Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice

Rationale Gamma-amino-butyric acid (GABA)_B receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical GABA_B agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia. Objectives We studied the role of GABA_B receptors in the spontaneous PPI deficits displayed by DBA/2J mice. Materials and methods We tested the effects of baclofen (1.25–5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, we investigated the expression of GABA_B receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography. Results Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABA_B antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABA_B receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions. Conclusions Our data highlight GABA_B receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA_B receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances. M. Paola Castelli, Giampaolo Mereu, and Francesco Marrosu have contributed equally to the study.     

γ-Hydroxybutyric acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABAB receptors

The effect of γ-hydroxybutyric acid (GHB) and baclofen, a GABA_B receptor agonist, on extracellular hippocampal acetylcholine levels was studied in freely moving rats by microdialysis. GHB (200 and 500 mg/kg, i.p.) reduced in a dose-dependent manner, extracellular hippocampal acetylcholine concentrations and this effect was prevented by the GABA_B receptor antagonist (2S)(+)-5,5-Dimethyl-2-morpholineacetic acid (SCH 50911), at the dose of 20 mg/kg (i.p.), while the putative GHB receptor antagonist 6,7,8,9-Tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS 382) was ineffective. Similar to GHB, the GABA_B agonist baclofen (10 and 20 mg/kg, i.p.) produced a dose-related reduction in extracellular acetylcholine concentrations which was prevented by SCH 50911. These findings indicate that GHB-induced reduction of hippocampal acetylcholine release is mediated by GABA_B receptors and support a possible involvement of hippocampal GABA_B receptors in the control of cognitive processes and in the claimed amnesic effect of GHB intoxication.     

Inhibition of firing rate and changes in the firing pattern of nigral dopamine neurons by γ-hydroxybutyric acid (GHBA) are specifically induced by activation of GABAB receptors

 Previous studies have shown that administration of γ-hydroxybutyric acid (GHBA) or the GABA_B receptor agonist baclofen are associated with a decrease in firing rate, a regularisation of firing pattern and a decrease in burst activity of midbrain dopamine (DA) neurons in the substantia nigra (SN). In the present study we compared the ability of the novel GABA_B receptor antagonist SCH 50911 and the selective antagonist of GHBA binding sites, NCS-382, to antagonise the effects of baclofen or GHBA, respectively, on the neuronal activity of DA neurons in anaesthetised rats. SCH 50911 (75 mg/kg, i.v.) was found to antagonise the decrease in firing rate, the regularisation of firing rhythm and the decrease of burst activity in DA cells, induced by baclofen (1–32 mg/kg, i.v.) or GHBA (12.5–1600 mg/kg, i.v.). NCS-382 (100 mg/kg, i.v.) did not affect the baclofen-induced changes in neuronal activity. Neither was the drug able to influence the GHBA-induced alterations in firing rate or in burst activity, although NCS-382 to some extent antagonised the regularisation of the firing pattern observed following low doses of GHBA (≤100 mg/kg). The results of the present study give further support for the notion that the GHBA-induced changes in neuronal activity of nigral dopamine neurons are mediated by stimulation of GABA_B receptors. Received: 13 October 1997 / Accepted: 10 March 1998     

DOI-induced deficits in prepulse inhibition in Wistar rats are reversed by mGlu2/3 receptor stimulation

Prepulse inhibition (PPI) of the acoustic startle response (ASR) provides a measure of sensorimotor gating mechanisms that are impaired in schizophrenia patients. Interactions of the serotonin (5-hydroxytryptamine, 5-HT) and glutamatergic systems, especially via the 5-HT_2A receptor subtype, have been implicated in the regulation of PPI. The present study investigated the involvement of interactions between 5-HT_2A and metabotropic glutamate (mGlu)2/3 receptors in modulating PPI in Wistar and Lister Hooded rats. Systemic administration of the 5-HT_2A/2C receptor agonist DOI ((+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride; 3 mg/kg) reduced PPI and ASR magnitude in Wistar but not in Lister Hooded rats. In Wistar rats, pre-treatment with the mGlu2/3 receptor agonist LY379268 (1 mg/kg) attenuated the DOI-induced disruption of PPI as well as the DOI-elicited reductions of ASR magnitude. LY379268 itself did not alter PPI in both strains and only slightly increased ASR magnitudes in Wistar rats. Taken together, these findings support the notion of functionally antagonistic interactions between 5-HT_2A and mGlu2/3 which might be involved in regulating sensorimotor gating mechanisms. Additionally, the data suggest that stimulation of mGlu2/3 receptors may be useful to ameliorate sensorimotor gating deficits resulting from an overstimulation of 5-HT_2A receptors.     

Attenuation of <Emphasis Type="Italic">d</Emphasis>-amphetamine self-administration by baclofen in the rat: behavioral and neurochemical correlates

Rationale Recent reports have demonstrated that gamma-aminobutyric acid (GABA)-ergic compounds attenuate the reinforcing effects of cocaine in rats. Baclofen, a GABA_B receptor agonist, appears to be particularly effective in this respect, suggesting that GABA_B receptor activation is critically involved in mediating anti-cocaine effects. Amphetamine, like cocaine, is a psychomotor stimulant with high abuse potential in humans.Objectives The purpose of the present investigation was to determine whether baclofen may attenuate the reinforcing effects of d-amphetamine (dAMPH) in rats. Dose–response curves were generated to examine the effect of three doses of baclofen (1.8, 3.2 or 5.6 mg/kg, IP) on dAMPH intravenous self-administration (IVSA). Separate groups were trained to self-administer two doses of dAMPH (0.1 mg/kg or 0.2 mg/kg per injection) under either a fixed-ratio (FR) or progressive ratio (PR) schedule of reinforcement. Microdialysis was performed in an additional group of rats to examine the effect of baclofen on dAMPH-induced increases in dopamine (DA) efflux in the nucleus accumbens (NAc).Results Pretreatment with baclofen produced dose-dependent reductions in responding for dAMPH under both the FR and PR schedules, and attenuated dAMPH-induced increases in DA levels in the NAc.Conclusion These results add to previous findings showing that baclofen attenuates the reinforcing effects of psychostimulant drugs, and suggest that further investigation into the effects of GABA_B receptor agonists on drug self-administration is warranted.     

The GABAB receptor agonist baclofen administered into the median and dorsal raphe nuclei is rewarding as shown by intracranial self-administration and conditioned place preference in rats

Rationale

The midbrain raphe regions have long been implicated in affective processes and disorders. There is increasing evidence to suggest that the median (MR) and dorsal raphe nuclei (DR) tonically inhibit reward-related processes.

Objectives

Stimulation of GABA_B receptors in the midbrain raphe nuclei is known to inhibit local neurons, especially serotonergic neurons. We sought to determine if injections of the GABA_B receptor agonist baclofen into the MR or DR are rewarding, using intracranial self-administration and conditioned place preference.

Results

Rats quickly learned to lever press for infusions of baclofen (0.1–2.5 mM) into the MR, but not the ventral tegmental area or central linear nucleus. Rats increased lever pressing associated with intra-DR baclofen infusions, but not readily. Baclofen self-administration into the MR or DR was attenuated by coadministration of the GABA_B receptor antagonist SCH 50911 (1 mM) or systemic pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). In addition, intra-DR and intra-MR injections of baclofen induced conditioned place preference; injection into DR was more effective.

Conclusions

Baclofen injections into the midbrain raphe nuclei are rewarding. Baclofen was more readily self-administered into the MR than into the DR, while baclofen injections into the DR more readily induced conditioned place preference than those into the MR. These sites may be differentially involved in aspects of reward. These findings suggest that MR or DR neurons containing GABA_B receptors are involved in tonic inhibitory control over reward processes.     

Positive allosteric modulators at GABAB receptors exert intrinsic actions and enhance the influence of baclofen on light-induced phase shifts of hamster circadian activity rhythms

Light-induced phase shifts of hamster circadian activity rhythms are modulated by GABA_B receptors. Recently, positive allosteric modulators (PAM)s at GABA_B receptors were described, but it is not known whether they affect light-induced entrainment of circadian rhythms. Therefore, we studied the effects of two GABA_B PAMs, GS39783 and RacBHFF, upon light-induced phase advances and delays of hamster circadian wheel-running activity rhythms. Wheel running activity was recorded for Syrian hamsters maintained in constant darkness. Drugs administered intraperitoneally were evaluated for their ability to modulate a light-induced shift of the circadian activity rhythm. Baclofen (3.75-15 mg/kg) dose-dependently inhibited both light-induced phase advances and delays of hamster wheel running rhythms, and its actions were blocked by the selective GABA_B antagonist, SCH50911 (5 mg/kg). Neither GS39783 (3-30 mg/kg) nor RacBHFF (0.63-10 mg/kg) affected phase advances when injected alone, but both GS39783 (3 mg/kg) and RacBHFF (10 mg/kg) augmented the inhibitory effect of baclofen (5 mg/kg). At doses above 3 mg/kg, GS39783 and RacBHFF significantly inhibited phase delays alone, consistent with the notion of “agonist-allosteric” properties. GS39783 (0.5 mg/kg), but not RacBHFF (10 mg/kg), augmented the inhibitory action of baclofen on phase delays. These data are consistent with the possibility that GS39783 and RacBHFF act as PAMs at GABA_B receptors inhibiting light-induced phase advances, yet that they also posses “allosteric agonist” actions at the (presumably separate) population of GABA_B receptors modulating light-induced phase delays. GABA_B receptors clearly warrant further investigation as agents for modulation of circadian dysfunction associated with CNS disorders such as depression.     

The role of GABAB receptors in mediating the stimulatory effects of ethanol in mice

Recently, the GABA_B receptor antagonist phaclofen has been shown to attenuate the stimulation of locomotor activity induced by ethanol (Allan and Harris 1989). In the present study, the effects of a range of recently developed GABA_B receptor antagonists (phaclofen, 2-hydroxysaclofen, beta-phenyl-beta-alanine, CGP 35348) and the GABA_B receptor agonist baclofen, were studied for their ability to block the locomotor stimulation induced by a low dose of ethanol administered IP to mice (1.75 g/kg). Results showed that phaclofen, 2-hydroxysaclofen, BPBA and baclofen all dose-dependently decreased ethanol-induced locomotor activity, and, of these, baclofen and BPBA did so at doses which did not attenuate locomotor activity when administered alone. CGP 35348 had no effect on the activity produced by ethanol. The action of baclofen on ethanol-induced activity appeared to be GABA_B receptor mediated, as the effects were stereospecific and were reversed by the antagonist, CGP 35348. However phaclofen, 2-hydroxysaclofen and BPBA failed to reverse the effects of baclofen. These results suggest that the GABA_B receptor may modulate locomotor stimulation induced by low doses of ethanol, and furthermore, that agonist, rather than antagonist activity at the GABA_B receptor is responsible for this reduction. The GABA_B receptor subtype responsible for modulating the effects of ethanol may have properties different from those GABA_B receptors characterised to date.     

GABA<Subscript>B</Subscript> receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

Rationale A growing number of studies suggest that -aminobutyric acid type-B (GABA_B) receptor agonists reduce alcohol use and craving.Objectives This study was designed to further clarify behavioral mechanism(s) by which GABA_B agonists may decrease alcohol reinforcement.Methods Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA_B agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA_B agonists was examined in ethanol naive and self-administering mice.Results Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA_B agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA_B agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA_B agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.Conclusions GABA_B agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA_B agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA_B positive modulation. These data question the safety of prescribing GABA_B agonists to alcoholics since these drugs may potentiate ethanols sedative/hypnotic effects during relapse.     

Effects of α4/β2- and α7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice

RATIONALE: Nicotine and agonists at subtypes of the nicotine acetylcholine receptor (nAChR) affect auditory gating, but the magnitude and direction of such effects appear highly variable. This variability may be due to differences in the tested dose range, selectivity of the test compound, species and strain, and suggests that nAChR subtypes are differentially involved in the control of auditory gating. OBJECTIVES AND METHODS: This study aimed to characterise the effects of nicotine and agonists with preferential activity at alpha4/beta2- and alpha7-nAChRs on auditory sensorimotor gating using a prepulse inhibition (PPI) paradigm. Similar experimental conditions were employed in rats and two strains of mice. The paradigm used startle stimuli of 120 dB and prepulse intensities of 3, 6 and 12 dB above a background of 70 dB. RESULTS: In Sprague-Dawley rats, nicotine disrupted PPI [minimal effective dose (MED): 1 mg/kg, SC] and this effect was mimicked by the potent nAChR agonist, epibatidine, (MED: < or = 0.001 mg/kg, IP) and the potent, and relatively selective, alpha4/beta2-nAChR agonist A-85380 (MED: < or = 0.1 mg/kg, IP). The effects of epibatidine, A-85380 and, to a lesser extent, nicotine were blocked by the non-selective nAChR antagonist mecamylamine. The relatively selective alpha7-nAChR agonists, GTS-21 and AR-R-17779, did not affect PPI in a consistent manner, both in rats and in DBA/2 mice, a strain expressing a disrupted gating phenotype, presumably due to altered activity of hippocampal alpha7-nAChRs. In BALB/c mice, a strain expressing a normal gating phenotype, nicotine (MED: 10 mg/kg, SC), epibatidine (MED: 0.03 mg/kg, IP) and A-85380 (MED: 0.3 mg/kg, IP) predominantly augmented PPI and mecamylamine attenuated these effects. CONCLUSIONS: The present results confirm that the effects of nAChR agonists on PPI are species dependent and suggest that stimulation of heteromeric nAChRs containing both alpha and beta subunits, and possibly of the alpha4/beta2 type, affect sensorimotor gating. Evidence supporting a role for alpha7-nAChRs in the control of PPI of the acoustic startle response was not obtained.     

Effects of ethanol and GABA<Subscript>B</Subscript> drugs on working memory in C57BL/6J and DBA/2J mice

Rationale It has been suggested that GABA_B receptors may be part of a neural substrate mediating some of the effects of ethanol.Objective The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA_B receptors.Methods Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice.Results Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance.Conclusions Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA_B drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Do GABAB receptors have a role in causing behavioural hyperexcitability,both during ethanol withdrawal and in naive mice?

The effects of the GABA_B agonist baclofen and the GABA_B antagonist CGP35348 were examined on the behavioural hyperexcitability which is seen on cessation of chronic ethanol treatment. When baclofen was given to mice of the TO strain after withdrawal from ethanol inhalation, there was evidence of increased hyperexcitability with one dose, 2.5 mg/kg, but no significant change was seen with other doses, 1.25 and 10 mg/kg. When given after withdrawal from a liquid diet containing ethanol, baclofen, 10 mg/kg, produced a large, but short lasting, increase in the ratings of hyperexcitability during the withdrawal period. This effect was significantly decreased when the antagonist CGP35348, 300 mg/kg, was given with baclofen 10 mg/kg. When the antagonist was given alone at 300 mg/kg it significantly decreased the hyperexcitability during ethanol withdrawal. Increases in the ratings of hyperexcitability were seen when baclofen was given to control mice, which had not received ethanol, and these effects were significant, so the effects during ethanol withdrawal were not confined to that syndrome. CGP35348 decreased the behavioural ratings in control animals, and blocked the effects of baclofen 10 mg/kg. When the effects of the compounds on spontaneous locomotor activity in control mice were measured, this parameter was decreased both by baclofen and by CGP35348, at does which were effective in altering the handling-induced behaviour.     

Modification of d-amphetamine-induced responses by baclofen in rats

RATIONALE: d-Amphetamine is known to have effects on heart rate, body temperature and locomotor activity. However, it is not known if GABAB receptor stimulation modifies these actions of d-amphetamine. OBJECTIVES: Using telemetry recordings, this study examined the interactions between the GABAB receptor agonist baclofen and d-amphetamine, on heart rate responses, body temperature and locomotor activity, and whether these effects could be blocked by the GABAB receptor antagonist SCH 50911. METHODS: Rats were prepared with telemetry implants, which allowed continuous monitoring of heart rate, core temperature and spontaneous locomotor activity. Drugs were subsequently administered subcutaneously to the animals for simultaneous recording over a period of 180 min. RESULTS: d-Amphetamine alone (0.3, 1.0 and 3.0 mg/kg) produced a dose-related increase in heart rate, but was without any effect on body temperature, whilst at 1.0 mg/kg, it significantly increased locomotor activity. Baclofen increased heart rate without affecting locomotor activity, and, at the highest dose of 10.0 mg/kg, it induced a significant reduction in body temperature. Graded doses of baclofen (3.0-10.0 mg/kg), when co-administered with d-amphetamine (1.0 mg/kg), did not modify the d-amphetamine-induced increase in heart rate, but the combination produced significant reductions of body temperature. The latter was only partially reversed by the GABAB receptor antagonist SCH 50911 (10.0 mg/kg). By contrast, the increase in locomotor activity by d-amphetamine was markedly blocked by baclofen in a dose-related manner, and this effect was abolished by SCH 50911 (10.0 mg/kg). SCH 50911 alone at doses of 3.0, 6.0 and 10.0 mg/kg had no effect on temperature or locomotor activity. Heart rate was increased significantly, but the magnitude of change was small. CONCLUSIONS: The results of the present study suggest that stimulation of GABAB receptors by baclofen completely blocks the locomotor stimulatory effects of d-amphetamine. Baclofen did not significantly modify the increase in heart rate produced by d-amphetamine and decreased body temperature, both alone and in combination with d-amphetamine. GABAB receptor ligands may well have potential as pharmacotherapies in the treatment of amphetamine abuse and dependence.     

Effects of GABAB receptor ligands in animal tests of depression and anxiety

Preclinical evidence strongly implicates GABA(B) receptors in the pathophysiology of several psychiatric disorders including anxiety and depression. In the present study, we investigated the effects of the selective GABA(B) receptor agonists baclofen and SKF 97541, the GABA(B) receptor positive allosteric modulator CGP7930 and the GABA(B) receptor antagonist SCH 50911 in the modified forced swimming test (FST) and in the elevated zero maze test (EZM), i.e. in animal models predictive of antidepressant and antianxiety activities, respectively. The classical antidepressant imipramine and the anxiolytic diazepam were employed as control drugs in the FST and in the EZM, respectively. In the FST, baclofen (0.25 mg/kg), SKF 97541 (0.01-0.05 mg/kg) or CGP 7930 (1-3 mg/kg) and SCH 50911 (1-3 mg/kg) showed antidepressant-like activity, significantly decreasing immobility time; these effects were not related to changes in locomotor activity. The antidepressant effects produced by the GABA(B) receptor ligands were compared with that of imipramine (30 mg/kg). In the EZM, CGP 7930 (1 mg/kg) and SCH 50911 (1-3 mg/kg) produced anxiolytic-like effects, significantly increasing time spent in the open areas of the maze; those effects were comparable with the effects of diazepam (1-2 mg/kg). Our results indicate that differential manipulation of GABA(B) receptors can modify behaviors relevant to depression and anxiety. The GABA(B) receptor positive allosteric modulator CGP 7930 and the antagonist SCH 50911 show both antidepressant and anxiolytic profile, while the GABA(B) receptor agonists (baclofen and SKF 97541) produce effects that are characteristic of antidepressant drugs.     

The effects of oxytocin and its analog, carbetocin, on genetic deficits in sensorimotor gating

Converging evidence from preclinical and clinical studies suggest that oxytocin has therapeutic potential for schizophrenia and other neuropsychiatric disorders. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating, an important brain function involved in filtering environmental information. We previously demonstrated that systemically administered oxytocin reversed psychostimulant-induced PPI deficits in rats suggesting that oxytocin can produce antipsychotic-like central effects. That finding was supported by a recent trial in humans, which found that intranasal oxytocin reduced symptoms of schizophrenia. The goal of this study was to extend this line of investigation by testing the effects of oxytocin, and a structural analog of oxytocin, carbetocin, on non-pharmacological deficits in PPI. In experiment 1, Brown Norway (BN) rats, a rat strain that has naturally low PPI, were given either saline or one of three doses of oxytocin (0.04-1.0 mg/kg, sc). In experiment 2, BN rats were given either saline, one of three doses of carbetocin (0.04-1.0 mg/kg) or oxytocin (1 mg/kg). PPI and acoustic startle response (ASR) of rats were tested. Oxytocin significantly increased PPI (P<0.01) and decreased ASR levels (P<0.01) in BN rats in a dose-dependent fashion. In contrast, carbetocin had no effect on PPI levels or ASR. The facilitation of BN PPI by oxytocin is similar to what we have previously observed with clozapine and thus further supports oxytocin having antipsychotic properties. In contrast to oxytocin, our data do not support the use of carbetocin as an antipsychotic drug.     

Effects of GABA(B) receptor antagonist, agonists and allosteric positive modulator on the cocaine-induced self-administration and drug discrimination

Preclinical and clinical findings indicate that a GABA(B) receptor agonist baclofen decreases cocaine use. The present study investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541) and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl-4-hydroxy-beta,beta-dimethylbenzenepropanol (CGP 7930) in cocaine-and food-maintained responding under a fixed ratio 5 schedule of reinforcement in male Wistar rats. The effects of the GABA(B) receptor ligands on cocaine (10 mg/kg)-induced discriminative stimulus in a two-lever, water-reinforced fixed ratio 20 task and on basal locomotor activity were also assessed. Baclofen (2.5-5 mg/kg), SKF 97541 (0.1-0.3 mg/kg) and CGP 7930 (30-100 mg/kg) decreased the cocaine (0.5 mg/kg/injection)-maintained responding; SCH 50911 (3-10 mg/kg) was inactive in this respect. Baclofen (5 mg/kg) and SKF 97541 (0.3 mg/kg), but not CGP 7930 or SCH 50911 attenuated the food-maintained responding. The inhibitory effects of the GABA(B) receptor agonists and the modulator were blocked by SCH 50911. SKF 97541 (0.1 mg/kg) or CGP 9730 (30-100 mg/kg) did not produce a significant shift in the cocaine (1.25-10 mg/kg) dose-response curve in a drug discrimination procedure, while baclofen (1.5 mg/kg) or SCH 50911 (10 mg/kg) attenuated the effects of separate doses of cocaine. Baclofen (5 mg/kg) and CGP 7930 (100 mg/kg) significantly reduced basal horizontal activity. We found that pharmacological stimulation of GABA(B) receptors by direct agonists or allosteric positive modulation reduces cocaine reinforcement while this property of cocaine is not related to tonic activation of GABA(B) receptors. The GABA(B) receptor stimulation-induced reduction of cocaine reinforcement was separated from its discriminative stimulus effects. Moreover, a dissociation between effects of direct GABA(B) receptor agonists and a GABA(B) allosteric positive modulator on cocaine vs. food-maintained responding was demonstrated.     

Decreased prepulse inhibition and increased sensitivity to muscarinic,but not dopaminergic drugs in M<Subscript>5</Subscript> muscarinic acetylcholine receptor knockout mice

Rationale Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition of startle (PPI). In preclinical models, these measures may be used to predict antipsychotic activity. While current antipsychotic drugs act largely at dopamine receptors, the muscarinic acetylcholine receptors offer promising novel pharmacotherapy targets. Of these, the M₅ receptor gene was recently implicated in susceptibility to schizophrenia. Due to the lack of selective ligands, muscarinic receptor knockout mice have been generated to elucidate the roles of the five receptor subtypes (M₁–M₅). Objectives Here, we used M₅ receptor knockout (M₅−/−) mice to investigate the involvement of M₅ receptors in behavioral measures pertinent to schizophrenia. We tested the hypothesis that disruption of M₅ receptors affected PPI or the effects of muscarinic or dopaminergic agents in PPI or psychomotor stimulation. Materials and methods We measured PPI in M₅−/−, heterozygous and wild-type mice without drugs, and with clozapine (0.56–3.2 mg/kg) or haloperidol (0.32–3.2 mg/kg) alone, and as pretreatment to d-amphetamine. In addition, we evaluated locomotor stimulation by the muscarinic antagonist trihexyphenidyl (0.56–56 mg/kg) and by cocaine (3.2–56 mg/kg). Results The M₅−/− mice showed decreased PPI relative to wild-type mice, and clozapine appeared to reduce this difference, while haloperidol increased PPI regardless of genotype. The M₅−/− mice also showed more locomotor stimulation by trihexyphenidyl than wild-type mice, while cocaine had similar effects between genotypes. Conclusions These data suggest that disruption of the M₅ receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs.     

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D₁-like and D₂-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing ad adults (60–75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390: 0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D₁-like or D₂-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D₁-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D₁/D₂ DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.     

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats

 This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, IP) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, SC) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed. Received: 15 May 1997/Final version: 7 July 1997     

Sedative and hypothermic effects of γ-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: Assessment using biotelemetry

The recreational drug γ-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000 mg/kg) caused profound sedation for more than 2 h and a complex triphasic effect on body temperature: an initial hypothermia (5–40 min), followed by hyperthermia (40–140 min), followed again by hypothermia (140–360 min). A lower GHB dose (500 mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6 h. The dopamine D₁ receptor antagonist SCH 23390 (1 mg/kg), the opioid antagonist naltrexone (1 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the 5-HT_2A/2C receptor antagonist ritanserin (1 mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000 mg/kg). However the GABA_B antagonist SCH 50911 (50 mg/kg) prevented the hyperthermia induced by GHB (1000 mg/kg). Repeated daily administration of GHB (1000 mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA_B receptor agonist baclofen (10 mg/kg). A high ambient temperature of 28 °C prevented the hypothermia obtained with GHB (500 mg/kg) at 20 °C, while GHB (500 mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5 mg/kg) or METH (1 mg/kg) at 28 °C. These results further confirm a role for GABA_B receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.