II. Effect of aminooxyacetic acid and bicuculline on prolactin release in castrated male rats

To investigate the role of gamma aminobutyric acid (GABA) on prolactin secretion, castrated male rats were infused with aminooxyacetic acid (AOAA) or bicuculline, two drugs that affect GABA metabolism or its binding to the receptors, respectively. The infusion of AOAA or bicuculline for 2 hr did not significantly modify serum prolactin levels. A quick iv injection of sulpiride, a drug that induces hyperprolactinemia, brought about a significantly lower release of prolactin in rats infused with AOAA than in control rats, infused with saline. The response to sulpiride in rats infused with bicuculline was significantly greater, in terms of prolactin release, than in control rats. These results suggest that GABA may have an inhibitory role on the regulation of prolactin release.     

葆包牡丹碱对垂体前叶组织块释放促肾上腺皮质激素的刺激效应

本实验利用垂体组织块离体灌流技术,观察到γ－氨基丁酸Ａ受体拮抗剂荷包牡丹笃切除双侧肾上腺９６ｈ后的大鼠垂体前叶ＡＣＴＨ的分泌具有强烈的刺激作用。但同样浓度的荷包牡丹笃分离的垂体前叶细胞的ＡＣＴＨ分泌无影响,提示肾上腺切除后,γ－氨基丁酸在垂体前叶直接或通过间接途径抑制ＡＣＴＨ分泌。     

GABAergic modulation of ventilation and peak oxygen consumption in obese Zucker rats.

Obesity is often associated with a reduced ventilatory response and a decreased maximal exercise capacity. GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. Altered GABAergic mechanisms have been detected in obese Zucker rats and implicated in their hyperphagic response. Whether altered GABAergic mechanisms also contribute to regulate ventilation and influence exercise capacity in obese Zucker rats is unknown and formed the basis of the present study. Eight lean [317 +/- 18 (SD) g] and eight obese (450 +/- 27 g) Zucker rats were studied at 12 wk of age. Ventilation at rest and ventilation during hypoxic (10% O(2)) and hypercapnic (4% CO(2)) challenges were measured by the barometric method. Peak O(2) consumption (VO(2 peak)) in response to a progressive treadmill test to exhaustion was measured in a metabolic treadmill. Ventilation and VO(2 peak) were assessed after administration of equal volumes of DMSO (vehicle) and the GABA(A) receptor antagonist bicuculline (1 mg/kg). In lean animals, bicuculline administration had no effect on ventilation and VO(2 peak). In obese rats, bicuculline administration significantly (P < 0.05) increased resting ventilation (465 +/- 53 and 542 +/- 72 ml. kg(-1). min(-1) for control and bicuculline, respectively), ventilation during exposure to hypoxia (899 +/- 148 and 1,038 +/- 83 ml. kg(-1). min(-1) for control and bicuculline, respectively), and VO(2 peak) (62 +/- 3.7 and 67 +/- 3.5 ml. kg(-0.75). min(-1) for control and bicuculline, respectively). However, in obese Zucker rats, ventilation in response to hypercapnia did not change after bicuculline administration (608 +/- 96 vs. 580 +/- 69 ml. kg(-1). min(-1)). Our findings indicate that endogenous GABA depresses ventilation and limits exercise performance in obese Zucker rats.     

GABA-mediated neurotransmission in the nucleus of the solitary tract alters resting ventilation following exposure to chronic hypoxia in conscious rats

This study investigated whether changes in GABA-mediated neurotransmission within the nucleus of the solitary tract (NTS) contribute to the changes in breathing (resting ventilation and the acute HVR) that occur following exposure to chronic hypoxia (CH). Rats were exposed to 9 days of hypobaric hypoxia (0.5 atm) and then subjected to acute hypoxic breathing trials before and after bilateral microinjections of GABA, bicuculline (a GABAA-receptor antagonist), or bicuculline plus CGP-35348 (a GABAB receptor antagonist) into the caudal regions of the NTS. Breathing was measured using whole body plethysmography. CH caused an increase in resting ventilation when the animals were breathing 30% O2 but did not alter ventilation during acute hypoxia (10% O2). GABA alone had no effect on breathing in either the control or chronically hypoxic rats. Bicuculline and bicuculline/CGP had no effect on breathing in control rats. Following CH, bicuculline and bicuculline/CGP reduced minute ventilation (VI) during acute exposure to 30% O2 but had no effect during acute exposure to 10% O2. The bicuculline-induced reduction in VI resulted from a decrease in breathing frequency (fR) and tidal volume (VT). The bicuculline/CGP-induced reduction in VI was due to a decrease in fR with no change in VT. The results suggest that changes in GABA receptor-mediated neurotransmission, within the NTS, are involved in the increase in resting ventilation that occurs following CH.     

荷包牡丹碱对垂体前叶组织块释放促肾上腺皮质激素的刺激效应

本实验利用垂体组织块离体灌流技术,观察到－氨基丁酸Ａ受体拮抗剂荷包牡丹碱对切除双侧肾上腺９６ｈ后的大鼠垂体前叶ＡＣＴＨ的分泌具有强烈的刺激作用。但同样浓度的荷包牡丹碱对分离的垂体前叶细胞的ＡＣＴＨ分泌无影响。提示肾上腺切除后,－氨基丁酸在垂体前叶直接或通过间接途径抑制ＡＣＴＨ分泌。     

Bicuculline Up-Regulation of GABAA Receptors in Rat Brain

Effects of acute and subacute administration of bicuculline on [3H]muscimol, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the KD nor the Bmax of the three receptor sites. In rats treated subacutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [3H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower KD of high-affinity sites in the striatum and in a significantly lower KD of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the Bmax value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [3H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [3H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent Ki of bicuculline for the GABAA receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the KD nor the Bmax of [3H]flunitrazepam and [35S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABAA receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picrotoxin binding sites.     

NKCC1 transporter facilitates seizures in the developing brain

During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). GABA becomes inhibitory as net outward neuronal transport of Cl(-) develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.     

Suppression of detrusor-sphincter dysynergia by GABA-receptor activation in the lumbosacral spinal cord in spinal cord-injured rats

We investigated the effects of intrathecal application of GABAA- or GABAB-receptor agonists on detrusor-sphincter dyssynergia (DSD) in spinal cord transection (SCT) rats. Adult female Sprague-Dawley rats were used. At 4 wk after Th9-10 SCT, simultaneous recordings of intravesical pressure and urethral pressure were performed under an awake condition to examine the effect of intrathecal application of GABAA and GABAB agonists (muscimol and baclofen, respectively) or GABAA and GABAB antagonists (bicuculline and saclofen, respectively) at the level of L6-S1 spinal cord. In spinal-intact rats, the effects of bicuculline and saclofen on bladder and urethral activity were also examined. During urethral pressure measurements, DSD characterized by urethral pressure increases during isovolumetric bladder contractions were observed in 95% of SCT rats. However, after intrathecal application of muscimol or baclofen, urethral pressure showed urethral relaxation during isovolumetric bladder contractions. The effective dose to induce inhibition of urethral activity was lower compared with the dose that inhibited bladder contractions. The effect of muscimol and baclofen was antagonized by intrathecal bicuculline and saclofen, respectively. In spinal-intact rats, intrathecal application of bicuculline induced DSD-like changes. These results indicate that GABAA- and GABAB-receptor activation in the spinal cord exerts the inhibitory effects on DSD after SCT. Decreased activation of GABAA receptors due to hypofunction of GABAergic mechanisms in the spinal cord might be responsible, at least in part, for the development of DSD after SCT.     

GABAergic contribution to rat bladder hyperactivity after middle cerebral artery occlusion

To evaluate the influences of gamma-aminobutyric acid (GABA) mechanisms on bladder hyperactivity after left middle cerebral artery occlusion, cystometric recordings were obtained from unanesthetized female rats. Intracerebroventricular administration of both muscimol (GABA(A) receptor agonist; 0.1-10 nmol) and baclofen (GABA(B) receptor agonist; 0.1-3 nmol) produced dose-dependent inhibitions of micturition with increases in bladder capacity (BC). The effects of high doses (1-10 nmol) were similar in sham-operated (SO) and cerebral-infarcted (CI) rats. However, lower doses of muscimol (0.1 or 0.3 nmol) and baclofen (0.1 nmol) reduced BC in CI rats. After bicuculline (GABA(A) receptor antagonist; 1 or 3 nmol) administration, BC in both SO and CI rats first decreased and subsequently increased. An increase in urethral pressure was observed after administration of bicuculline (3 nmol) but not with either muscimol or baclofen. Infarct volumes in muscimol-, bicuculline-, or baclofen-treated rats were not significantly different from those of vehicle-treated rats. These results suggest that GABAergic mechanisms inhibit the micturition reflex at the supraspinal level but that this can change as a result of CI.     

Valproic acid and bicuculline affect the formation of glycerolipid in rat brain

To ascertain the effects of bicuculline and of sodium valproate on the incorporation of glycerol into rat brain lipid, rats were divided into 5 groups: (a) controls; (b) treated with sodium valproate (400 mg/kg body wt); (c) treated with bicuculline (12.5 μmol/kg body wt); (d) treated with sodium valproate as in (b) + bicuculline as in (c); and (e) treated with bicuculline (25 μmol/kg body wt). Only rats of group (c) had seizures, which lasted until the end of the experiment. Each animal received 20 μCi of [2-³H]glycerol by intraventricular route and was sacrificed 12 min afterwards. Hippocampi and cerebella were taken and lipid extracted and separated by chromatography.

The type of treatment influenced very much the fate of injected, labeled glycerol. Indeed, total recovered radioactivity increased following either convulsions or the administration of valproate, whereas both treatments decreased the amount of radioactivity incorporated into lipid. These effects were more evident in cerebella than in hippocampi.

The distribution of radioactivity among lipid classes (diglyceride, triglyceride and total phospholipid) was also affected by seizures, which decreased the labeling ratio phospholipid/neutral lipid. The distribution of radioactivity among phospholipid classes was influenced by bicuculline (both at convulsant and non-convulsant doses) and these effects were sometimes antagonized by valproate. We conclude that some effects of bicuculline are exerted through the systemic modifications due to seizures and that other effects are probably connected to neuronal hyperfiring. The data reported in this paper are consistent with both mechanisms of action proposed for valproate, i.e. increased membrane permeability and modifications of GABAergic systems.     

Coactivation of renal sympathetic neurons and somatic motor neurons by chemical stimulation of the midbrain ventral tegmental area

We examined whether neurons in the midbrain ventral tegmental area (VTA) play a role in generating central command responsible for autonomic control of the cardiovascular system in anesthetized rats and unanesthetized, decerebrated rats with muscle paralysis. Small volumes (60 nl) of an N-methyl-D-aspartate receptor agonist (L-homocysteic acid) and a GABAergic receptor antagonist (bicuculline) were injected into the VTA and substantia nigra (SN). In anesthetized rats, L-homocysteic acid into the VTA induced short-lasting increases in renal sympathetic nerve activity (RSNA; 66 ± 21%), mean arterial pressure (MAP; 5 ± 2 mmHg), and heart rate (HR; 7 ± 2 beats/min), whereas bicuculline into the VTA produced long-lasting increases in RSNA (130 ± 45%), MAP (26 ± 2 mmHg), and HR (66 ± 6 beats/min). Bicuculline into the VTA increased blood flow and vascular conductance of the hindlimb triceps surae muscle, suggesting skeletal muscle vasodilatation. However, neither drug injected into the SN affected all variables. Renal sympathetic nerve and cardiovascular responses to chemical stimulation of the VTA were not essentially affected by decerebration at the premammillary-precollicular level, indicating that the ascending projection to the forebrain from the VTA was not responsible for evoking the sympathetic and cardiovascular responses. Furthermore, bicuculline into the VTA in decerebrate rats produced long-lasting rhythmic bursts of RSNA and tibial motor nerve discharge, which occurred in good synchrony. It is likely that the activation of neurons in the VTA is capable of eliciting synchronized stimulation of the renal sympathetic and tibial motor nerves without any muscular feedback signal.     

Influence of GABA-agonists and antagonists on neuroleptic-induced catalepsy in rats.

Direct (muscimol) or indirect (aminooxyacetic acid, diaminobutyric acid, pyrrolidinone) GABA-mimetic compounds significantly potentiate neuroleptic induced catalepsy in rats. In contrast at subconvulsant doses, direct (bicuculline, picrotoxinin and indirect (allylglycine) GABA antagonists antagonized haloperidol-induced catalepsy. The effect of bicuculline and picrotoxinin was biphasic with the lowest doses increasing catalepsy. These results indicate that GABA mechanisms are involved in the induction of catalepsy by neuroleptics.     

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

It is well established that GABAergic inputs to the paraventricular nucleus of the hypothalamus (PVN) tonically suppress heart rate and the activity of several sympathetic nerves. However, whether GABA similarly inhibits PVN control of baroreflex function has not been previously investigated. To test this hypothesis, it was determined whether microinjection of the GABA(A) antagonist, bicuculline, into the PVN enhances the baroreflex in anesthetized female virgin rats. In addition, because GABAergic inhibition of PVN preautonomic neurons is decreased during pregnancy, it was also determined whether the effects of PVN bicuculline administration on baroreflex function were less in pregnant animals. In virgin rats, PVN microinjection of bicuculline increased (P < 0.05) baroreflex gain and maximum levels of heart rate (gain, from 1.6 ± 0.6 to 3.8 ± 1.3 bpm/mmHg; maximum, from 406 ± 18 to 475 ± 14 bpm) and of lumbar sympathetic nerve activity (gain from 2.6 ± 0.7 to 4.8 ± 1.6%/mmHg; maximum, 149 ± 32 to 273 ± 48%), indicating that PVN GABA normally suppresses baroreflex function. Pregnancy decreased heart rate baroreflex gain (pregnant, 0.9 ± 0.3 bpm/mmHg; virgin, 1.9 ± 0.2 bpm/mmHg; P < 0.05). Following PVN bicuculline administration in pregnant rats, smaller (P < 0.01) increments in baroreflex gain (pregnant, 0.6 ± 0.1 bpm/mmHg; virgin, 2.4 ± 0.9 bpm/mmHg) and maximum (pregnant, 33 ± 7 bpm; virgin, 75 ± 12 bpm; P < 0.05) were produced. Collectively, these data suggest that the PVN normally inhibits the baroreflex via tonic GABAergic inputs and that this inhibition is less during pregnancy.     

GABA(A) and GABA(B) receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats.

The aim of this study was to investigate whether GABA(A) and/or GABA(B) receptor-mediated mechanisms contribute to the impaired ventilatory response and reduced maximal aerobic exercise capacity in obese Zucker rats. Ten lean and 10 obese Zucker rats were studied at 12 wk of age. Minute ventilation (Ve), tidal volume (Vt), and breathing frequency (f) during room air breathing and in response to 10 min of hypercapnia (8% CO(2)) and 30 min of hypoxia (10% O(2)) were measured by the barometric method, and peak oxygen consumption (Vo(2 peak)) was measured by an enclosed metabolic treadmill following the randomized blinded subcutaneous administration of equal volumes of DMSO (vehicle), bicuculline (selective GABA(A) receptor antagonist, 1 mg/kg), and phaclofen (selective GABA(B) receptor antagonist, 1 mg/kg). Administration of bicuculline and phaclofen to lean animals had no effect on Ve and Vo(2 peak). Similarly, phaclofen failed to alter Ve and Vo(2 peak) in obese rats, although it did significantly increase f after 5-20 min of hypoxia. In contrast, bicuculline increased Ve and Vt relative to DMSO during room air breathing and after 10-30 min of hypoxic exposure in obese rats, but it did not increase Ve at 5 min of hypoxemia. Bicuculline increased Vo(2 peak) relative to DMSO in obese Zucker rats. We conclude that endogenous GABA acting on GABA(A) receptors can modulate Ve and Vo(2 peak) in obese but not in lean Zucker rats, whereas endogenous GABA acting on GABA(B) receptors modulates f during hypoxia (5-20 min) in obese rats in a very different manner from that when acting on GABA(A) receptors.     

Restoration of the luteinizing hormone surge in middle-aged female rats by altering the balance of GABA and glutamate transmission in the medial preoptic area

Hypothalamic glutamate and gamma-aminobutyric acid (GABA) neurotransmission are involved in the ovarian hormone-induced GnRH-LH surge in rodents. We previously reported that middle-aged rats have significantly less glutamate release in the medial preoptic area than young rats on the day of the LH surge. The present study tested the hypothesis that the delayed and attenuated LH surge in ovariohysterectomized middle-aged rats primed with ovarian steroids results from reduced hypothalamic glutamate and increased GABA(A) neurotransmission. Microdialysis results show that middle-aged rats with attenuated LH surges had reduced extracellular glutamate and increased extracellular GABA levels in the medial preoptic area compared with young rats. Blocking GABA(A) receptors with bicuculline or inhibiting synaptic glutamate reuptake with L-trans-pyrrolidine-2,4-dicarboxylic acid increased extracellular Glu in the medial preoptic area and partially restored LH surge amplitude in middle-aged rats without altering LH surge onset. Complete recovery of LH surge amplitude was observed in middle-aged rats treated with the combination of bicuculline and L-trans-pyrrolidine-2,4-dicarboxylic acid. This treatment also restored the extracellular glutamate:GABA ratio in the medial preoptic area of middle-aged rats to the level of young rats. Immunoblot analysis revealed that estradiol and progesterone treatment reduced SLC32A1(formerly known as vesicular GABA transporter) levels and increased SLC17A6 (formerly known as vesicular glutamate transporter 2) levels in the anterior hypothalamus of ovariohysterectomized young but not middle-aged rats. These data suggest that both reduced availability of glutamate and increased activation of GABA(A) receptors under estrogen-positive feedback conditions contribute to the age-related delay in onset and attenuated amplitude of the LH surge.     

In the ventral tegmental area, progestins have actions at D1 receptors for lordosis of hamsters and rats that involve GABA A receptors

In the ventral tegmental area (VTA), progestins facilitate lordosis via actions at gamma-aminobutyric acid (GABA)(A)/benzodiazepine receptor complexes (GBRs) and dopamine type 1 receptors (D1). The relationship between progestins' actions at GBRs and D1 in the VTA for facilitating sexual behavior of hamsters and rats was examined. Ovariectomized (ovx), estradiol (E(2); 10 microg)+progesterone (P; 250 microg; SC)-primed hamsters, with bilateral guide cannulae to the VTA, were pre-tested for sexual and motor behavior and infused with the GBR antagonist bicuculline (100 ng/side) or vehicle. Thirty minutes later, hamsters were re-tested and then infused with the D1 agonist SKF38393 (100 ng/side) or vehicle. Hamsters were post-tested 30 min later. Ovx, E(2) (10 microg)-primed rats were pre-tested, infused first with bicuculline or vehicle, second with SKF38393 or vehicle, third with 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP; 0, 100, or 200 ng) and were post-tested 10 and 60 min after 3alpha,5alpha-THP infusions. VTA infusions of SKF38393 increased lordosis of hamsters or rats. Bicuculline pretreatment reduced SKF38393- and/or progesterone-mediated increases in lordosis of E2-primed hamsters. In E2-primed rats, bicuculline blocked SKF38393- and/or 3alpha,5alpha-THP-mediated increases in lordosis. There were no effects on motor behavior. Thus, in the VTA, GBR activity modulates D1-mediated actions for lordosis of hamsters and rats.     

Participation of GABA in mediating the effects of ethanol in rats with differing susceptibility to the development of experimental alcoholism

The influence of ethanol and of GABA receptors blocker bicuculline on recovery cycles of primary response of the sensorimotor cortex was studied in rats with strong and weak inclination to development of experimental alcoholism. It is found that in rats of the first group, inhibition in the cerebral cortex was weakened in comparison with the rats of the second group. Ethanol in non-narcotic doses intensified the inhibitory processes and its effects could be prevented or suppressed by bicuculline. The conclusion is made about GABA participation in mediation of ethanol effects on inhibitory processes in the cerebral cortex.     

Induction of cytochrome P-450 forms in liver microsomes of rats in the early neonatal period after administration of phenobarbital and 3-methylcholanthrene

The activity of cytochrome P-450 dependent monooxygenase system from rat liver microsomes after induction by phenobarbital and 3-methylcholantrene in early neonatal period (3-16 days after birth) was studied. It was found that the total amount of cytochrome P-450 increases after injection of these inducers in neonatal rats of all age groups. In parallel, in the case of 3-methylcholantrene induction the benz(a)pyrene hydroxylase and 7-ethoxyresorufin deethylase activities increase; phenobarbital induction causes a rise in the benzphetamine-N-demethylase and benz(a)pyrene hydroxylase activities. Immunochemical analysis involving the use of antibodies specifically directed against cytochrome P-450 of adult rats revealed that the level of cytochrome P-450 in the case of 3-methylcholantrene induction increases from 5 to 50%, whereas that of cytochrome P-450 upon phenobarbital induction increases from 5 to 40% in liver microsomes of 3- and 16-day-old rats. The mode of inhibition of various substrates metabolism by antibodies in neonatal rat microsomes suggests that the 3-methylcholantrene-induced cytochrome P-448, like in adult rats, participates in the hydroxylation of benz(a)pyrene and O-deethylation of 7-etoxyresorufin. The participation of phenobarbital-induced cytochrome P-450 in the metabolism of benzphetamine and aldrin in neonatal rats is much lower than in the adult ones. The metabolism of benz(a)pyrene in phenobarbital-induced neonatal rat microsomes in all age groups is not inhibited by antibodies. The age-dependent differences in inhibition of metabolism and the increase in the benz(a)pyrene hydroxylase activity in phenobarbital-induced rats suggest that the spectrum of inducible forms of cytochrome P-450 in neonatal rats differ from that in adult animals.     

Locomotor behavior in rats after separate and simultaneous intrastriatal microinjections of GABA-ergic drugs

The effects of daily intrastriatal bilateral microinjections of 45 mog GABA, 1 mcg of picrotoxine and 5 mcg of bicuculline on rats, were investigated. Impairment of the avoidance conditioning in shuttle box was registered in rats with picrotoxine or bicuculline and the choreo-myoklonic limb jerks, with distinct generalization stage after the picrotoxine microinjections. The combined microinjections--GABA with picrotoxine, and bicuculline with picrotoxine inhibited the hyperkinesis manifestation and changed avoidance conditioning behaviour and open-field locomotor activity. The findings suggest involvement of neostriatal GABAergic system in avoidance conditioning and complex locomotor behavioural acts regulation. The ultimate aim of the research is to find the cause, neurotransmitter mechanisms of neuromotor diseases, and to research principal new orders in treatment of neuromotor deviations.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.