Hans-Rudolf Olpe

CGP 35348 : a centrally active blocker of GABAB receptors

The biochemical, electrophysiological and pharmacological properties of the new GABAB receptor blocker CGP 35348 are described. In a variety of receptor binding assays CGP 35348 showed affinity for the GABAB receptor only. CGP 35348 had an IC50 of 34 microM at the GABAB receptor. The compound antagonized (100, 300, 1000 microM) the potentiating effect of L-baclofen on noradrenaline-induced stimulation of adenylate cyclase in rat cortex slices. In electrophysiological studies CGP 35348 (10, 100 microM) antagonized the effect of L-baclofen in the isolated rat spinal cord. In the hippocampal slice preparation CGP 35348 (10, 30, 100 microM) blocked the membrane hyperpolarization induced by D/L-baclofen (10 microM) and the late inhibitory postsynaptic potential. CGP 35348 appeared to be 10-30 times more potent than the GABAB receptor blocker phaclofen. Ionophoretic and behavioural experiments showed that GABAB receptors in the brain were blocked after i.p. administration of CGP 35348. This compound may be of considerable value in elucidating the roles of brain GABAB receptors.

Central actions of somatostatin

Somatostatin (SRIF) was applied microiontophoretically to neurons in the frontal and parietal neocortex, the hippocampus and the striatum of rats anaesthetized with either urethane or chloral hydrate. Qualitatively identical results were obtained under both anaesthetic conditions. In urethane-treated rats SRIF elicited a dose-dependent increase of the firing rate of 74% of the neurons studied in the frontal cortex and of 46% of the neurons studied in the parietal cortex. All cortical cells identified as pyramidal cells were excited. In the hippocampus SRIF provoked excitatory responses in two thirds of all neurons. Six out of the nine cells identified as pyramidal cells were excited by SRIF. In the striatum 80% of all neurons were excited. Following repeated exposure of central neurons to SRIF, the magnitude of the excitatory response gradually diminished, indicating desensitisation. SRIF in concentrations ranging from 10(-8) to 10(-4) M did not interfere with the binding of (3H)-muscimol to GABA receptor sites. The release of GABA from synapses preloaded with (3H-GABA) was not influenced by SRIF in the concentration range from 10(-6) to 10(-4) M. These results indicated that SRIF does not evoke the excitatory responses through attenuation of GABA-mediated inhibition. In conclusion, the findings support the hypothesis that somatostatin may function as a neurotransmitter in the central nervous system.

The selective nicotinic acetylcholine receptor α7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain

Several lines of evidence suggest that the nicotinic acetylcholine receptor alpha7 (nAChR alpha7) is involved in central nervous system disorders like schizophrenia and Alzheimers disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR alpha7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR alpha7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety.

The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning.

BACKGROUND The rostral anterior cingulate cortex (rACC) and the amygdala consistently emerge from neuroimaging studies as brain regions crucially involved in normal and abnormal fear processing. To date, however, the role of the rACC specifically during the acquisition of auditory fear conditioning still remains unknown. The aim of this study is to investigate a possible top-down control of a specific rACC sub-region over amygdala activation during pavlovian fear acquisition. METHODS We performed excitotoxic lesions, temporal inactivation, and activation of a specific sub-region of the rACC that we identified by tracing studies as supporting most of the connectivity with the basolateral amygdala (r(Amy)-ACC). The effects of these manipulations over amygdala function were investigated with a classical tone-shock associative fear conditioning paradigm in the rat. RESULTS Excitotoxic lesions and transient inactivation of the r(Amy)-ACC pre-training selectively produced deficits in the acquisition of the tone-shock associative learning (but not context). This effect was specific for the acquisition phase. However, the deficit was found to be transient and could be overcome by overtraining. Conversely, pre-training transient activation of the r(Amy)-ACC facilitated associative learning and increased fear expression. CONCLUSIONS Our results suggest that a subregion of the rACC is key to gating the efficiency of amygdala-dependent auditory fear conditioning learning. Because r(Amy)-ACC inputs were confirmed to be glutamatergic, we propose that recruitment of this brain area might modulate overall basolateral amygdala excitatory tone during conditioned stimulus-unconditioned stimulus concomitant processing. In the light of clinical research, our results provide new insight on the effect of inappropriate rACC recruitment during emotional events.

Age-related decline in the activity of noradrenergic neurons of the rat locus coeruleus

Abstract Spontaneous neuronal activity of noradrenergic neurons located in the rat locus coeruleus was compared in 3-, 10- and 22-month-old rats. A statistically significant change in the frequency distribution pattern between the 3-month and the older rats was noticed. The mean firing rate was reduced by 21% and 25% in the 10- and 22-month-old rats, respectively.

The effects of baclofen and two GABAB-receptor antagonists on long-term potentiation

SummaryThe aim of the present study was to investigate whether activation or inhibition of GABAB receptors in hippocampal slices of rats has an impact on the synaptic plasticity in the CA1 area. Long-term potentiation (LTP) was induced by tetanic stimulation of the Schaffer collateral/commissural fiber tract and the responses of CA1 pyramidal neurons were recorded extracellularly. The increase in population spike amplitude after tetanic stimulation was taken as a measure of LTP.The selective GABAB receptor blockers phaclofen (1 mM) and CGP 35348 (100 μM) facilitated the induction of LTP. Although baclofen (1 μM) reduced the population spike amplitude, it did not affect LTP. If, however, the stimulation voltage was increased to compensate for the baclofen-induced decline in population spike amplitude, LTP was facilitated. Under these conditions the induction of LTP was accompanied by the appearance of additional population spikes.In conclusion, GABAB receptors appear to exert a modulatory action on LTP.

The action of new potent GABAB receptor antagonists in the hemisected spinal cord preparation of the rat

CGP 52432 (3-N-(3,4-dichlorobenzyl)aminopropyl-P-diethoxymethylphosphinic acid), CGP 54062 (3-N[1-(R,S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzy l- phosphinic acid), CGP 54626 (3-N[[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-cyclohexylmethylphosphinic acid) and CGP 55845 (3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid) are novel selective GABAB receptor antagonist. The apparent Kd values for the complex formed between the GABAB receptor and these compounds were determined using the monosynaptic reflex in the hemisected rat spinal cord preparation in vitro. CGP 55845 was found to be the most potent GABAB receptor antagonist tested (apparent Kd = 30 nM). On the same preparation 0.3 microM CGP 55845 was equipotent with 100 microM of CGP 35348 (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid) for reversal of the depressant action of (R)-(-)-baclofen.

Electrophysiological and neurochemical investigations on the action of carbamazepine on the rat hippocampus.

Carbamazepine moderately depressed the input fiber volley resulting in attenuation of the dendritic epsp and the population spike in CA1 of rat hippocampal slices with a threshold concentration of 20 microM. The depressant effect on the population spike was not antagonized by the adenosine receptor blocker caffeine. Paired-pulse inhibition was not affected by carbamazepine (40 microM). Epileptic-like rhythmic discharge of CA1 neurons in medium containing low Ca2+/high Mg2+ was attenuated at even lower concentrations of carbamazepine (8 microM) indicating that there was also a postsynaptic site of action. Imipramine being significantly more potent than carbamazepine in the rabbit corneal test for local anaesthetic activity had no effect on the population spike (20 microM). In neurochemical studies, carbamazepine reduced the [22Na]- and [3H]L-glutamate efflux induced by potassium and veratridine from hippocampal slices with a threshold concentration of 10 microM. The drug (400 microM) failed to affect Na+-dependent binding of [3H]L-glutamate to hippocampal synaptic membranes. In conclusion, the present findings demonstrate pre- and postsynaptic depressant actions of carbamazepine in CAI of hippocampus.

The action of anticonvulsant drugs on the firing of locus coeruleus neurons: Selective, activating effect of carbamazepine

The action of various doses of intraperitoneally administered carbamazepine, ethosuximide, Na-valproate, phenobarbital and diphenylhydantoin on the neuronal firing rate of presumed noradrenergic neurons of the locus coeruleus was investigated in the anaesthetized rat. Carbamazepine was the only compound which produced a statistically significant, dose-dependent activation of these neurons. The other anticonvulsant drugs caused a small but non significant reduction in locus coeruleus cell firing. It is concluded that this brain nucleus is not a main target of anticonvulsant drugs.

GABAA and GABAB receptors in locus coeruleus: effects of blockers

Racemic baclofen, (-)-baclofen and muscimol depressed all spontaneously firing locus coeruleus neurons tested in a slice preparation. Racemic phaclofen (100 microM; 1 mM) moderately antagonized the effects of racemic baclofen without antagonizing those of muscimol. Bicuculline (10, 30, 100 microM) potently antagonized the action of muscimol without affecting the inhibition of baclofen. Phaclofen and bicuculline had no pronounced effect on the spontaneous discharge rate of cells. The results suggests that there are GABAA and GABAB receptors in the locus coeruleus.