly, glutamate excitation of secondary neurons in the VTA increases firing rates without causing bursting (Steffensen et al. 1998). Therefore not only does glutamate appear to have a very different postsynaptic function in secondary neurons compared with that in principal and tertiary cells, but the opioid regulation of these inputs seems to be fundamentally different.
Unlike the combinations of postsynaptic KOP-Rs and MOP-Rs that are differentially expressed in different VTA cell classes, presynaptic KOP and MOP receptor activation does inhibit glutamate release onto all VTA neurons. This provides a broad functional range of opioid modulation of VTA neuronal activity. Similar presynaptic KOP inhibition of glutamate release onto cell types having different postsynaptic opioid responses has also been observed in the nucleus raphe magnus (Bie and Pan 2003). Functional roles for these multiple opioid receptor sites in the VTA may be related to the synaptic location and timing of release of endogenous KOP and MOP receptor ligands. Projections to the VTA of neurons containing enkephalin, a MOP and 
opioid receptor agonist peptide, arise from the ventral pallidum, and those immunoreactive for endomorphin, a MOP-R selective agonist peptide, arise from the hypothalamus (Greenwell et al. 2002; Kalivas et al. 1993). It is possible then that endogenous ligands acting at the MOP-R in the VTA could be released by different events and at different times from those that lead to the release of the endogenous KOP-R selective ligand dynorphin, which is released from terminals of neurons located in the nucleus accumbens, lateral hypothalamus, and amygdala (Chou et al. 2001; Fallon et al. 1985).
Postsynaptic inhibitions by both KOP-R and MOP-R agonists in the VTA have previously been examined (Cameron et al. 1997; Johnson and North 1992; Margolis et al. 2003). Postsynaptically, only subsets of dopaminergic principal and tertiary neurons are inhibited by KOP-R agonists, while, by definition, all secondary and tertiary cells are directly inhibited by MOP-R agonists. Thus concurrent KOP- or MOP-induced presynaptic inhibition of glutamate release and postsynaptic hyperpolarization would be synergistic in secondary and tertiary neurons. It is also important to point out that principal and tertiary neurons fire in the absence of synaptic input. Therefore opioids can modify the output of these VTA neurons in the absence of an excitatory input, and this modulation may have very different consequences from inhibiting excitatory inputs to the same neuron. There may also be an anatomical difference between the different actions of opioids on these signals. Endogenous opioids may have a limited radius of effect when released and therefore depending on their precise location, pre- and postsynaptic KOP-Rs and MOP-Rs could be activated independently in vivo. Such mechanisms could account for the seeming contradiction that MOP-R agonists both inhibit excitatory input and indirectly disinhibit principal neurons.
The sources of the differences in the responses to opioids reported here and their possible functional implications are unclear. Since in most cases, especially in the principal neurons, inhibition of glutamatergic inputs by KOP-R ligands was only partial, it is likely that not all glutamatergic terminals bear the KOP-R. Thus it is tempting to hypothesize that variation in EPSC modulation by opioids across cell types depends on the source of glutamatergic afferents. For instance, Carr and Sesack (2000) showed that glutamate afferents from the mPFC to the VTA synapse selectively on DA neurons that project back to the mPFC and GABAergic neurons that project to the NAc, but not DA neurons that project to the NAc or GABA neurons that project to the mPFC. Therefore some combination of PPN, STN, and hypothalamus afferents to the VTA likely provides major glutamate input to the nondopaminergic neurons that comprise 60% of the VTA projection to the mPFC, the dopaminergic neurons that comprise 80% of the VTA projection to the NAc, and possibly the VTA neurons that project to other targets such as the amygdala and hippocampus (Swanson 1982). However, since in other brain regions a single axon can give rise to multiple excitatory synapses with significantly different properties (Maccaferri et al. 1998; Markram et al. 1998; Scanziani et al. 1998), we cannot conclude that the observed differences are due to differential anatomical origins of the glutamatergic afferents. Further work needs to be done to discern if there is indeed an anatomical correlate to the effects observed here.
In conclusion, we show that KOP and MOP receptor agonists inhibit glutamatergic input onto all neuron types in the VTA. Presynaptic regulation of synaptic transmission by opioids in the VTA provides a mechanism for selective control of specific inputs to VTA neurons. How these presynaptic effects interact with the postsynaptic inhibitions through MOP and KOP receptor activation in the VTA not only depends on whether the glutamatergic afferents are active when opioid ligands are present, but may also depend on the site of origin of the neuron giving rise to the glutamatergic terminal or the projection target of the postsynaptic neuron. The modulation of glutamate release by KOP and MOP receptor agonists reported here provides important information for understanding signal modulation in the VTA and is an important key to elucidating the influence on motivation and reward of endogenous opioids acting in the VTA.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. B. Margolis, Ernest Gallo Clinic and Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608 (E-mail: elyssam{at}egcrc.net)
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 H. D. Mansvelder Yin and Yang of VTA Opioid Signaling. Focus on "Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons" J Neurophysiol, June 1, 2005; 93(6): 3046 - 3047. [Full Text] [PDF]
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