Seizure: European Journal of Epilepsy
Volume 19, Issue 4 , Pages 226-231, May 2010

GABAB receptor activation exacerbates spontaneous spike-and-wave discharges in DBA/2J mice

  • Marco Bortolato

      Affiliations

    • Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, USA
    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • Corresponding Author InformationCorresponding authors at: Department of Neurological and Cardiovascular Sciences, University of Cagliari, Policlinico Universitario, S.S. 554 Km 4.500, 09042 Monserrato (CA), Italy. Tel.: +39 070 51096191; fax: +39 070 51096032.
    • ,
  • Roberto Frau

      Affiliations

    • Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, USA
    • Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy
    • ,
  • Marco Orrù

      Affiliations

    • Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy
    • ,
  • Mauro Fà

      Affiliations

    • Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy
    • ,
  • Christian Dessì

      Affiliations

    • Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy
    • ,
  • Monica Puligheddu

      Affiliations

    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • ,
  • Luigi Barberini

      Affiliations

    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • ,
  • Giuliano Pillolla

      Affiliations

    • Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy
    • ,
  • Lorenzo Polizzi

      Affiliations

    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • ,
  • Federico Santoni

      Affiliations

    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • ,
  • Giampaolo Mereu

      Affiliations

    • Department of Experimental Biology and CNR Neuropsychopharmacology Section, University of Cagliari, Italy
    • ,
  • Francesco Marrosu

      Affiliations

    • Department of Neurological and Cardiovascular Sciences, University of Cagliari, Italy
    • Corresponding Author InformationCorresponding authors at: Department of Neurological and Cardiovascular Sciences, University of Cagliari, Policlinico Universitario, S.S. 554 Km 4.500, 09042 Monserrato (CA), Italy. Tel.: +39 070 51096191; fax: +39 070 51096032.

Received 18 July 2009; received in revised form 13 February 2010; accepted 19 February 2010. published online 16 March 2010.

Article Outline

Abstract 

Rich evidence has highlighted that stimulation of γ-amino-butyric acid (GABA)B receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABAB activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand γ-hydroxybutyrate (GHB) and its precursor γ-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABAB agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5–10mg/kg, i.p.) and GBL (5–100mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice.

While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABAB selective antagonist, SCH50911 (50mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABAB receptor signaling might exert differential effects on SWDs in DBA/2J mice.

Keywords: DBA/2J mice, Absence rodent models, GABAB receptors, Baclofen, GBL, EEG pattern

 

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1. Introduction 

Absence epilepsy (AE) is an idiopathic, non-convulsive epilepsy characterized by brief, sudden interruptions of consciousness and minor automatisms.1 Such episodes, generally benign and self-limited, are concomitant with distinct electrocorticographic (ECoG) alterations, consisting in bilateral synchronous bursts of spike–wave discharges (SWDs) at typical frequency around 3–4Hz.2 Although the molecular bases of AE are largely elusive, the wealth of evidence supports the involvement of γ-aminobutyric acid (GABA) transmission in their pathophysiology. In particular, several studies suggest that GABAB receptor activation may exacerbate AE in several animal models.3 Recent studies have suggested that abnormalities in GABAB receptor signaling may account for several phenotypical alterations exhibited by DBA/2J mice,4, 5 a strain exhibiting EEG patterns reminiscent of those observed in AE.5, 6 Capitalizing on this background, we addressed the present study to investigate the role of GABAB receptors in the expression of SWDs in DBA/2J mice.

Recent lines of evidence suggest that the in vivo outcomes of GABAB activation are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand γ-hydroxybutyrate (GHB) and its precursor γ-butyro-lactone (GBL) have been shown to elicit GABAB-dependent behavioral effects which differ from those mediated by the prototypical agonists of this receptor,7, 8, 9 such as baclofen.

Although both GHB and baclofen have been shown to induce, in both humans and laboratory animals, EEG abnormalities similar to those associated with AE,10, 11 the specific impact of each agonist has not been compared to date. This premise prompted us to test the EEG response of DBA2/J mice to baclofen and GBL, in comparison with the locomotor alterations induced by both drugs. The latter compound was preferred to GHB on account of its numerous experimental advantages: first, it exhibits a greater ability to cross the blood–brain barrier12; second, it is inherently inactive and rapidly converted to GHB after parenteral administration13; finally, it shows a better dissociation between EEG abnormalities and alterations of thermoregulation than its metabolite.14

To understand whether the differences between baclofen and GBL may be actually mediated by GABAB receptors, the effects of the two compounds were also studied in presence of a GABAB selective antagonist, SCH50911.

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2. Materials and methods 

2.1. Animals 

Juvenile (4–5 weeks old) male DBA/2J mice (Harlan, Como, Italy) (n=131; weight: 25–30g each) were housed four per cage under a 12h light/dark cycle (light on at 8:00AM), in conditions of constant temperature (21±2°C) and humidity (60%), with food and water ad libitum. All experimental procedures were approved by the local ethical committee and conducted in conformity with the University of Cagliari guidelines. The experimental preparation followed the methods previously described.5 Briefly, mice were anesthetized and placed in a stereotaxic apparatus (David Kopf, mod. 900). Each skull was exposed and perforated in four points, located above both sensorimotor cortices (FPr and FPl), 0.5mm anterior to the bregma (Cz), and over the cerebellum (G2). A four-pin male socket was positioned into the holes, secured to the skull with epoxy resin and covered with acrylic cement to improve retention.

2.2. Drugs 

The following drugs were used in this study: GABAB receptor agonists baclofen and γ-butyro-lactone (GBL), as well as GABAB antagonist SCH50911 (Tocris Cookson, UK). All drugs were dissolved in saline 0.9% and administered intraperitoneally (i.p.) in an injection volume of 10ml/kg. The dose ranges of baclofen and GBL were selected so as to have similar efficacy, based on the comparison of their ED50 values8 and on preliminary observations by our group.

2.3. EEG recordings 

EEG recordings were acquired on a portable EEG polygraph (BQS 98 System Micromed, Mogliano Veneto, Italy), and the Electrode impedance was maintained at <5kΩ. Digital EEG signals were filtered with elliptical filter banks to obtain the optimal resolution of broadband parameters. Given that synchronization analysis requires a zero-phase filtering distortion, data were further processed by forward–backward filtering.15 The off-line SWDs analysis was accomplished separately by trained researchers blinded to this experimental phase of the study. In addition to visual inspection, SWDs morphology was assessed by means of a customized algorithm aimed at detecting significant variations occurring under a pre-settled threshold, based on the analysis of the fractal dimension of the EEG signal.16

DBA/2J mice exhibited an EEG pattern with 12–18Hz low-medium voltage background activity mixed with 6–12Hz high-voltage SWDs events. To maintain normality and homoscedasticity criteria in the sampled population, experiments were performed on the basis of SWD event frequency in the baseline EEG recording by selecting animals displaying between 6 and 25 SWDs/30min (with a median value of 13 in the overall tested population) while mice showing very low or very high number of SWDs (more than two standard deviations above or below group mean values) were excluded from the study. Each treatment group consisted of 5–7 animals, and each animal was injected with only one dose throughout the study. Recordings started between 8 and 10:30AM, and were analyzed in two blocks, respectively before and after drug administration. The first block, lasted 60min (two 30-min intervals) and was used to monitor the baseline conditions of each animal. In this phase of EEG recording, DBA/2J mice exhibited characteristic spontaneous short-lasting spiking activity bursts (4–12s duration and 250–550μV amplitude), superimposed to baseline activity of 50–120μV EEG rhythms.

The second block lasted 90–150min (three to five 30-min intervals) and was used to assess the effects of the treatment. SWD analysis was based on their number (calculated as the average number of events occurring in a 30-min interval) and mean duration for pre- and post-injection blocks were calculated.

Episodes of drowsiness and sleep were discarded, as previous studies in other rodent models of AE showed relevant SWDs variations during sleep.17

2.4. Locomotor activity 

We tested the impact of GABAB ligands on the locomotor activity in a different group of DBA/2J mice. The motility cages (Omnitech Digiscan Animal Activity Monitor, Columbus, OH, USA) featured 2 sets of 16 photocells located at right angles to each other, projecting horizontal infrared beams 2.5cm apart above the cage floor. After a 30-min acclimatization period in the apparatus, each animal was injected and its locomotor activity was studied for further 90min. Locomotion was measured with the horizontal activity counts in 10-min intervals.

2.5. Statistical analyses 

Number and mean duration of SWDs were analyzed by 2-factor ANOVAs, with treatment dose as an independent factor and blocks (pre- and post-injection) as repeated measures. Locomotor activity was analyzed by 2-factor ANOVAs, with dose as independent factor and time (consecutive 10-min intervals). Post hoc comparisons were performed with Tukey's test. Alpha was set at p<0.05.

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3. Results 

3.1. Effects of baclofen on SWD 

In the first experiment (Fig. 1), the effects of baclofen (0.5–10mg/kg, i.p.; n=5–7/group) on SWD number and mean duration were tested and compared with both vehicle-treated mice and their individual baseline values. Baclofen was found to exert a significant main effect on SWDs occurrence [F(1,29)=38.44, p<0.001]. The analysis of dose×block interactions also revealed a significant effect [F(5,29)=10.63, p<0.001]. Post hoc comparisons further established that the doses of 2.5, 5 and 10 produced a significant increase in comparison to their baseline and to vehicle-treated subjects. Conversely, baclofen did not produce any significant change in SWD duration (Fig. 1d) at any dose tested. No difference in baseline SWD number or duration was found.

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  • Fig. 1. 

    Baclofen increases number and mean duration of spike-and-wave discharges (SWDs), but does not affect their morphology. EEG patterns before (a) and after (b) baclofen treatment (5mg/kg, i.p.). (c) Number and (d) mean duration of SWDs after different baclofen doses (0.5–10mg/kg, i.p.). Values are expressed as mean SWDs±S.E.M. White columns: baseline SWDs; black columns: SWDs after baclofen injection; Baclofen doses are indicated in mg/kg (i.p.). VEH, vehicle. *p<0.05, **p<0.01, in comparison to relative baseline. n=5–7 for each group. For further details, see text.

3.2. Effects of baclofen on locomotor activity 

As changes in the number of SWDs may reflect behavioral alterations (such as profound sedation), we evaluated the behavioral impact of baclofen (2.5–10mg/kg, i.p.) on the motor activity of a different group of DBA/2J mice (n=5/group). The evaluation of the effects of baclofen (2.5–10mg/kg, i.p.) on locomotor activity revealed a main dose effect [F(3,16)=5.91, p<0.01], which was found to reflect a significant difference between the animals treated with vehicle and those injected with the 10mg/kg dose of the GABAB agonist (p<0.01, Tukey's test). Furthermore, we detected a main effect for time [F(9,144)=55.09, p<0.001] and a significant dose×time interaction [F(27,144)=2.08, p<0.01]. Post hoc scrutiny of this effect revealed that the 10mg/kg dose of baclofen induced a significant reduction in activity at 30 and 40min after injection (Fig. 2). None of the other doses triggered significant alterations in locomotor activity in comparison with vehicle-injected animals.

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  • Fig. 2. 

    Baclofen reduces locomotor activity of DBA/2J mice in a dose-dependent fashion. Values are expressed as mean±S.E.M. Baclofen doses are indicated in mg/kg (i.p.). VEH, vehicle. *p<0.05 in comparison to VEH-treated mice in the same time point. n=5 for each group. For further details, see text.

3.3. Effects of GBL on SWD 

The third experiment was designed to test the effect of different GBL doses (5–100mg/kg, i.p.; n=5–7/group) on SWD number and mean duration. GBL significantly increased SWD number [F(1,23)=20.09, p<0.001]. Further analysis revealed that such effect was dose-dependent [F(4,23)=7.50, p<0.001] and significant at the intraperitoneal doses of 50 (p<0.05) and 100mg/kg (p<0.01) (Tukey's test) (Fig. 3). Interestingly, GBL effects on SWD duration produced a reduction close to significance threshold [F(1,23)=4.00, p=0.056]. Further analysis revealed that such effect was significant at the dose of 100mg/kg (i.p.) [dose ×block interaction: F(4,23)=7.50, p<0.001, p<0.01 for 100mg/kg dose, Tukey's test]. No difference in baseline SWD number or duration was found.

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  • Fig. 3. 

    GBL modifies the number, mean duration and morphology of spike-and-wave discharges (SWDs). EEG patterns before (a) and after (b) GBL treatment (100mg/kg, i.p.). (c) Number and (d) mean duration of SWDs after different GBL doses (5–100mg/kg, i.p.). Values are expressed as mean SWDs±S.E.M. White columns: baseline SWDs; black columns: SWDs after GBL injection; GBL doses are indicated in mg/kg (i.p.). VEH, vehicle. *p<0.05, **p<0.01, in comparison to relative baseline. n=5–7 for each group. For further details, see text.

3.4. Effects of GBL on locomotor activity 

We then tested the impact of GBL (50–100mg/kg, i.p.; n=5/group) on locomotor activity, with a design mirroring the experiment on baclofen. ANOVA detected main effects for both treatment dose [F(2,12)=4.08, p<0.05 for comparison between vehicle and GBL 100mg/kg] and time [F(9,108)=22.33, p<0.001], as well as a significant dose×time interaction [F(18,108)=4.91, p<0.001]. As shown in Fig. 4, post hoc comparisons revealed that the highest dose of GBL caused a significant reduction of locomotor activity at 20 and 30min after administration (p<0.05) in comparison to vehicle-treated controls.

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  • Fig. 4. 

    GBL reduces locomotor activity of DBA/2J mice in a dose-dependent fashion. Values are expressed as mean±S.E.M. Baclofen doses are indicated in mg/kg (i.p.). VEH, vehicle. *p<0.05 in comparison to VEH-treated mice in the same time point. n=5 for each group. For further details, see text.

3.5. Effects of SCH50911 on the effects of baclofen and GBL 

In the next experiment, we verified whether the variations in SWDs and EEG produced by baclofen (5mg/kg, i.p.) and GBL (100mg/kg, i.p.) were reversed by pretreatment with SCH50911 (50mg/kg, i.p.) (Fig. 5). Indeed, ANOVA revealed that SCH50911 did not elicit any effect in either experiment in comparison with its vehicle [F(1,11)=3.13, NS; F(1,12)=3.87, NS], but reversed the increase in SWD number induced by both baclofen [F(1,11)=25.85, p<0.001; Tukey: p<0.01 for SCH vs VEH comparison] and GBL [F(1,12)=23.94, p<0.001; Tukey: p<0.01 for SCH vs VEH comparison]. SCH50911 also prevented GBL from reducing SWD mean duration [F(1,12)=4.97, p<0.05], suggesting that all the GBL-mediated variations are due to GABAB receptor activation.

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  • Fig. 5. 

    SCH50911 reverses both baclofen (BAC)- and GBL-induced SWD modifications in DBA/2J mice. (a) Number and (b) mean duration of SWDs after SCH50911 (50mg/kg, i.p.) in combination with BAC (5mg/kg, i.p.), GBL (100mg/kg, i.p.) or their vehicle (VEH). Values are expressed as mean SWDs±S.E.M. White columns: baseline SWDs; black columns: SWDs after treatment. **p<0.01, in comparison to relative baseline; ##p<0.01 in comparison to VEH-treated animals. n=8–10 for each group. For further details, see text.

In a separate experiment, we verified the impact of SCH50911 on the locomotor effects of baclofen (10mg/kg, i.p.) and GBL (100mg/kg, i.p.). As expected, the GABAB antagonist did not inherently modify the locomotor activity, and completely countered the effects of both agents (data not shown).

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4. Discussion 

The main result of the present study is that both baclofen and GBL, two GABAB receptor agonists, significantly increase SWD expression in DBA/2J mice. Notably, while baclofen and low doses of GBL enhanced the occurrence of SWDs without affecting their duration, high doses of GBL shortened the average duration of these phenomena. The selective GABAB antagonist SCH50911 prevented the increase in SWD number induced by baclofen and GBL, confirming that both compounds produced their effects through activation of GABAB receptors. Furthermore, the intermediate doses of baclofen (2.5–5mg/kg) and GBL (50mg/kg) increased the number of SWDs without eliciting any significant effect on locomotion, suggesting that the reported alterations in SWD manifestations are not completely secondary to behavioral changes.

Our findings are consistent with previous evidence, highlighting a key role for GABAB receptors in SWDs modulation. Indeed, GABAB receptor activation exacerbates SWDs in AE rodent models.18, 19 The different impact on SWD modulation elicited by equipotent doses of baclofen and GBL is also in line with recent lines of evidence documenting that their effects, albeit both mediated by GABAB receptors, are underpinned by partially divergent mechanisms.7, 8, 9 The distinctive effects of the two GABAB agonists have been posited to reflect separate contributions from different receptor subpopulations.8, 9 Although the evidence on GABAB subtypes is still inconclusive,22 converging lines of research support their existence and indicate that they may exert different roles in relation to their different regional distribution and intracellular segregation.23, 24, 25, 26 Thus, variations in affinity for different isoforms of GABAB subunits (or their combination) may condition the outcomes of different GABAB ligands in AE murine models.27 This conceptual framework may also help understand the different profile of Fos expression enkindled by GHB and baclofen.28

In a well-validated AE model, lethargic (lh/lh) mice, GABAB receptors modulate absence expression based on their regional-specific sensitivity in thalamo-cortical nuclei, as well as ventral thalamic nuclei and nucleus reuniens.29 Indeed, the effects of high GBL doses on SWD duration might also indicate a preferential action of this compound on cortical networks, as suggested by previous studies.25, 30 Conversely, baclofen increased SWDs without altering them, suggesting that this compound may activate mainly thalamo-cortical GABAB receptors.

The functional divergence between GHB and baclofen has been suggested to reflect specific interactions between specific GABAB receptor variants and the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors.31 This possibility is particularly intriguing, in view of the role of NMDA receptors in the initiation and maintenance of SWD,32, 33, 34 as well as the altered responsiveness of NMDA receptors in DBA/2J mice.35

An alternative possibility to account for the different effects of baclofen and GBL may reflect the specific contribution of GHB on its own receptors,36, 37 which may in turn modulate GABA release and alter the effects of GABAB receptor activation.38

The behavioral effects of baclofen and GBL on spontaneous locomotor activity followed a typical dose- and time-dependent fashion, with a substantially equivalent pattern in comparison to vehicle-treated controls. The shorter time of maximal action of GBL (20–40min) in comparison to baclofen (30–50) reflects previous observations on the behavioral impact of these two compounds8 and is likely to signify GHB's brief half-life.39 The hypomotility observed in this study is in keeping with previous results on the effects of both GABAB agonists.40, 41 It is worth noting the dosages of GBL and baclofen have been shown to be in a cataleptogenic range in mice,8 suggesting that the near-total lack of spontaneous activity induced by both agents may have reflected extrapyramidal deficits, plausibly due to the impingement of common mechanisms.

Our experiments have shown that the profile of SWD modulation by GABAB ligands in DBA/2J exhibits a number of atypical features. Firstly, GABAB agonists increased only the number, but not the duration, of SWD bursts.42 Secondly, SCH50911 did not suppress SWDs in DBA/2J mice. Particularly this last finding is at variance with a large body of evidence documenting that GABAB blockade reduces AE manifestations and SWDs in AE models.43, 44, 45, 46, 47, 48 By definition, the intrinsic effects of a receptor antagonist reflect a tone of the endogenous activator; therefore, the lack of effect of SCH50911 in DBA/2J mice is likely to indicate that, unlike other AE models, these animals may not have a physiological “GABAB tone”. While the present study cannot help identify the mechanisms underpinning such a critical difference, it is tempting to speculate that this phenomenon may be connected to our previous finding of a reduced expression of GABAB receptor in the cortex.4 Of note, this evidence is in seemingly striking contrast with the up-regulation of GABAB receptors in other models of AE.25 Further studies are warranted to establish the specific role of GABAB receptors in the circuitry underpinning SWD in DBA/2J mice and the functional valence of the variations in GABAB receptors in this strain.

Irrespective of these considerations, the present findings on DBA/2J mice warrant further studies on the role of GABAB receptor in SWD modulation, and suggest that distinctive actions on GABAB signaling might differentially regulate the expression of SWDs.

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PII: S1059-1311(10)00049-X

doi:10.1016/j.seizure.2010.02.007

Seizure: European Journal of Epilepsy
Volume 19, Issue 4 , Pages 226-231, May 2010

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