The locomotor-reducing effects of GABAergic drugs do not depend on the GABAA receptor

The locomotion-reducing effect of the GABA_B agonist baclofen was compared with that of the GABA_A agonists, aminopropanesulfonic acid (APSA) and THIP. It was found that baclofen was more potent than the other drugs. After intraventricular injection, baclofen induced almost complete immobility, whereas APSA did not affect locomotor activity. THIP had an intermediate effect. The GABA transaminase inhibitor -acetylenic GABA (GAG) provoked a dose-dependent reduction of locomotion. Neither the effects of THIP nor those of GAG could be blocked by concurrent administration of bicuculline. The antagonist itself did not affect locomotor activity. It is concluded that the GABA_A receptor is not important for the locomotionreducing effects of GABAergic drugs.     

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.     

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABA_A agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABA_B agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABA_A agonists, PB and diazepam, although similar to one another, differ from those of direct GABA_A receptor agonists, which produced only partial substitution for PB. The GABA_B agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.     

Effects of GABAB receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

The present study was designed to find out whether pharmacological activation of GABA_B receptors played a role in cocaine sensitization. To this end, male Wistar rats were injected with baclofen or 3-aminopropyl(methyl)phosphinic acid (SKF 97541), the potent and selective GABA_B receptor agonists. The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. Baclofen (1.25, 2.5 and 5 mg/kg), administered for 5 days prior to cocaine, dose-dependently attenuated cocaine sensitization. When injected in the same treatment regimen, SKF 97541 (0.03 mg/kg) reduced the development of cocaine sensitization. To examine the effects of baclofen and SKF 97541 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. Either baclofen (2.5 and 5 mg/kg) or SKF 97541 (0.1 mg/kg) decreased sensitization to cocaine. Our findings implicate a role of GABA_B receptors in locomotor responses to cocaine. More specifically, they show that stimulation of GABA_B receptors exerted inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, what may offer a therapeutic potential of GABA_B receptor agonists in the treatment of cocaine dependence.     

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.     

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.     

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.     

Ethanol-induced locomotor sensitization in DBA/2J mice is associated with alterations in GABAA subunit gene expression and behavioral sensitivity to GABAA acting drugs

Repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. Neuroadaptation within certain brain circuits, including those possessing GABA_A receptors, may underlie locomotor sensitization to ethanol. Indeed, GABA_A receptors are documented mediators of ethanol's cellular and behavioral actions. Moreover, because subunit composition of this receptor is predictive of its pharmacology, it is possible that alterations in subunit composition contribute to the expression of locomotor sensitization to ethanol. The goal of the present study was to determine if alterations in GABA_A subunit composition are associated with the expression of locomotor sensitization in DBA/2J mice, a strain known to be particularly susceptible to the development of this behavioral phenomenon. Following a modified 14 day sensitization procedure (Phillips et al., 1994) relative changes in GABA_A subunit gene expression were assessed in discrete mesolimbic brain regions. To determine if the observed changes in gene expression produced functional changes in the locomotor responses to drugs known to either preferentially or generally activate GABA_A receptors normally possessing the significantly altered subunits, separate cohorts of animals were challenged with one of several low doses of zolpidem (α1-selective), etomidate (β2/3-selective), or flurazepam (γ2-directed) and assessed for locomotor alterations. Sensitized animals displayed increased expression of the α1, β2, and γ2 (v1) subunits in the Nucleus Accumbens (NAc) but not Ventral Tegmental Area (VTA). Additionally, sensitized animals displayed altered sensitivity to the locomotor actions of etomidate and flurazepam. These results support the hypothesis that neuroadaptive changes in GABA_A subunit composition participate in the expression of locomotor sensitization.     

GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat

Female rats were allowed to pace sexual interactions in a bilevel chamber, where a sexually vigorous male was tethered to the bottom level. Exploratory behaviors (sniffing, rearing), locomotor activity (expressed as number of level changes and periods of inactivity) as well as items of sexual motivation (latency to descend to the male’s level, approaches towards the male and genital exploration) were recorded. In addition, sexual receptivity was evaluated in a non-paced situation. A test for motor impairment was also performed. The GABA transaminase inhibitor γ-acetylene GABA reduced exploratory behaviors at doses much lower than those needed to reduce receptivity. The GABA reuptake inhibitor SKF 100330A did not affect any behavior category at doses of 15 and 30 mg/kg, but had a sedative action at 60 mg/kg. This was shown as impaired motor coordination and an almost total absence of activity in the bilevel chamber. Receptivity was not impaired, however. The mixed GABA_A/ GABA_B agonist progabide reduced exploratory behaviors and receptivity without producing motor impairment at a dose of 400 mg/kg. The GABA_A agonist THIP impaired motor coordination and reduced receptivity and exploratory behaviors at a dose of 10 mg/kg. A larger dose, 20 mg/kg, had a strong sedative action. Only a small proportion of the animals descended to the males level. The GABA_B agonist baclofen reduced receptivity at a dose that had no effect on motor coordination or exploratory behaviors. None of the drugs had a specific effect on sexual motivation. Whenever behaviors reflecting motivation were reduced, there were also other behavioral effects indicative of sedation. These data show that GABA receptor agonists, particularly the GABA_B agonist baclofen, reduce sexual receptivity at doses that have only slight effect on motor functions or exploratory behaviors. In contrast, non-specific enhancement of GABAergic activity by a transaminase or reuptake inhibitor have effects on motor functions and exploratory behaviors at doses much lower than those needed to reduce receptivity. Received: 24 June 1996 /Final version: 18 September 1996     

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.     

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.     

Dissociating anxiolytic and sedative effects of GABA<Subscript>A</Subscript>ergic drugs using temperature and locomotor responses to acute stress

Rationale  The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as sedative side effects through nonselective binding to GABA_A receptor subunits. The GABA_A receptor α₁ subunit is associated with sedation, whereas the GABA_A receptor α₂ and α₃ subunits are involved in anxiolytic effects. Objectives  We therefore examined the effects of (non)subunit-selective GABA_A receptor agonists on temperature and locomotor responses to novel cage stress. Results  Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA_A receptor agonist diazepam as well as the α₃ subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA_A receptor α₁-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA_A receptor α₁-selective antagonist βCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the α₁ subunit in thermoregulation and sedation. Ligands of extrasynaptic GABA_A receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses. Conclusions  The present study confirms a putative role for the GABA_A receptor α₁ subunit in hypothermia and sedation and supports a role for α_2/3 subunit GABA_A receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABA_Aergic compounds.     

Suppression of GABA<Subscript>B</Subscript> receptor function in vivo by disulfide reducing agent, <Emphasis Type="SmallCaps">dl</Emphasis>-dithiothreitol (DTT)

Rationale A recent in-vitro study demonstrated that the potent disulfide reducing agent, dl-dithiothreitol (DTT), may alter the structural stability of the GABA_B receptor, probably inactivating the disulfide bonds between four cysteine residues located in the GABA_B1(a) receptor structure.Objectives The present study was designed to evaluate whether DTT treatment was capable of antagonizing some behavioral effects of pharmacological stimulation of the GABA_B receptor.Methods Experiments on sedation/hypnosis induced by the GABA_B receptor agonists baclofen, SKF 97541, CGP 44532 and -hydroxybutyric acid (GHB) in DBA mice and selectively bred GHB-sensitive (GHB-S) rats, and a GHB drug discrimination study in Long Evans rats were conducted. Specificity of the DTT action on the GABA_B receptor was investigated by assessing its effect on the sedative/hypnotic effect induced by diazepam, ketamine and ethanol.Results DTT prevented the sedative/hypnotic effect of all GABA_B receptor agonists tested and also reversed baclofen-induced sedation/hypnosis. In contrast, DTT had no effect on, or even potentiated, sedation/hypnosis produced by diazepam, ketamine or ethanol. DTT completely blocked the discriminative stimulus effects of GHB.Conclusions These results are discussed in terms of DTT altering the stability of the binding domain of the GABA_B receptor, hindering the drug-receptor interaction.     

Calcium channel antagonists attenuate cross-sensitization to the locomotor effects of nicotine and ethanol in mice

The present study was focused on evaluation of locomotor cross-sensitization between nicotine and ethanol in mice. First, we demonstrated that, after 5 daily injections, nicotine (0.5 mg/kg, ip) produced sensitization to its own locomotor stimulant effect. Moreover, nicotine-experienced mice manifested an enhanced response to ethanol challenge (2 g/kg, ip) indicating the development of cross-sensitization between nicotine and ethanol in mice. Additionally, the L-type voltage-dependent calcium channel antagonists: verapamil and diltiazem, but not nimodipine, at the dose of 20 mg/kg, injected before the ethanol challenge, blocked the expression of this cross-sensitization. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in the sensitization to locomotor stimulant effects of nicotine and ethanol and point to certain differences in acute behavioral effects of various classes of calcium channel inhibitors.     

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.     

Inhibitory influence of mecamylamine on the development and the expression of ethanol-induced locomotor sensitization in mice

Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5-2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanol-induced locomotor sensitization.     

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.     

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.     

Injections of baclofen into the ventral medial prefrontal cortex block the initiation,but not the expression,of cocaine sensitization in rats

Rationale Increased excitatory output from the medial prefrontal cortex (mPFC) is thought to play a key role in the development of sensitization to cocaine. Gamma-aminobutyric acid (GABA) inhibits this excitatory output.Objectives The present studies were designed to determine the effects of intra-mPFC injections of the GABA_B agonist baclofen on cocaine-induced motor activity and on the development of sensitization to cocaine.Methods Rats received bilateral cannula implants above the ventral mPFC. Initial studies examined the dose–response effects of injection of baclofen (0.05–0.5 nmol/side) into the mPFC on the acute motor-stimulant response to cocaine (15 mg/kg, i.p.). Additional studies determined whether coadministration of intra-mPFC baclofen (0.5 nmol/side) and systemic cocaine (15 mg/kg, i.p.) could alter the initiation and/or expression of cocaine-induced behavioral sensitization.Results Intra-mPFC baclofen dose-dependently blocked cocaine-induced motor activity. In sensitization studies, intra-mPFC baclofen was able to prevent the initiation, but not the expression of cocaine-induced sensitization.Conclusions The data suggest that the ability of GABA to modulate excitatory output from the mPFC may be attenuated in animals sensitized to cocaine.     

Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (?) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or γ-acetylenic GABA caused a dose-dependent inhibition of the locomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (?) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for γ-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (?) baclofen may prove to be useful in the management of PCP intoxication.Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (?) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (?) baclofen and PCP. The possible use of (?) baclofen as an adjuvant to general anesthetic is discussed.