GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA_B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA_B receptor agonist baclofen in FAST mice. We hypothesized that GABA_B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA_B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA_B receptor activation may instead enhance some of the behavioral effects of morphine.     

Additive inhibition of lordosis by simultaneous treatments with GABA(A) and GABA(B) receptor agonists, muscimol and baclofen, in female rats

In order to investigate the relationship between GABA_A and GABA_B receptors in the induction of lordosis behavior, agonists of these receptor subtypes were injected simultaneously to estrogen-treated ovariectomized rats and lordosis behavior was observed before and after the injections. The GABA_A receptor agonist, muscimol (MUS), at a dose in the range from 1.0 to 1.4 mg/kg body weight (bw) or the GABA_B receptor agonist, baclofen (BAC) at a dose in the range from 1 to 10 mg/kg bw, was injected intraperitoneally. The lordosis quotient (LQ) decreased after treatments with MUS or BAC and a dose-dependent decrease of LQ was observed in MUS or BAC-treated rats. When 1.2 mg/kg bw MUS and 5 mg/kg bw BAC were injected simultaneously, the mean LQ decreased strongly and was significantly lower than the values obtained after single injections of the agonists at these doses (P < 0.05). In addition, to ascertain the time-course of changes, a behavioral test was carried out 7 times from 15 to 180 min after the injection of agonists. The low LQ in the rats injected with both MUS and BAC continued longer than in rats given single injections. These results indicate that both GABA_A and GABA_B receptors are involved in lordosis-inhibiting mechanisms by the GABA neuron and operate independently.     

Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat

In the present study, an unbiased conditioned place preference paradigm was used to study the effects of intra-ventral tegmental area injections of Gama-amino-butyric acid (GABA)-A and B (GABA(A) and GABA(B)) receptor agonists and antagonists on the expression of morphine-induced conditioned place preference (CPP) in rats. Subcutaneous (s.c.) injections of morphine sulfate (5 mg/kg) induced CPP. Intra-ventral tegmental area administration of the GABA(A) receptor agonist, muscimol (6 microg/rat) reduced the expression of morphine-induced CPP. Muscimol (25 microg/rat) increased the expression of CPP induced by morphine. A reduction of the expression of morphine-induced CPP was observed on intra-ventral tegmental area injection of GABA(A) receptor antagonist bicuculline (25 microg/rat). Bicuculline (10 microg/rat) increased the expression of CPP induced by morphine. Baclofen (12 microg/rat) increased where as (19 and 25 microg/rat) reduced the expression of morphine-induced CPP. Injection of CGP38345 (10, 19, 25 and 50 microg/rat) into the ventral tegmental area significantly reduced the expression of CPP induced by morphine. It is concluded that GABA(A) and GABA(B) receptor subtypes within the ventral tegmental area may have different effects on the expression of morphine-induced CPP.     

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.     

Dopamine D<Subscript>3</Subscript> receptor ligands modulate the acquisition of morphine-conditioned place preference

Rationale The dopamine D₃ receptor has been shown to mediate conditioned effects of psychostimulants such as cocaine. The present work was aimed at determining whether drugs acting at D₃ receptors alter acquisition of conditioned effects of opiates.Methods We have used the conditioned place preference (CPP) in mice, which permits the measurement of approach behaviour to environmental stimuli previously paired with drug effects. To assess the interaction of morphine and D₃ receptor ligands during acquisition of CPP, we have used a particular procedure, in which the animals were given the choice between compartments associated with either morphine alone or the combination of morphine with the tested agent.Results D₃ receptor agonists (7-OH-DPAT, quinelorane, BP 897) did not induce, alone, a significant CPP but, all of them, at the doses tested, and notably BP 897, a highly selective partial agonist, significantly enhanced acquisition of morphine-induced CPP when administered together with morphine at each conditioning session. PNU-99194A, a D₃ receptor-preferring antagonist, induced a CPP itself at the dose of 10 mg/kg but not at 5 or 15 mg/kg and impaired significantly at 10 and 15 mg/kg the morphine-induced CPP. In contrast, BP 897 did not alter morphine-induced analgesia, an unconditioned effect of this drug.Conclusions These results suggest the stimulation of D₃ receptors has no rewarding effect per se, but may synergize upon opiate-induced dopamine release with stimulation of other dopamine receptor subtypes to enhance approach behaviour to morphine-associated environment.     

GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice

In this study, we investigated the effects of GABA_A and GABA_B receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA_B receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA_A receptor agonist, had no significant effect. GABA_B receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.     

GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala

The central nucleus of the amygdala (CeA) has an important role in pain perception and analgesia. Opioid and GABA_A receptors, which are both involved in pain modulation, are found in high concentration in the CeA. The present study was designed to examine the interaction of opioidergic and GABAergic systems in the CeA during modulation of acute thermal pain. In the present study, different doses of morphine (25, 50 and 100 μg/rat), either alone or after 5 min pretreatment with the selective GABA_A receptor agonist muscimol (60 ng/rat) or the selective GABA_A receptor antagonist bicuculline (50 ng/rat), were injected bilaterally into the CeA of each rat. Tail‐flick latencies (TFL) were measured every 5 min for 60 min. The results revealed that microinjection of morphine into the CeA significantly increased TFL in a dose‐dependent manner. Microinjection of bicuculline or muscimol in combination with morphine into the CeA increased and decreased TFL, respectively. It seems that morphine in the CeA facilitates the function of descending inhibitory systems by interacting with the activity of local GABA_A receptors.     

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.     

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

Deficits in N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA_B receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC-EC in freely moving rats. Infusion of the GABA_B receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA_B agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABA_B receptors on DA terminals, with both GABA_B ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.     

Involvement of dopamine D2 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injections of dopamine (DA) D2-like receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the DA D2/D3 receptor agonist, quinpirole (0.3-3 microg/rat), or the DA D2 receptor antagonist, sulpiride (0.04-5 microg/rat), did not produce a significant place preference or place aversion. Intra-CeA administration of quinpirole (0.3 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. On the other hand, quinpirole (0.3 microg/rat) injection into the CeA induced CPP in combination with the lower doses of morphine (0.5 and 2.5 mg/kg), but decreased the response of higher dose (7.5 mg/kg) of morphine. This response of quinpirole was attenuated by sulpiride (0.2 microg/rat). Sulpiride by itself (0.04-5 microg/rat) reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of the higher dose of sulpiride (1 and 5 microg/rat) or the higher dose of quinpirole (3 microg/rat) during acquisition decreased the locomotor activity of the animals on the testing days. The injection of the low dose of quinpirole (0.3 microg/rat) on the test day reduced the expression of morphine-induced CPP, but the high dose of quinpirole (3 microg/rat) potentiated this expression. The administration of sulpiride (5 microg/rat) attenuated the quinpirole response. The injection of sulpiride (1 and 5 microg/rat) abolished the expression of morphine-induced CPP. It is concluded that the CeA DA D2-like receptors may play an active role in morphine reward.     

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.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

Effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor,CGP7930, on the development and expression of amphetamineinduced locomotor sensitization in rats

BackgroundSeveral of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, evidence shows that γ-aminobutyric acid B (GABA_B) receptors are involved in the behavioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABA_B receptor agonist baclofen and a positive allosteric modulator of theGABA_B receptor, CGP7930, on AMPH-induced locomotor sensitization.MethodsIn a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg), or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the development and expression of locomotor sensitization produced by AMPH (1.0 mg/kg).ResultsThe results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABA_B receptor, CGP7930, increased the effects of a lower dose of baclofen on AMPH-induced locomotor sensitization under both conditions.ConclusionThese data provide further evidence thatGABA_B receptor ligands may modulate psychostimulant-induced behaviors.     

Differential involvement of GABAA and GABAB receptors in propofol self-administration in rats

Aim:

Propofol has shown abuse potential. The aim of the present study is to investigate the effects of GABA_A antagonist and GABA_B agonist on propofol reinforcement.

Methods:

Sprague-Dawley rats were trained to self-administer propofol at a dose of 1.7 mg/kg per infusion under a fixed ratio (FR1) schedule of reinforcement for 14 d. In a separate set of experiments, food-maintained self-administration under a fixed ratio (FR5) schedule and locomotor activities of Sprague-Dawley rats were examined.

Results:

GABA_A receptor antagonist bicuculline (0.25 mg/kg, ip) significantly increased the number of injections and active responses. Pretreatment with GABA_B receptor agonist baclofen (3 mg/kg, ip) significantly decreased the number of active responses and total infusions of propofol during the training session. Moreover, microinjection of baclofen (50 and 100 ng/side) into the ventral tegmental area (VTA) significantly decreased the number of active responses and total infusions of propofol. Neither baclofen (1-3 mg/kg, ip) nor bicuculline (0.25-1 mg/kg, ip) affected food-maintained responses or motor activities.

Conclusion:

Propofol maintains its reward properties partially through GABA_A receptor activation. Stimulation of GABA_B receptors in VTA may counteract the reinforcing properties of propofol.     

GABA(A) receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference.

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABA(A) receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5-7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABA(A) receptor agonist, muscimol (0.25, 0.5 and 1 microg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABA(A) receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 microg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 microg/rat) or bicuculline (0.5, 1 and 2 microg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABA(A) receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.     

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.     

The role of nitric oxide within the nucleus accumbens on the acquisition and expression of morphine-induced place preference in morphine sensitized rats

In the present study, the effects of intra-accumbal administration of L-arginine, a nitric oxide precursor, and N(G)-nitro-L-arginine methyl-ester (L-NAME), a nitric oxide synthase inhibitor, on the acquisition and expression of morphine-induced place conditioning in morphine-sensitized rats were studied. Subcutaneous (s.c.) administration of morphine (2.5, 5 and 7.5 mg/kg) induced conditioned place preference. Repeated pretreatment of morphine (5 mg/kg, i.p.) followed by 5 days without drug treatment, increased conditioning response induced by morphine (0.25, 0.5 and 0.75 mg/kg). Intra-accumbal (intra-nucleus accumbens; 1 microg/rat) administration of L-arginine (0.3, 1 and 3 microg/rat) significantly increased or reduced the acquisition of morphine place conditioning in non-sensitized and sensitized rats respectively. However, the drug reduced expression of place conditioning by morphine in sensitized animals. Intra-nucleus accumbens injections of L-NAME (0.3, 1 and 3 microg/rat) reduced the acquisition and expression of morphine place conditioning in the sensitized animals. The results indicate that nitric oxide (NO) within the nucleus accumbens is involved in the acquisition and expression of morphine place conditioning in morphine-sensitized rats.     

Combined discriminative stimulus effects of midazolam with other positive GABA<Subscript>A</Subscript> modulators and GABA<Subscript>A</Subscript> receptor agonists in rhesus monkeys

Rationale Interactions among compounds at GABA_A receptors might have important implications for the therapeutic and other effects of positive GABA_A modulators (e.g. benzodiazepines).Objectives This study examined whether a midazolam discriminative stimulus is modified by GABA_A agonists that act at sites other than benzodiazepine sites.Methods Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA_A receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA_A receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam.Results When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1–3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32–1 mg/kg), gaboxadol (3.2–10 mg/kg) and progabide (10–32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive.Conclusions Direct-acting GABA_A receptor agonists are qualitatively different from positive GABA_A modulators in rhesus monkeys trained to discriminate midazolam. Although GABA_A receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA_A receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl^– flux at the GABA_A receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.     

Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats

Rationale

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress.

Objectives

We tested the hypothesis that DRN GABA_A receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP).

Methods

First, we tested if activation of GABA_A receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABA_A receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABA_A receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABA_A receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP.

Results

Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement.

Conclusions

These data provide evidence that GABA_A receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.     

Effects of the 5-HT1 receptor agonists DP-5-CT,CGS 12066B,and RU 24969 on plasma adrenaline and glucose levels in the rat

Summary Recent results have indicated that the 5-HT_1A receptor subtype mediates the adrenaline-releasing and hyperglycemic effects of 8-hydroxy-2-(di-n-propylamino)tetralin in the rat. The aim of this study was to analyse, by means of the peripherally acting 5-HT_1A receptor agonist, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT), whether these 5-HT_1A receptors are peripherally or centrally localised. In view of the appreciable affinity of DP-5-CT for the 5-HT_1D receptor subtype, the effects of the mixed 5-HT_1B/5-HT_1D receptor agonist 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo(1,2-a)quinoxaline (CGS 1206613), and the mixed 5-HT_1A5-HT_1B/5-HT_1D receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)1H-indole (RU 24969) were also investigated.Administration of DP-5-CT (0.3 and 1 mg/kg i. v.) increased plasma glucose levels dose-dependently, whereas only the 1 mg/kg dose of DP-5-CT elicited a rise in plasma adrenaline levels. In contrast, CGS 1206613(1.5 and 4.5 mg/kg 1. v.) did not affect either plasma adrenaline or plasma glucose levels. Administration of RU 24969 (0.5–4.5 mg/kg i. v.) increased dose-dependently both plasma adrenaline and glucose levels. The data suggest that central 5-HT_1A receptors, but neither 5-HT_1B nor 5-HT_1D receptors, regulate plasma adrenaline and glucose levels. Send offprint requests to F. Chaouloff at the above address