Evidence for GABA-BZ receptor modulation in short-term memory passive avoidance task paradigm in mice

The possible involvement of gamma-aminobutyric acid/benzodiazepine (GABA-BZ) receptor modulation in scopolamine-induced short-term memory deficit was investigated in mice. Passive avoidance step-down task behavior was observed. Latency of mice to reach shock-free zone (SFZ) and number of mistakes the animal made in 15 min were used as separate parameters for acquisition and memory retention, respectively. Scopolamine (0.3 mg/kg) caused a delay in reaching SFZ and an increased number of mistakes. Physostigmine reversed the scopolamine-induced increase in number of mistakes; however, it caused a delay in the time to reach SFZ. Subeffective dose of GABA, when combined with physostigmine, further delayed the latency to reach SFZ, but reduced the number of mistakes very significantly. GABA (50, 75 and 100 mg/kg, i.p.) and GABA agonists sodium valproate (30 and 60 mg/kg, i.p.), fengabine (5 and 10 mg/kg, i.p.), (+/-)baclofen (0.25, 0.5 and 1.0 mg/kg, i.p.) and (-)baclofen (0.25 and 0.5 mg/kg i.p.) reversed the scopolamine-induced effect; however, sodium valproate at higher dose delayed time to reach SFZ. Combined administration of lower dose (+/-)baclofen and subeffective dose of GABA showed significant decrease in latency and number of mistakes in scopolamine-treated animals. The specific benzodiazepine antagonist flumazenil (Ro-15-1788) (5 and 10 mg/kg, i.p.) and inverse agonist FG-7142 (10 mg/kg, i.p.) very significantly reversed scopolamine-induced increase in number of mistakes, but Ro-15-1788 failed to show any effect on latency per se and in scopolamine-treated experiments, as well.(ABSTRACT TRUNCATED AT 250 WORDS)     

GABA-mediated modification of despair behavior in mice

Summary Gamma-aminobutyric acid (GABA) and GABA agonists exhibited biphasic response on forced swimming-induced despair behavior in mice; smaller doses, GABA (100 mg/kg), muscimol (0.05 and 0.1 mg/kg), baclofen (0.5 and 1 mg/kg), sodium valproate (100 mg/kg), piracetam (25 mg/kg), and fengabine (10 and 20 mg/kg) decreasing forced swimming-induced immobility period, while higher doses enhancing the immobility period. GABA, muscimol, and baclofen also reversed reserpine-induced prolongation of the forced swimming-induced immobility. When GABA was administered with antidepressant agents, it potentiated the effect of some classical antidepressants. Bicuculline and picrotoxin, the GABAergic antagonists, by themselves enhanced the forced swimming-induced immobility period, but they had no significant effect on reserpine-induced prolongation of the immobility period. When animals were chronically exposed to forced swimming, there was a gradual increase of the immobility period which was reduced on treatment with GABAergic agents. It is suggested that GABA has a modulatory role in reversing forced swimming-induced despair and also in potentiating the effect of antidepressants.     

Modification of GABAergic activity and thyrotropin secretion in male rats

The effect of GABA on basal and stimulated TSH secretion was studied in male rats. The effects of drugs on basal TSH levels were not consistent. Muscimol(0.5 mg/kg subcutaneously, but not 2 mg/kg) increased whereas baclofen (10 mg/kg intraperitoneally), amino-oxyacetic acid (AOAA, 20 mg/kg intraperitoneally) and bicuculline (2 mg/kg intraperitoneally, but not 1 or 4 mg/kg) decreased basal TSH concentrations. Muscimol, AOAA and baclofen dose-dependently reversed the TSH cold-response, as did a large dose of di-n-propylacetate (DPA, 400 mg/kg intraperitoneally) and 500 mg/kg (but not 50, 100 or 1500 mg/kg intraperitoneally) of GABA itself. Bicuculline was not effective alone. Neither did it modify the effects of muscimol, AOAA and GABA on the cold-stimulated TSH response. None of the drugs studied (AOAA, GABA, bicuculline) modified TRH-induced (100 ng intraperitoneally) TSH-response. GABA injected into the third ventricle (5-50 microgram/rat) or into the medial basal hypothalamus (MBH, 5 microgram/rat) had no effect on the basal TSH levels. However, the TSH cold-response was inhibited when GABA (5 microgram/rat) was infused into the MBH but not when it was infused into the third ventricle (5-50 microgram/rat). The results suggest that GABAergic pathways may have an inhibitory effect on the stimulated TSH secretion in male rats. The locus of this inhibition is not situated in the anterior pituitary, but possibly in the MBH.     

Baclofen analgesia: involvement of the GABAergic system.

The effect of baclofen, a GABA(B) agonist, has been studied in the hot plate test in mice, to analyze the possible involvement of the GABAergic system in baclofen analgesia. Baclofen (1-3 mg kg(-1) intraperitoneal (i.p.)) was found to elicit a dose-dependent antinociceptive effect. The antinociceptive effect of baclofen cannot be due to motor incoordination or sedation as the doses of baclofen which produce analgesia did not induce these effects during the rota-rod test. The antinociceptive effect of baclofen was reversed by 2-hydroxysaclofen, a GABA(B) antagonist by both systemic (3 mg kg(-1)) and intra cisterna magna (intracisternal (i.c.)) (0.3 mg kg(-1)) administration. The antagonist dose administered via i.c. produced a complete blockade and was 10-fold lower than the dose employed in i.p. administration. The data suggest that the antinociceptive effect of baclofen is GABA(B) receptor-mediated and reveal a central location of the analgesic effect of baclofen.     

Role of cholinergic and GABAergic neuronal systems in cycloheximide-induced amnesia in mice

The role of cholinergic and GABAergic neuronal systems on the cycloheximide (CXM)-induced amnesia was investigated using the step-down-type passive avoidance task in mice. CXM (7.5-120 mg/kg, SC) given just after the training caused amnesia (indicated by short latency to step down from the platform on the grid floor) in the retention test conducted 24 hr later in a dose-dependent fashion. In the CXM (60 mg/kg)-treated mice, a choline esterase inhibitor, physostigmine (PHY; 0.125 and 0.25 mg/kg, IP), or GABA agonists, muscimol (1 and 2 mg/kg, IP) and baclofen (6 and 12 mg/kg, IP), given just after training markedly prolonged step down latency (SDL), indicating reversal of amnesia. The antiamnesic action of PHY (0.125 mg/kg) was almost completely antagonized by a central acetylcholine antagonist, scopolamine (3 mg/kg, SC), but not by a peripheral acetylcholine antagonist, butylscopolamine (3 mg/kg, SC). Furthermore, the antiamnesic action of muscimol (2 mg/kg) was reversed by GABA antagonists, picrotoxin (0.5 mg/kg, SC) and bicuculline (0.5 mg/kg, SC), while the effect of baclofen (12 mg/kg) was reversed by picrotoxin (0.5 mg/kg), but not by bicuculline (0.5 mg/kg). These results suggest that the dysfunction of cholinergic and GABAergic neuronal systems play an important role in the CXM-induced memory impairment on the passive avoidance task.     

GABA(B) receptors and amnesia in mice withalternative stereotypes of behavior

The influence of agonists and antagonists of GABA(B) receptors on the development of amnesia has been studied using the passive avoidance test in C57Bl/6J mice with previously generated aggressive and submissive behavioral stereotypes. It is established that baclofen in a dose of 1 mg/kg produces amnesia in aggressive mice and imparts stability with respect to the amnestic influence in submissive mice. Phaclofen in a dose of 5 mg/kg prevents the development of amnesia that is most strongly pronounced in submissive mice.     

Modulatory role of D-1 and D-2 dopamine receptor subtypes in nociception in mice

The role of D-1 and D-2 dopamine (DA) receptors in nociception in naive as well as reserpinized mice and the modulation of the nociceptive action of morphine or naloxone by the selective D-1 and D-2 DA agonists, was investigated in mice. The D-2 DA agonists, B-HT 920 and bromocriptine produced an anti-nociceptive effect in naive mice and reversed the hyperalgesic effect of reserpine (2 mg/kg, 4 h prior) pre-treatment. The D-1 DA agonist, SKF 38393 (5 mg/kg) failed to alter the nociceptive responsiveness of naive and reserpinized mice. Apomorphine, a mixed D-1/D-2 DA agonist, produced significant analgesia in naive mice and also reversed reserpine-induced hyperalgesia. SKF 38393 (5 mg/kg) enhanced the anti-nociceptive effect of B-HT 920 (0.1 mg/kg) in naive and reserpine-pre-treated mice. The anti-nociceptive response of morphine (5 mg/kg) was enhanced by B-HT 920 while SKF 38393 reduced the same. Apomorphine (0.5 mg/kg) or the combination of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) failed to enhance the anti-nociceptive effect of morphine. Reserpine (2 mg/kg, 4 h prior) pre-treatment significantly reduced the anti-nociceptive effect of morphine. Similarly, the hyperalgesic action of naloxone (20 mg/kg) was reversed by B-HT 920, bromocriptine and apomorphine but not by SKF 38393. The reversal of the hyperalgesic action of naloxone by B-HT 920 was blocked by pre-treatment with haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). SKF 38393 (5 mg/kg) failed to potentiate the reversal action of B-HT 920 against naloxone. These data suggest a predominant role of D-2 DA receptors in anti-nociception and the possibility of the existence of an interlink between the DAergic and opioid systems.     

The effects of intraperitoneal administration of the GABA(B) receptor agonist baclofen on food intake in CFLP and C57BL/6 mice

The effects of the GABA(B) receptor agonist baclofen were investigated on food intake in non-deprived CFLP and C57BL/6 mice. In Experiment 1, baclofen (1-8 mg /kg) administered i.p. to CFLP mice, produced a dose-related increase in food intake. The 4 and 8 mg/kg doses produced significant increases in cumulative feeding when measure 120 min after administration (at least P < 0.05, in each case). In Experiment 2, baclofen (1-10 mg/kg), administered intraperitoneally (i.p.) to C57BL/6 mice, also produced a dose-related increase in food intake. The 4 mg/kg dose of baclofen significantly increased cumulative food intake at 60 min (P < 0.05), while the 2 and 4 mg/kg doses significantly increased cumulative food intake at 120 min (P < 0.01, in each case). The 10mg/kg dose was without effect. These data show that systemic administration of the GABA(B) agonist baclofen produces an increase in food consumption in two different strains of mice and extend previous observations made in rat to another rodent species.     

GABA(B) receptors involvement in the effects induced by nicotine on anxiety-related behaviour in mice

The aim of the present study was to evaluate the possible involvement of GABA(B) receptors in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Animals were exposed to nicotine only once. The acute administration of low (0.05mg/kg, sc) or high (0.8mg/kg, sc) doses of nicotine produced opposite effects in the elevated plus maze test; respectively, anxiolytic- and anxiogenic-like responses. The effect of pretreatment with either the GABA(B) receptor antagonist 2-OH-saclofen (0.25, 0.5 and 1mg/kg; ip) or the GABA(B) receptor agonist baclofen (0.5, 1 and 2mg/kg; ip), was evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. 2-OH-saclofen completely abolished both nicotine-induced effects (p<0.001) at the highest dose tested, suggesting an involvement of GABA(B) receptors in these behavioural responses. On the other hand, baclofen failed to modify the anxiety-related effects of nicotine. These results suggest that the GABA(B) receptors are involved in the regulation of nicotine-induced anxiety-related behavioural responses in mice, and provide new findings to support a potential pharmaco therapeutic use of GABAergic drugs in the treatment of tobacco addiction.     

The effect of baclofen on the locomotor activity of control and small-platform-stressed mice.

The effect of baclofen on the locomotor activity of control and small-platform-stressed mice was studied. In the small platform technique, mice are forced to stay on small platforms (d= 3.5 cm) surrounded by water for 24 h. Small platform stress increased the locomotor activity of mice in the actometer. Baclofen administered at doses of 0.25, 0.5 and 1.0 mg kg(-1)(i.p.) had no effect on the locomotor activity of control mice. In small-platform-stressed mice, the locomotor depressant effect of baclofen was pronounced, being statistically significant at a dose of 1.0 mg kg(-1). These data suggest that small platform stress induces hypersensitivity of mice to the motor depressant effect of baclofen. On the basis of these data it could be proposed that small platform stress induces changes in the function of GABA(B)receptors and that GABA(B)receptors participate in the behavioural changes caused by small platform stress.     

The significance of central nicotine receptors in the aggression of isolated mice

The effect of nicotine, and some nicotinic antagonists on aggressive behavior of isolated mice was tested. Nicotine in doses of 0.5-2 mg/kg ip and 0.005-0.06 mg/mouse ivtr potentiated the aggressiveness. However, higher doses nicotine (4 mg/kg ip and 0.09 mg/kg (Polfa). Co-suppressed the aggression. Mecamylamine, a central nicotinic antagonist in a dose of 2 mg/kg facilitated the aggression while in doses of 4 and 8 mg/kg inhibited it. Hexamethonium, a peripheral nicotinic antagonist, partially suppressed the aggressive behavior. Our results indicate that central nicotinic receptors have also a certain role in mediating the investigated type of mouse aggression.     

人参茎叶皂甙对正常和利血平化小鼠心肌cAMP和cGMP含量的影响

口服人参茎叶皂甙25mg/kg,连续服用7天组小鼠心肌 cAMP 含量显著升高(p<0.01),而对 cGMP 含量无明显影响;50mg/kg GSL 对 cAMP,cGMP 含量均无明显影响。对利血平化小鼠,50mg/kg 能明显提高小鼠心肌中 cAMP 的含量(p<0.01),对 cGMP 含量影响不明显。cAMP/cGMP 比值提示,25mg/kg 和50mg/kg GSL 对 cAMP/cGMP 比值均增高;对利血平化小鼠心肌 cAMP/cGMP 比值无明显变化。     

Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice

γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs.     

Reduced aggression in mice lacking the serotonin transporter

Abstract Rationale. The possible role of γ-aminobutyric acid (GABA) in human aggression was evaluated by administering baclofen, a GABA-B agonist and comparing the effects on laboratory measures of aggression and escape among subjects with and without a history of conduct disorder. Methods. Twenty male subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and escape responses. Ten subjects had a history of childhood conduct disorder (CD+) and ten control subjects had no history of CD. Aggression was measured using the point subtraction aggression paradigm (PSAP), which provides subjects with aggressive, escape, and monetary-reinforced response options. Results. Acute doses (0.07, 0.14 and 0.28 mg/kg) of baclofen had remarkably different effects on aggressive responses among CD+ subjects relative to control subjects. Aggressive responses of CD+ subjects decreased, while aggressive responses of control subjects increased following baclofen administration. Baclofen decreased escape responses for both CD+ and control subjects. No changes in monetary-reinforced responses were observed, indicative of no central nervous system stimulation or sedation. Conclusions. The GABA-B agonist baclofen suppressed aggressive responses in subjects with a history of childhood CD, while producing the opposite effect in control subjects. These suggest a possible unique role for GABA in the regulation of aggression in CD+ population. Electronic Publication     

GABA mechanisms and antinociception in mice with ligated sciatic nerve

In the present study, the effects of GABA (gamma-aminobutyric acid) receptor agonists and antagonists on hyperalgesia induced by sciatic nerve ligation was investigated in mice. The response to morphine or GABA receptor agonists was examined 14 days after unilateral nerve ligation by hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), muscimol (0.5, 1 and 2 mg/kg) or baclofen (1, 2.5 and 5 mg/kg) induced a dose-related antinociception in both intact and ligated mice. The response of morphine but not that of muscimol or baclofen, in nerve-ligated mice was significantly less than that induced in the intact animals. The responses induced by muscimol or baclofen in nerve-ligated animals, were reduced by bicuculline or CGP35348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid], respectively. However, morphine in combination with muscimol (2 mg/kg) tends to induce higher response; the combination of the GABA receptor agonists with morphine did not show potentiation, but additive effect. The opioid receptor antagonist naloxone reduced the response induced by muscimol in nerve-ligated animals. It was concluded that although ligation of the sciatic nerve clearly reduced the analgesic effect of morphine and not that of the GABA agonists, the results nevertheless indicated that morphine and the GABA(A) agonist shared the same mechanism of action.     

Interaction between beta-adrenoceptor agonists and alpha 1-adrenergic system. A behavioral study with the clonidine-induced aggression test

The effects of beta-adrenoceptor agonists on the clonidine-induced aggression in mice were studied. Clenbuterol (0.05-2 mg/kg ip), salbutamol (5-20 mg/kg ip) and terbutaline (10, 20 mg/kg ip) significantly potentiated the effect of clonidine. The enhancement of clonidine aggressiveness induced by clenbuterol (0.5 mg/kg) was prevented by propranolol (2.5, 5 mg/kg) and reduced by prazosin (1 mg/kg). The obtained results provide evidence that stimulation of beta-adrenoceptors facilitates the alpha 1-adrenoceptor-mediated behavior.     

Effects of the training dose on generalization of morphine stimulus to clonidine

The relationship between the stimulus properties of morphine and clonidine was tested in rats trained to discriminate morphine sulfate (4, 2 or 1 mg/kg) from saline in a two-lever food-rewarded task. The response trained in the low dose group generalized only to higher doses of clonidine (0.125 to 0.5 mg/kg) whereas the response trained with the high dose of morphine generalized only to higher doses of clonidine (0.625 to 1.0 mg/kg). Naloxone blocked the generalization in the low dose group but only partially blocked it in the high dose group. Yohimbine blocked the generalization to clonidine in the high morphine dose group and reversed the response rate suppressant effect of clonidine in all groups.     

GABA(B) receptor mechanism and imipramine-induced antinociception in ligated and non-ligated mice

This study concerned the effects of GABA(B) receptor agents on imipramine-induced antinociception in ligated and non-ligated mice in hot-plate test. The data showed that different doses of morphine (3, 6 and 9 mg/kg) induced a dose-dependent antinociception in non-ligated or ligated mice. However, the opioid response was decreased in the ligated animals. Intracerebroventricular (i.c.v.) administration of imipramine (5, 10, 20 and 40 microg/mouse) did not induce antinociception in either non-ligated or ligated mice. However, the response induced in the ligated mice was less than that induced in the non-ligated animals. Intraperitoneal (i.p.) administration of imipramine (10, 20, 30 and 40 mg/kg) induced antinociception in both ligated and non-ligated animals. The responses to the drug were not significantly different in the two groups. Administration of baclofen either i.c.v. (0.125, 0.25 and 0. 5 microg/mouse) or i.p. (0.5, 1, 2 and 4 mg/kg) induced antinociception. The response to the drug was not significantly different in ligated and non-ligated mice. I.c.v. administration of a lower dose of baclofen (0.125 microg/mouse) with different doses of imipramine (2.5, 5 and 10 mg/kg) potentiates the response of imipramine. This effect was reduced by i.c.v. injection of GABA(B) receptor antagonist, CGP35348 [P-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid] (20 microg/mouse). The higher dose of antagonist (20 microg/mouse) also decreased the response induced by baclofen or imipramine. CGP35348 itself (2.5, 5, 10 and 20 microg/mouse) induced dose-dependent antinociception with no significant difference in the ligated and non-ligated mice. It is concluded that a GABA receptor mechanism(s) may modulate the antidepressant-induced antinociception.     

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.     

Role of opioidergic mechanisms and GABA uptake inhibition in the heroin-induced discriminative stimulus effects in rats

The present study was designed to investigate the involvement of opioidergic component as well as to study GABAergic mechanisms in the expression of heroin discrimination. Male Wistar rats were trained to discriminate heroin (0.5 mg/kg, i.p.) from saline (i.p.) in a two-choice water reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, heroin (0.0625-0.5 mg/kg) and morphine (0.5-2 mg/kg, i.p.) evoked a dose-dependent generalization for the drug lever-responding, while muscimol (1 mg/kg, i.p., a GABA(A) receptor agonist) produced a weak partial substitution (ca. 48% heroin-lever responding). Neither tiagabine (2.5 mg/kg, i.p.; a GABA reuptake inhibitor), vigabatrin (75-150 mg/kg, i.p.; an irreversible inhibitor of GABA transaminase), nor baclofen (0.5 mg/kg, i.p.; a GABA(B) receptor agonist) substituted for heroin. In combination studies, the stimulus effects produced by heroin (0.5 mg/kg) or morphine (2 mg/kg) were dose-dependently blocked by opioid receptor antagonists naltrexone (0.1-1 mg/kg, i.p.), and naloxone (0.5-1 mg/kg, i.p.). The peripherally-acting naloxone methiodide at a dose of 1 mg/kg, i.p. did not alter, while at a dose of 10 mg/kg that penetrates across the blood-brain barrier, it reduced the stimulus effects of heroin or morphine. Pretreatment with tiagabine (2.5-5 mg/kg) produced a rightward shift of a heroin dose-response curve, while vigabatrin (75-300 mg/kg), baclofen (0.5-2.5 mg/kg) or muscimol (0.5-2 mg/kg) given prior to heroin (0.0625-0.5 mg/kg) failed to alter heroin discrimination. Our findings confirm previous studies on the significance of mu-opioidergic mechanisms in the expression of heroin discrimination and add the observation that selective inhibition of GABA reuptake, but not inhibition of GABA transaminase or direct stimulation of GABA(A) and GABA(B) receptors, can decrease the overall effects of heroin.