Theme : Dreams

Effects of Gamma-Hydroxybutyrate on Ventral Tegmental Unit Activity in the Rat: Considerations on REM Sleep Control

Hugo Tremblay 1, Roger Godbout 1,2, Véronique Girodias 1, Martine Schmitt 3 and Jean-Jacques Bourguignon 3
1Centre de Recherche, Hôpital du Sacré-Coeur, Montréal, Québec, Canada, H4J 1C5 2Département de psychiatrie, Université de Montréal, Succ. Centre-Ville Montréal, Québec, Canada, H3C 3J7 3Laboratoire de Pharmacochimie moléculaire, Strasbourg Cedex, 67084, France
Abstract
The effect of gamma-hydroxybutyrate (GHB) administration on spontaneously active dopaminergic cells of the ventral tegmental area (VTA) was determined using extracellular single unit recordings in urethane-anesthetized rats. High doses (160-250 mg/kg, i.p.) of GHB reversibly decreased firing rate in 63.6% of the cells tested (n=11); remaining cells (36.4%) were unaffected. When the GHB receptor antagonist NCS-382 (10 mg/kg, i.p.) was co-administered with GHB at high doses, 50% of the cells became excited while remaining cells were unaffected. Of the 34 cells tested with GHB at low doses (10 mg/kg, i.p.), 21 (61.8%) changed their firing activity. Of these, 12 (57.1%) were excited, five (23.8%) were inhibited, and four (19.0%) were first excited then totally inhibited (E/Ipattern). Out of the three E/I cells tested, two resumed their firing activity after apomorphine (50 µg/kg s.c.), showing that they were in a state of depolarization inactivation. When NCS-382 (10 mg/kg, i.p.) was co-administered with GHB at low doses, only two of the seven cells tested (28.6%) changed their firing activity, both with excitations. We conclude that only low doses of GHB selectively activate GHB receptors. Mechanisms by which low doses of GHB facilitate REM sleep are discussed.

Current Claim: Gamma-hydroxybutyrate decreases at high doses and increases at low doses the firing activity of dopaminergic neurons of the Ventral Tegmental Area in anesthetized rats.

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Gamma-hydroxybutyrate (GHB) is an endogenous fatty acid that acts as a neurotransmitter in the mammalian central nervous system (CNS) (Vayer et al., 1987; Maitre, 1997). Among other characteristics, low and high affinity states of the central GHB receptor were described (Maitre et al., 1983). GHB was first synthesized as an agonist of gamma-aminobutyric acid (GABA) that could readily cross the blood-brain barrier (Laborit, 1964). However, instead of significantly increasing GABA levels in the CNS, it was found that GHB selectively increased dopamine (DA) levels (Gessa et al., 1966). Indeed it was shown that the cessation of impulse flow in DA neurotransmission systems caused by GHB activates tyrosine hydroxylase (Roth, 1987). Given the effect of GHB on DA impulse flow, the drug was widely used as a tool to induce a reversible lesion of the dopaminergic nigro-striatal pathway in experimental studies of the Parkinson's disease models (Roth, 1987).
GHB has long been used as a sedative-hypnotic both in animals and humans and it has been shown that it can readily induce rapid eye movement (REM) sleep at least in three species: rats, cats, and humans (Girodias et al., 1996; Jouvet et al., 1961; Lapierre et al., 1990). Taken at bedtime GHB is an efficient treatment for cataplexy, a symptom related to the inappropriate daytime disinhibition of REM sleep muscle atonia in narcoleptic patients. It has been proposed that the therapeutic effect of this compound is achieved by consolidating nocturnal REM sleep, thus decreasing daytime pressure for REM sleep (Broughton and Mamelak, 1979).

The mechanism by which GHB interferes with normal and abnormal REM sleep physiology is still unknown. Available evidence, however, points to the limbic system as the preferential site of action of GHB (for a review, see Maitre, 1997). GHB synthesis, binding, and uptake sites are preferentially distributed in areas where DA neurons and terminal fields are found. Moreover, this system has been recently shown to be particularly important in the control of REM sleep in the canine model of narcolepsy-cataplexy (for a review, see Nishino and Mignot, 1997). For these reasons, we have chosen to characterize the effects of GHB in various sites of the meso-cortico-limbic system using clinically relevant doses. In a first series of experiments, we studied the effects of various peripheral doses of GHB (5 to 320 mg/kg, i.p.) on the spontaneous firing activity of output neurons in the prefrontal cortex (PFC). We found that low doses of GHB increased the firing activity of PFC output neurons, while highest doses decreased it; only the effect of low doses were blocked by NCS-382, the selective GHB receptor antagonist (Godbout et al., 1995). These results suggested that only the effect of low doses of GHB on PFC neuronal firing could be attributed to a selective activation of GHB receptors.

The PFC is a major target of the ascending dopaminergic pathway originating from the ventral tegmental area (VTA) and PFC neurons are inhibited by DA release from VTA terminals (Godbout et al., 1991). Thus, in the present study, we investigated the effects of GHB at high and at low (i.e., REM sleep-inducing doses) on the firing activity of VTA cells bearing the electrographic characteristics of DA neurons. Moreover, we tested the selectivity of GHB effects by challenging these treatments with the specific GHB receptor antagonist NCS-382.

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Male Sprague-Dawley rats weighing 250 to 400 g were used (Charles River, St-Constant, Canada). Rats were housed 2 to 3 per cage in a room with a 12:12 hour light/dark cycle (lights on at 06:00). Food and water were available ad libitum. Experiments occurred during daytime hours. Animals were anesthetized with urethane (1.5 g/kg i.p.; additional injections administered as needed) and were then mounted on a stereotaxic apparatus. Stereotaxic coordinates were determined according to Paxinos and Watson (1986). Body temperature was maintained throughout the experiments at 37°C with a thermostatically regulated electrical heating pad. Extracellular single unit recordings of spontaneously active VTA neurons (4.8 to 5.3 mm posterior to bregma, 0.6 to 1.2 mm lateral to midline, and 7.5 to 8.5 mm below the cortical surface) were obtained using glass micropipettes filled with 4% Chicago Sky Blue dissolved in 2M NaCl solution (impedance 3 to 9 M at 1000 Hz). Electrophysiological signal was amplified, displayed on an oscilloscope, separated from noise using a window discriminator and then fed to a computer. Spike frequencies were monitored on-line using 10 sec. bins histograms.
At the end of each experiment, Chicago Sky Blue was ejected from the recording electrode by iontophoresis (8 µA cathodal, 20 min.). Localization of recording sites were verified on serial frozen sections (20 µm) under light microscopic examination.

Prior to drug administration, rats were injected with the vehicle (1 ml/kg) and firing activity was monitored for at least five minutes; this was considered baseline. After baseline recording, GHB (pH 6.5, dissolved in distilled water) was administered i.p. at a dose of 10 mg/kg, 160 mg/kg, or 250 mg/kg, in a volume of 1 ml/kg. Each dose was administered either alone or in conjunction with NCS-382 at a dose of 10 mg/kg i.p. (1 ml/kg). Each data point is based on the injection of one GHB dose to one rat while recording from one VTA neuron.

The following variables were measured: the delay from time of injection to a change of at least 25% of the baseline firing rate, the amount of maximum change (expressed as % of the baseline firing rate), the latency to maximum change, and the duration of the effect (from 25% change until return to baseline firing rate ±10%). We chose 25% of the baseline firing rate as a cut-off value since it corresponded to three times the standard error of the mean (S.E.M.) of the baseline firing rate.

Statistical analysis
Results are expressed as means ± S.E.M. Contingency tables were constructed for all treatment levels. Results were compared using the 2 statistic, using the Fisher's Exact Test for 2x2 tables.

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Figure 1

Figure 2

Figure 3

A total of 58 neurons were recorded, all within the region of the VTA (see Figure 1). During baseline recording these cells displayed the electrographic characteristics of DA cells (Bunney et al., 1973; Chiodo et al., 1984): a long bi- or triphasic action potential (3-4 ms), a positive-going first segment, and a high-amplitude negative-going second segment (Figure 2). Firing rate was tonic in all but one bursting cell; activity ranged from 2.0 Hz to 8.7 Hz (mean = 4.6 ± 0.3). NCS-382 did not have any effect of its own on VTA firing at 10 mg/kg (n=6). Results are summarized in the table below. Seven (63.6%) of the 11 cells tested were sensitive to high doses of GHB (160, 250 mg/kg) while the remaining (all tested at 160 mg/kg) were unresponsive (p<.004); high GHB doses produced an inhibition of firing in all responsive cells (p<.00001).
At 10 mg/kg, GHB modified the firing in 61.8% of the 34 cells tested while the remaining 13 cells were unresponsive (p<.0001). Three types of effects were noted at this dose: the majority of cells (57.1%; p<.0002) responded by increasing their firing rate, five other cells decreased it while the remaining four cells showed an excitation/inhibition (E/I) pattern (Figure 3).

In order to document the possibility that E/I cells were in a state of depolarization inactivation (DI) (Hand et al., 1987), a low, i.e., pre-synaptic dose of apomorphine (50 µg/kg s.c.) was injected during the inhibitory period in order to repolarize the cells (n=3). Of these three cells, two resumed their firing activity shortly after the apomorphine injection, showing that they were indeed in a state of depolarization inactivation (see Figure 3). This phenomenon was replicated with a classical model of DI, i.e., using the injection of sulfated cholecystokinin octapeptide (CCK-8S, 10 µg/kg i.v.) (Skirboll et al., 1981). In this series of experiments, one of the 11 cells tested entered a state of depolarization inactivation and its firing activity was restored by apomorphine.

When NCS-382 was co-administered with a high GHB dose, the number of responsive cells was not statistically different from the condition where high GHB doses were given alone (50.0% vs. 63.6%, respectively). However, the nature of the response to high doses of GHB was reversed: the number of inhibited cells decreased from 100% to 0% and the number of excited cells increased from 0% to 100% (p<0.008).

The co-administration of NCS-382 and GHB 10 mg/kg significantly decreased the proportion of responsive cells compared to when GHB 10 mg/kg was given alone, falling from 61.8% to 22.3% (p<.05). The nature of the response to the low dose of GHB was not changed, however: both responsive cells were excited by GHB 10 mg/kg.

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It is generally reported that the peripheral administration of high GHB doses produces a cessation of impulse flow in meso-telencephalic dopaminergic neurons together with a decreased release of DA in terminal fields of meso-cortico-limbic and nigro-striatal pathways (Roth, 1987). The present study shows that GHB displays a dose-related effect on VTA DA cell firing rate in the anesthetized rat: highest doses (160-250 mg/kg) produced a decrease of firing rate while low doses (10 mg/kg) induced an increase. These results are consistent with previous work on the effects of high and low doses of GHB on PFC unit firing (Godbout et al., 1995). The data is also congruent with previous work in conscious rats using the same dosages as in the present study: core body temperature was shown to decrease with high GHB doses and increase with low GHB doses (Kaufman et al., 1990; Godbout et al., 1994), and REM sleep was shown to be facilitated only by low doses of GHB (Girodias et al., 1996).
The effects of high GHB doses on the firing activity of DA cells of the VTA
In our previous work on the effects of GHB on PFC firing activity, we showed that the inhibitory effects of high GHB doses was not reversed by NCS-382. It was thus concluded that the effects of GHB at high doses involved non-GHB mechanisms and that only low doses of GHB selectively activated GHB receptors. These results were in accordance with those of Endberg and Nissbrandt (1993) who showed that high doses of GHB inhibited the firing activity of substantia nigra DA cells firing; these authors further suggested that this effect was dependent upon the activation of GABA-B receptors. No such conclusions can be as easily drawn from the results of the present study in DA VTA neurons. Indeed we observed that, following the combined injection of high doses of GHB and NCS-382, the inhibitory effect of GHB on the firing activity of VTA DA cells was no longer present (as opposed to 100% of responsive cells when high doses of GHB were injected alone); instead, it was found that all three responsive cells (100%) actually increased their firing activity (versus 0% with GHB alone) while the other three remained unaffected (versus 36.4% with GHB alone). One explanation regarding these discrepancies is that in the former PFC study, NCS-382 itself was also used at high doses (160-320 mg/kg) and it is possible that at such high doses NCS-382 loses its antagonistic effect on the activation of high affinity GHB receptors. This possibility is substantiated by recent electrophysiological studies performed using high concentrations of NCS-382 in thalamocortical and hippocampal neurons in vitro (Emri et al., 1996; King et al., 1997).

We can speculate that the low dose of NCS-382 used against high GHB doses in the present study acted in two different ways. First it is possible that such a low dose of NCS-382, having bound to GHB receptors, totally blocked the access of GHB to its receptors so that VTA firing activity remained unchanged in half the cells tested. Second, in the case of cells that were excited, it is possible that the low dose of NCS-382 insufficiently reduced the number and availability of GHB receptors, transforming the action of the high dose of GHB to that of a low dose. Increased firing rate following co-administration of GHB at 160-250 mg/kg combined with NCS-382 at 10 mg/kg could thus be a residual low-dose activation phenomenon. Whether this phenomenon concerns specific subclasses of GHB receptors, i.e., with high and low affinity states (Maitre et al., 1983) still needs to be determined.

The effects of low GHB doses on the firing activity of DA cells of the VTA
The low dose of GHB produced three types of effects on DA cells of the VTA: excitation, inhibition and a sequence of excitation/inhibition. Excitatory effects in the VTA first appear to be consistent with our previous results in the PFC where the majority of responsive cells showed an increased firing rate at 5 and 10 mg/kg of GHB (Godbout et al., 1995). Also consonant is the fact that a co-administration of NCS-382 caused a majority of VTA cells (77.7%) to become no longer sensitive to GHB, suggesting that this excitatory effect was associated to the selective activation of GHB receptors. The combined results from PFC and VTA firing do not, however, seem to be consistent with our previous work showing that DA innervation of the PFC by the VTA is inhibitory (Pirot et al., 1992). Indeed, one should expect to observe a decrease of activity in DA cells of the VTA upon a low GHB dose since the same treatment causes PFC cells to be excited. On the contrary, what we observed was an increase of firing of VTA DA cells. Our speculation is that low doses of GHB affect primarily sites that feedback onto the VTA with an excitatory input, such as the aspartate-glutamate innervation of the VTA by the PFC (Christie et al., 1985a; Gariano and Groves, 1988), an area where GHB receptors are found (Maitre et al., 1990). In such cases, GHB would first increase PFC firing which, in turn, would activate the VTA via its excitatory cortico-fugal input. In cases where this excitatory afferent drive to the VTA would be particularly massive, sustained excitation of the VTA would lead to a depolarization inactivation of VTA neurons as it was documented here (Figure 3). Alternatively, the few cases (23.8%) where VTA cells were inhibited by a low dose of GHB would involve an inhibitory feedback loop impinging onto the recorded VTA cell. The GABAergic input to the VTA from the nucleus accumbens (Yim and Mogenson, 1980), where GHB receptors are found in high concentrations (Hechler et al., 1992), is a plausible candidate: nucleus accumbens could either be directly excited by GHB (which still need to be demonstrated, however), or it could be excited by PFC excitatory inputs impinging onto it (Christie et al., 1985b).

REM sleep triggering mechanisms involved with GHB administration
Our results show that the doses of GHB which stimulate the firing of DA neurons of the VTA are in the same range as those capable of inducing REM sleep both in rats and in humans (Girodias et al., 1996; Lapierre et al., 1990). Given that the stimulation of the mesencephalic dopaminergic nuclei is known to inhibit dorsal raphe nucleus neurons (Stern et al., 1979), it is possible that low activating doses of GHB trigger REM sleep by an inhibition of dorsal raphe (REM-off) neurons due to increased DA release from VTA terminals. However, an additional but not incompatible hypothesis is proposed here. It is known that while GHB has no effects on brain acetylcholine (ACh) levels per se, it potentiates increases of ACh induced by neuroleptics such as clozapine and chlorpromazine in the striatum (Stadler et al., 1974). We raise here the possibility that GHB could potentiate the already increased ACh (REM-on) neurotransmission that occurs just before natural REM sleep, therefore precipitating its onset. In support of this possibility is the fact that GHB was shown to induce REM sleep in the cat only when it was administered at a time close enough to the onset of the next expected REM sleep period (Delorme et al., 1966). Accordingly, GHB was also shown to potentiate REM sleep-triggering mechanisms in human cases where REM sleep was already facilitated such as in patients with depression or narcolepsy (Mamelak et al., 1977) or in older subjects upon morning naps (Lapierre et al., 1990). Whether the propensity for REM sleep in these conditions is a matter of increased REM-on tonus or decreased REM-off tonus (Hobson et al., 1975) is still a matter of debate. With these hypothesis in mind, we are presently investigating the effects of GHB on neurotransmission in REM-on and REM-off systems.

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This research was supported by the Natural Science and Engineering Research Council of Canada, the "Fonds de la recherche en santé du Québec" and the "Conseil national de la recherche scientifique" (France). The authors wish to thank the skillful assistance of Annie Chantale Dallaire in helping with the electrophysiological recordings. Roger Godbout is a Chercheur Boursier Junior 2 of the "Fonds de la Recherche en Santé du Québec".

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