Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the α7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague–Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25 mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the α7* nicotinic receptor methyllycaconitine (MLA; 1–4 mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6 mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10 mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.     

GABA(B) receptor-mediated effects on vagal pathways to the lower oesophageal sphincter and heart

GABA(B) receptors influencing vagal pathways to the lower oesophageal sphincter and heart were investigated. In urethane-anaesthetized ferrets, the GABA(B) agonist baclofen (7 micromol kg(-1) i.v.) increased basal lower oesophageal sphincter (LOS) pressure. This was reversed by antagonism with CGP35348 (100 micromol kg(-1) i.v.). Baclofen's effect was abolished by vagotomy, suggesting a central action, yet it was ineffective when given centrally (3 - 6 nmol i.c.v.). Peripheral vagal stimulation (10 Hz, 5 s duration) caused LOS inhibition, followed by excitation, then prolonged inhibition. Bradycardia was also evoked during stimulation. Bradycardia and LOS responses were abolished after chronic supranodose vagotomy, indicating that they were due to stimulation of vagal pre-ganglionic neurones, not antidromic stimulation of afferents. Baclofen (1 - 10 micromol kg(-1)) reduced bradycardia and enhanced LOS excitation, which was also seen in animals pretreated with atropine (400 microgram kg(-1) i.v.) and guanethidine (5 mg kg(-1) i.v.), but not in those pretreated with L-NAME (100 mg kg(-1) i.v.). Effects of baclofen (7 micromol kg(-1) i.v.) on vagal stimulation-induced LOS and cardiac responses were unchanged by the GABA(B) antagonists CGP35348 or CGP36742 (up to 112 micromol kg(-1) i.v.), but were reversed by CGP62349 (ED(50) 37 nmol kg(-1) i.v.) or CGP54626 (ED(50) 100 nmol kg(-1) i.v.). Responses of isolated LOS strips to electrical stimulation, capsaicin, NK-1, NK-2 and nicotinic receptor agonists were all unaffected by baclofen (相似文献   

γ-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors

Summary In the present study the actions of -hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABA_B-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABA_B-receptor antagonist CGP 35348 (200 mg/kg, i.v.).Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABA_B-receptors. Correspondence to: G. Engberg at the above address     

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

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

GABA(B) receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area

2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) is a recently reported positive allosteric modulator of gamma-aminobutyric acid (GABA)(B) receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen-induced depression of dopamine (DA) neuron activity via the activation of GABA(B) receptors in the ventral tegmental area in rat midbrain slices. The selective GABA(B) receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration-dependent manner (EC50 = 0.27 microM, n = 11). CGP7930 (30 microM) significantly (P < 0.05) shifted the baclofen concentration-response curve to the left (EC50 = 0.15 microM, n = 5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 microM (2S)-3-[[(1S)-1-(3,4-dichloropheny)ethyl]amino-2-hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABA(B) receptor antagonist.In similar experiments, N-[3,3-diphenylpropyl]-alpha-methylbenzylamine (fendiline) (30 or 50 microM), a compound shown to potentiate GABA(B) receptor-mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen.It is therefore concluded that the recently reported GABA(B) receptor modulators, CGP7930 and fendiline, can enhance GABA(B) receptor-mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABA(B) potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system.     

The action of GABAB antagonists in the trigeminal nucleus of the rat.

The iontophoretic administration of the GABAB antagonists (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 35348) and 2-hydroxy-saclofen blocked the action of iontophoretically applied L-baclofen on neurons in the trigeminal nucleus of rats, anesthetized with halothane. The substance CGP 35348 appeared to be more potent than 2-hydroxy-saclofen. The iontophoretic administration of GABA resembled L-baclofen in depressing excitatory transmission and facilitating segmental inhibition in the trigeminal nucleus. The depression of excitatory transmission was also blocked by CGP 35348 and the facilitation of segmental inhibition produced by GABA was partially blocked. These observations indicate that CGP 35348 is not only a baclofen antagonist but actually a GABAB receptor antagonist and the baclofen was acting at GABAB receptors in the trigeminal nucleus. The portion of the effect of GABA, not blocked by CGP 35348, was probably mediated by GABAA receptors, since it was previously found that segmental inhibition in the trigeminal nucleus could be modulated by GABAA agonists and antagonists as well.     

Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia

Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.     

Effects of the GABAB receptor agonist baclofen on primary drinking in rats

The effects of subcutaneous (s.c.) administration of the GABA(B) receptor agonist baclofen were investigated on primary drinking in rats. Baclofen (1-4 mg/kg) produced a dose-related reduction in cumulative water intake in 16 h water-deprived rats during the 120 min measurement period (Experiment 1). The suppressant effect of baclofen (2mg/kg) on water intake 16 h water-deprived rats was significantly attenuated by pretreatment with the GABA(B) receptor antagonist CGP 35348 (3-aminopropyl (diethoxymethyl)-phosphinic acid; 50mg/kg; s.c., Experiment 2.), indicating that the hypodipsic effects of the drug in thirsty rats are mediated by an action at GABA(B) receptors. Experiment 3 was undertaken to investigate the effects of baclofen on volemic drinking induced in rats pretreated with propylene glycol. S.C. administration of polyethylene glycol induces volemic drinking in rats by reducing extracellular fluid. Baclofen (2mg/kg, s.c.) significantly reduced the volemic drinking in rats pretreated with polyethylene glycol (30% w/v solution). Experiment 4 was conducted to investigate the effects of baclofen on osmotic drinking in non-deprived rats pretreated with hypertonic sodium chloride (NaCl) solution. Hypertonic NaCl will draw out intracellular fluid to stimulate osmotic drinking. Baclofen (2mg/kg; s.c.) significantly reduced osmotic drinking in rats pretreated with 1 ml hypertonic NaCl (16% w/v). The results of this study indicate that (i) the hypodipsic effect of baclofen in water-deprived rats is mediated by an action at GABA(B) receptors and (ii) baclofen suppresses both volemic and osmotic drinking.     

Acetaldehyde increases dopaminergic neuronal activity in the VTA.

Acetaldehyde is the first and principal metabolite of ethanol administered systemically. To its rise in blood, after administration of disulfiram, is ascribed the aversive reaction that should discourage alcoholics from drinking. In the present study, we sought to determine the effect of acetaldehyde on the electrophysiological properties of dopamine (DA)-containing neurons in the ventro tegmental area (VTA) of rats in vivo. Intravenous (i.v.) administration of acetaldehyde (5-40 mg/kg) readily and dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. Ethanol (250-1000 mg/kg/i.v.) administration produced similar increments in electrophysiological parameters. In addition, a second group of rats was pretreated with the alcohol-dehydrogenase inhibitor 4-methyl-pyrazole (90 mg/kg) intraperitoneally (i.p.), and ethanol and acetaldehyde were administered i.v. at the same doses, 48 h later. In this group, ethanol effects were drastically reduced and the firing rate, spikes/burst, and burst firing were not significantly altered. In contrast, acetaldehyde fully retained its capacity to stimulate electrophysiological indices. The results indicate that acetaldehyde produces electrophysiological actions on VTA neurons in vivo, similar to those produced by ethanol, and significantly participate in ethanol-induced increment in DA neuronal activity. These results also suggest that acetaldehyde, by increasing DA neuronal activity in the VTA, may significantly contribute to the centrally mediated positive motivational properties of ethanol, which would oppose the well-known peripherally originating aversive properties.     

GABA(A) but not GABA(B) receptor stimulation induces antianxiety profile in rats.

The effect of GABA receptor agonists and antagonists on anxiety behavior in rats in the elevated-plus-maze has been investigated. The increase in two parameters of %open arm entries (%OAE) and %time spent in the open arms (%OAT) and decrease in the %time spent in closed arm (%CAT) was considered as antianxiety effects. Intracerebroventricular (i.c.v.) injection of different doses of the GABA(A) receptor agonist muscimol (0.25, 0.5, and 1 microg/rat) increased %OAE and %OAT and decreased %CAT in rats dose-dependently. The higher response was obtained with 1 microg/rat of the drug. Neither icv (0.05, 0.1, and 0.2 microg/rat) nor intraperitoneal (i.p.) (1, 2, and 4 mg/kg) injection of the GABA(B) receptor agonist baclofen altered %OAE, %OAT, and %CAT. However, the GABA(B) receptor antagonist CGP35348 (5, 10, and 30 microg/rat i.c.v.) increased %OAE and %OAT and decreased %CAT in the animals. The response induced by injection of muscimol (0.5 microg/rat i.c.v.) or administration of CGP35348 (10 microg/rat i.c.v.) was reduced by i.c.v. (1, 2, and 4 microg/rat) or i.p. (0.25, 0.5, and 0.75 mg/kg) injection of the GABA(A) receptor antagonist bicuculline, except the effect of CGP35348 on %CAT which was not significantly altered by i.p. administration of bicuculline. Ip but not i.c.v. administration of bicuculline by itself reduced both %OAE and %OAT but did not alter %CAT. None of the drugs altered the locomotor activity of the animals. The current findings support our hypothesis that the anxiolytic effects of GABA(B) antagonist are mediated by autoreceptor blockade-induced release of endogenous GABA, which in turn activates postsynaptic GABA(A) receptors.     

The effects of intraperitoneal and intracerebroventricular administration of the GABAB receptor antagonist CGP 35348 on food intake in rats

In order to test the hypothesis that endogenous gamma-aminobutyric acid (GABA), acting at central GABAB receptors, plays a physiological role in the control of feeding behaviour, it was reasoned that blocking these receptors with a centrally active GABAB receptor antagonist should reduce food intake in hungry rats. In the present study, experiments were carried out to test this possibility using the GABAB receptor antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid (CGP 35348), which is water-soluble and can penetrate the blood-brain barrier from the systemic circulation. CGP 35348 (50 and 100 mg/kg, i.p.) had no effect on food intake in 22-h fasted rats, but a higher dose (i.e. 500 mg/kg., i.p.) significantly reduced cumulative food consumption. These findings are consistent with previous observations that high systemic doses of CGP 35348 are needed to block central GABAB receptors. However, to eliminate the possibility that the 500 mg/kg dose of CGP 35348 decreased food intake by a peripheral, rather than a central mode of action, further experiments were undertaken where the drug was given directly into the brain by the intracerebroventricular (i.c.v.) route. I.c.v. administration of CGP 35348 (5 and 10 microg) significantly decreased cumulative food intake food intake in rats that had been fasted for 22 h. By contrast, i.c.v. administration of CGP 35348 (10 microg) had no effect on water intake in 16-h water-deprived rats. The results indicate that CGP 35348 reduces food consumption in hungry rats by blocking central GABAB receptors in a behaviourally specific manner. These findings suggest that endogenous GABA acting at central GABAB receptors plays a physiological role in the regulation of feeding behaviour.     

Increased acetylcholine and quisqualate responsiveness after blockade of GABAB receptors.

The aim of this study was to gain further insight into the function of cortical GABAB receptors. In chloral hydrate-anaesthetized rats, microiontophoretic administration of the GABAB receptor blocker CGP 35348 induced a moderate increase in firing of spontaneously active neurons in the rostral and caudal sensorimotor cortex. This increase in cell firing was accompanied by a reduction in the baclofen-induced inhibition of cell activity. In contrast to the GABAA receptor antagonist bicuculline methiodide, CGP 35348 did not induce any paroxysmal discharges. The excitatory responses of rostral cortical neurons elicited by iontophoretically applied acetylcholine and quisqualate were potentiated in most neurons after both microiontophoretic and intravenous administration of CGP 35348. The potentiation was observed in the absence of any change in the spontaneous firing rate. These effects were dose-dependent for both routes of administration. The potentiation of the quisqualate response was reversed by intravenously applied baclofen. In conclusion, these findings suggest that cortical GABAB receptors are involved in the control of cortical neuronal excitability.     

Effects of GABAergic system on naloxone-induced jumping in morphine-dependent mice.

The effect of GABA (gamma-aminobutyric acid system) receptor agonists and antagonists on naloxone-induced jumping in morphine-dependent mice was examined. Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of different doses of the GABA(B) receptor agonist, baclofen (2.5, 5 and 10 mg/kg), reduced naloxone-induced jumping in morphine-dependent mice. The i.p. administration of the GABA(B) receptor antagonist, CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid), but not the i.c.v. injection of the drug, increased naloxone-induced jumping. The antagonist also decreased the baclofen response. Administration of the GABA(A) receptor agonist, muscimol, but not the GABA(A) receptor antagonists bicuculline and picrotoxin, decreased the naloxone response in morphine-dependent animals. It is concluded that both GABA(A) and GABA(B) receptor subtypes may have an inhibitory influence on naloxone-induced withdrawal jumping in mice.     

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.     

Baclofen and midazolam alter c-fos induction by peripheral noxious or innocuous stimulation in the spinal cord of normal and monoarthritic rats

In order to further clarify the role of gamma-aminobutyric acid (GABA) receptors in spinal sensory processing we have studied the effects of baclofen, a GABA(B) agonist, and midazolam, a benzodiazepine agonist, on the activation of spinal neurones by peripheral innocuous or noxious stimulation, in normal or monoarthritic rats, as signalled by the induction of the proto-oncogene c-fos. Baclofen (10 mg/kg, i.v.) caused a significant reduction in the number of Fos-positive neurones following noxious stimulation of both normal and monoarthritic animals, which was prevented by the GABA(B) antagonist CGP 35348 (200 mg/kg, i.v.). The latter caused an increase of c-fos expression in normal animals subject to noxious stimulation, suggesting an endogenous tonic activation of GABA(B) receptors. This effect was not observed in monoarthritic animals. Baclofen also reduced the number of Fos-positive neurones in monoarthritic animals subject to innocuous stimulation. Midazolam (5 mg/kg, i.v.) had no effect in normal animals, but caused an increase in c-fos expression induced by noxious stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a benzodiazepine antagonist, prevented the effect of midazolam, and if given alone evoked a decrease in Fos-positive neurones. It can be concluded that although GABA(B) receptors modulate sensory input at the spinal level, high doses of systemic baclofen are required to inhibit nociceptive-induced c-fos expression. The paradoxical facilitation of c-fos expression by midazolam in monoarthritic animals, may be due to the reported increase in spinal GABA levels found in those animals.     

Involvement of GABA(B) receptors in the motor inhibition produced by agonists of brain cannabinoid receptors

The present study was designed to investigate the possibility of activation of GABA(B) receptors during the motor inhibition caused by cannabimimetics. Adult male rats were injected with an acute dose of arachidonylethanolamide (AEA), Delta(9)- tetrahydrocannabinol (THC), beclofen or vehicle, after pretreatment with CGP 35348, a specific antagonist for GABA(B) receptors, or vehicle, and the behavioral response produced by these compounds tested in an open field. As expected, the administration of either AEA or THC produced a very pronounced motor inhibition, reflected by decreased ambulation and increased time spent in inactivity. The administration of baclofen also produced a marked motor deficit, with similar changes to those observed with both cannabimimetics. Pretreatment with the GABA(B) antagonist, CGP 35348, prevented the motor inhibition induced by baclofen and also attenuated the motor deficit caused by both cannabimimetics, suggesting a role for this receptor. In summary, a GABAergic influence, acting through GABA(B) receptors, seems to be involved in mediating motor effects of cannabimimetics, since the blockade of these receptors attenuates cannabimimetic-induced signs of motor inhibition.     

Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid.

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and alpha7(*) nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.     

Baclofen-induced antinociception and nicotinic receptor mechanism(s)

In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5-2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 microg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA(B) antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.     

Down-regulation of ICBP90 contributes to doxorubicin resistance

Brain-derived neurotrophic factor (BDNF) has been suggested as a target for antidepressant treatment and chronic antidepressant drug administration shows a 'biphasic effect' on BDNF mRNA in rat hippocampus (transient decrease followed by an increase). In comparison, following acute administration only, an inhibitory action on BDNF gene expression is detected. The present study aimed to understand the mechanism behind the acute inhibitory action on BDNF gene expression by investigating the possible involvement of γ-aminobutyric acid (GABA) receptors in mediating this effect. Rats were injected with either saline, the GABA(A) selective compound 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), the benzodiazepine flunitrazepam or the GABA(B) selective compound baclofen. BDNF mRNA levels were measured 4h later using in-situ hybridization. Baclofen (10mg/kg, i.p.), but not THIP (10mg/kg, i.p.) or flunitrazepam (10mg/kg, i.p.), administration resulted in significant inhibition of BDNF mRNA expression in the cornu ammonis 3 and dentate gyrus but not in the cornu ammonis 1 region of the hippocampus. The inhibitory effect of baclofen on hippocampal BDNF mRNA expression was significantly attenuated by pre-treatment the selective GABA(B) antagonists, CGP 46381 and CGP 55845 (10mg/kg, i.p.). The inhibitory action by the selective serotonin re-uptake inhibitor (SSRI) paroxetine on hippocampal BDNF mRNA was also attenuated by CGP 46381. Our findings suggest a role for GABA(B), but not GABA(A), receptor-mediated mechanisms in the inhibitory regulation of basal hippocampal BDNF gene expression. Our results indicate that GABA(B) receptor activation may play a role in the antidepressant drug-induced inhibition of BDNF gene expression in the hippocampus.     

Effects of intraperitoneal administration of the GABAB receptor positive allosteric modulator 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) on food intake in non-deprived rats

γ-Aminobutyric acid-(B) (GABA(B)) receptor positive allosteric modulators (PAMs) act on an allosteric site on the GABA(B) receptor to potentiate the effects of GABA and GABA(B) receptor agonists. It has previously been demonstrated that the GABA(B) receptor agonist baclofen increases food intake in non-deprived rats. The aim of this study was to investigate whether the GABA(B) receptor PAM 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) would (i) increase food intake, and (ii) potentiate the hyperphagic effects of baclofen in rats. In Experiment 1, the effects of intraperitoneal (i.p.) administration of CGP7930 (1, 6 and 12 mg/kg) was investigated on food intake in non-deprived male Wistar rats. The 12 mg/kg dose of CGP7930 significantly increased cumulative food intake 30, 60 and 120 min (P<0.05, in each case) after administration. The 1 and 6 mg/kg doses were without effect. In Experiment 2, the effects of pretreatment with CGP7930 (6 mg/kg; i.p.) 5 min prior to administration of baclofen (2mg/kg, i.p.) was investigated on 30min cumulative food intake in non-deprived male Wistar rats. Baclofen (2mg/kg) significantly increased food intake compared with vehicle treatment (P<0.01). CGP7930 (6 mg/kg) had no effect on feeding. However, pretreatment with CGP7930 (6 mg/kg) significantly potentiated the hyperphagic effects of baclofen (2mg/kg) (P<0.01). These findings show that CGP7930 increases food intake and enhances the hyperphagic effects of baclofen, and are consistent with in vitro studies that suggest that it potentiates the effects of endogenous GABA and GABA(B) receptor agonists by allosteric modulation of the GABA(B) receptor.