The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice

Abstract

Background and purpose: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied.

Experimental approach: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed.

Key results: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs.

Conclusion and implications: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.

Figure 1

Locomotor activity. (A) effect of the GABA_B receptor agonist CGP44532 and the positive modulator GS39783 on the locomotor activity in mice habituated to activity cages. Compounds were given i.p. in doses of 0.250 mg·kg⁻¹ (CGP44532) and 30 mg·kg⁻¹ (GS39783) after 30 min of the habituation period. Locomotor activity was monitored over 100 min after drug administration. (B) spontaneous locomotor activity after i.p. administration of the GABA_B receptor agonist CGP44532 and the positive allosteric modulator, GS39783. Values represent the mean ± SEM ambulation scores during 100 min. CGP44532 was administered 120, 60 and 30 min before measurements and GS39783 was administered 30 min before the test, *P < 0.05.

Figure 2

Effects of reference compounds on the MK-801-induced (A,B) and amphetamine-induced (C,D) hyperactivity test. Haloperidol (Hal: A,C) was given in doses 0.1 and 0.25 mg·kg⁻¹ while clozapine (Clo; B,D) was given in doses of 5 and 10 mg·kg⁻¹. Both compounds were administered 30 min before the MK-801 or amphetamine (Amph) injection. Locomotor activity was monitored over 30 min. The data presented are means ± SEM. ***P < 0.001 versus MK-801 or amphetamine only; #P < 0.001 versus control.

Figure 3

Effects of the GABA_B receptor agonist CGP44532 (A), the GABA_B positive allosteric modulator GS39783 (B) and the GABA_B antagonists CGP51176 (C) or CGP36742 (D) in the MK-801-induced hyperactivity test in mice. CGP44532 was given i.p. in doses of 0.060, 0.125 and 0.250 mg·kg⁻¹; GS39783 was given in doses of 5, 10 and 30 mg·kg⁻¹, and both antagonists were given in doses of 15 and 30 mg·kg⁻¹. All the compounds were administered 30 min before the experiments. Locomotor activity was monitored over 30 min immediately following injection of MK-801 (0.3 mg·kg⁻¹). The data presented are means ± SEM. #P < 0.001 versus control; ***P < 0.001 versus vehicle-treated group.

Figure 4

Effect of the GABA_B receptor antagonists CGP51176 (15 mg·kg⁻¹; A,B) and CGP36742 (15 mg·kg⁻¹; C,D) on the inhibitory effects of CGP44532 (0.250 mg·kg⁻¹; A,C) and GS39783 (30 mg·kg⁻¹; B,D) on MK-801-induced hyperactivity. Locomotor activity was monitored over 30 min immediately following the administration of MK-801 (0.3 mg·kg⁻¹). The data presented are means ± SEM. #P < 0.001 versus vehicle; **P < 0.001 versus vehicle-treated group; ^@P < 0.05 versus CGP44532 or GS39783 alone.

Figure 5

Effects of the GABA_B receptor agonist CGP44532 (A), the GABA_B positive allosteric modulator GS39783 (B) and the GABA_B antagonists CGP51176 (C) or CGP36742 (D) in the amphetamine-induced hyperactivity test in mice. CGP44532 was given i.p. in doses of 0.060, 0.125 and 0.250 mg·kg⁻¹; GS39783 was given in doses of 5, 10 and 30 mg·kg⁻¹, and both antagonists were given in dose of 15 and 30 mg·kg⁻¹. CGP44532 was administered 120 min while GS39783 and antagonists were administered 30 min before amphetamine (Amph) administration. Locomotor activity was monitored over 30 min immediately following injection of amphetamine (3 mg·kg⁻¹). The data presented are means ± SEM. #P < 0.001 versus control; *P < 0.05 and ***P < 0.001 versus vehicle-treated group.

Figure 6

Effect of the GABA_B antagonists CGP51176 (15 mg·kg⁻¹; A,B) and CGP36742 (15 mg·kg⁻¹; C,D) on the inhibitory effects of CGP44532 (0.250 mg·kg⁻¹; A,C) and GS39783 (30 mg·kg⁻¹; B,D) on amphetamine-induced hyperactivity. Locomotor activity was monitored over 30 min immediately following the injection of amphetamine (Amph) (3 mg·kg⁻¹). The data presented are means ± SEM. #P < 0.001 versus control; **P < 0.001 versus vehicle-treated group; ^@P < 0.05 versus CGP44532 or GS39783 alone.

Figure 7

Effects of CGP44532 (A) and GS39783 (B) on haloperidol-induced catalepsy. CGP44532 was administered in doses 0.060, 0.125 and 0.250 mg·kg⁻¹ and GS39783 was administered in doses of 5, 10 and 30 mg·kg⁻¹. Both compounds were administered 30 min before haloperidol and the catalepsy was measured 90 min after haloperidol administration. Values represent the immobility time (mean ± SEM). *P < 0.05 and **P < 0.01 versus vehicle-treated group.

Figure 8

Effects of CGP44532 and GS39783 on (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches. In (A), dose-dependent suppression of DOI (2.5 mg·kg⁻¹)-induced head twitches by the reference compounds haloperidol (Hal) and clozapine (Clo). In (B), the GABA_B receptor agonist CGP44532 was given in doses of 0.020, 0.060, 0.125 and 0.25 mg·kg⁻¹ and in (C), GS39783 was given in doses of 2.5, 5, 10 and 30 mg·kg⁻¹. Values represent the number of head twitches (means ± SEM) during a 20 min session. **P < 0.01 versus vehicle-treated group.

Figure 9

In (A), the effect of the GABA_B antagonists CGP51176 and CGP36742 given in doses of 15 and 30 mg·kg⁻¹ on (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches. In (B), the effect of GABA_B receptor antagonist CGP51176 (B) and in (C) of CGP36742 on the inhibitory effects on GABA_B receptor activators CGP44532 (0.250 mg·kg⁻¹) and GS39783 (30 mg·kg⁻¹) on DOI-induced head twitches in mice. All the compounds were administered 30 min before the test. Values represent the number of head twitches (mean ± SEM) during a 20 min session. **P < 0.001 versus vehicle-treated group; #P < 0.01 versus GS39783 or CGP44532 alone.

Figure 10

Suppression of the excitatory effect of (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (10 µM) on the frequency of spontaneous EPSCs (sEPSCs) by CGP44532. (A) Examples of recordings from a representative neuron. (1) Baseline activity; (2) recording after 10 min incubation with DOI; (3) recording after 10 min incubation with by CGP 44532 (5 µM) in the presence of DOI. (B) Dose-dependent suppression of the effect of 10 µM DOI on the mean frequency (±SEM) of spontaneous EPSCs by CGP44532. *Significant difference between the effect of CGP44532 and that of DOI alone (5 µM: T = 2.35, P = 0.025, d.f. = 30; 10 µM: T = 4.19, P = 0.0002, d.f. = 30).

Figure 11

Suppression of the excitatory effect of (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (10 µM) on the frequency of spontaneous EPSCs (sEPSCs) by GS39783. (A) Examples of recordings from a representative neuron. (1) Baseline activity; (2) recording after 10 min incubation with DOI; (3) recording after 10 min incubation with GS39783 (5 µM) in the presence of DOI. (B) Dose-dependent suppression of the effect of 10 µM DOI on the mean frequency (±SEM) of spontaneous EPSCs by GS39783. *Significant difference between the effect of GS39783 and that of DOI alone (5 µM: T = 2.22, P = 0.034, d.f. = 32; 10 µM: T = 3.63, P = 0.001, d.f. = 32).