Georg Andrees Böhme

Possible involvement of nitric oxide in long-term potentiation

Long-term potentiation (LTP) in the hippocampus is known to involve NMDA (N-methyl-D-aspartate) receptors. Since activation of NMDA receptors in the cerebellum results in the formation of nitric oxide (NO), we studied the possible involvement of this messenger in hippocampal synaptic plasticity. We report here that the NO-synthase inhibitor, L-N omega-nitro-arginine, blocks LTP and that sodium nitroprusside, which releases NO, produces a long-lasting enhancement in synaptic efficacy which is not additive with tetanus-induced LTP.

Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse.

The rewarding effects of morphine, cocaine, amphetamine and nicotine were evaluated in CB1 receptor knockout mice by means of an intravenous self-administration model. Experiments were carried out on drug-naive animals using a nose-poking response (NPR)-like as operandum. The results of the present study indicate that morphine did not induce intravenous self-administration in mutant CB1 receptor knockout mice, whereas it was significantly self-administered by the corresponding wild type mice. On the contrary, cocaine, amphetamine and nicotine were self-administered to the same extent by both wild type and CB1 receptor knockout mice. These data clearly indicate that the CB1 cannabinoid receptor is essential not only for the expression of cannabinoid reinforcing effects but also for the modulation of morphine rewarding effects. The specificity of such interaction is supported by the finding that contrary to morphine, cocaine, d-amphetamine and nicotine were self-administered by mice at the same extent either in presence or in absence of the CB1 receptor.

Enhancement of memory in cannabinoid CB1 receptor knock-out mice.

We have used cannabinoid CB knock-out mice in a two-trial object recognition test to assess the role of cannabinoid CB receptors in memory. Cannabinoid CB1 knock-out mice are able to retain memory for at least 48 h after the first trial whereas the wild-type controls lose their capacity to retain memory after 24 h. These results suggest that endogenous cannabinoid CB receptors play a crucial role in the process of memory storage and retrieval.

A Role for Nitric Oxide in Long‐term Potentiation

Nitric oxide production in the cerebellum and induction of long‐term potentiation (LTP) in the hippocampus have some characteristics in common: both phenomena are induced by activation of N‐methyl‐D‐aspartate receptors and both are highly dependent on calcium‐mediated processes. Here we provide evidence that endogenous nitric oxide production is necessary for synaptic plasticity in the CA1 hippocampus of the rat. LTP recorded in slices was blocked in a concentration‐dependent manner by the nitric oxide synthase inhibitors L‐NG‐nitroarginine and L‐NG‐nitroarginine methyl ester, but L‐NG‐monomethylarginine was only marginally active. Bathing the slices with haemoglobin, a protein that scavenges nitric oxide, also resulted in a concentration‐dependent blockade of LTP. Nitric oxide released locally from hydroxylamine produced a stable potentiation of synaptic transmission that was not additive with LTP induced by high‐frequency stimulation. These results are fully consistent with the presumed retrograde messenger role of nitric oxide in LTP.

Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury

The aim of this study was to investigate the effect of N‐(3‐(aminomethyl)benzyl)acetamidine (1400W), a selective inhibitor of inducible calcium‐independent nitric oxide synthase (iNOS), on the functional and histopathological outcomes of experimental transient focal cerebral ischaemia in rats. Transient ischaemia was produced by the occlusion for 2 h of both the left middle cerebral artery and common carotid artery. Treatments with 1400W (20 mg kg−1) or vehicle were started 18 h after occlusion of the arteries and consisted in seven subcutaneous injections at 8 h interval. Ischaemic outcomes and NOS activities (constitutive and calcium‐independent NOS) were evaluated 3 days after ischaemia. 1400W significantly reduced ischaemic lesion volume by 31%, and attenuated weight loss and neurological dysfunction. 1400W attenuated the calcium‐independent NOS activity in the infarct by 36% without affecting the constitutive NOS activity. These findings suggest that iNOS activation contributes to tissue damage and that selective inhibitors of this isoform may be of interest for the treatment of stroke.

Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors.

Marijuana is known to affect learning and memory in humans, and cannabinoids block long-term potentiation in the hippocampus, a model for the synaptic changes that are believed to underlie memory at the cellular level. We have now examined the physiological properties of the Schaffer collateral-CA1 synapses in mutant mice in which the CB1 receptor gene has been invalidated and found that these animals exhibit a half-larger long-term potentiation than wild-type controls. Other properties of these synapses, such as paired-pulse facilitation, remained unchanged. This indicates that disrupting CB1 receptor-mediated neurotransmission at the genome level produces mutant mice with an enhanced capacity to strengthen synaptic connections in a brain region crucial for memory formation.

Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice

Morphine (10 and 20 mg/kg, s.c.) does not modify dopamine release in the nucleus accumbens of cannabinoid CB(1) knock-out mice under conditions where it dose-dependently stimulates the release of dopamine in the corresponding wild-type mice. These results demonstrate that cannabinoid CB(1) receptors, regulate mesolimbic dopaminergic transmission in brain areas known to be involved in the reinforcing effects of morphine.

Evidence for an endogenous cholecystokininergic balance in social memory

The cholecystokinin (CCK) peptide family is involved in a variety of physiological processes, including neurotransmission in the brain. Pharmacological responses to CCK are mediated through at least two receptor subtypes termed CCK-A and CCK-B. Studies with CCK agonists suggest a possible role for CCK in cognition. Using selective antagonists and a behavioural recognition test based on the olfactory discriminative capacities of rats, we found that endogenous CCK acting at CCK-A and CCK-B receptors modulates olfactory recognition positively and negatively, respectively. CCK-B receptor antagonists therefore have facilitatory potentialities on memory processes.

CCK-A and CCK-B selective receptor agonists and antagonists modulate olfactory recognition in male rats

Modulation of learning and memory is one of the physiological roles that the neuropeptide cholecystokinin (CCK-8) may play. We have used a behavioural model of olfactory recognition among rats to test this hypothesis and to explore the relationship between CCK-A and CCK-B receptors and memory retention. Adult male rats form a transient memory of a juvenile congenere as indicated by a reduction in the duration of investigatory behaviour upon re-exposure 30 min after an initial exposure, but not when re-exposure is delayed until 120 min afterwards. In the present study, rats were treated after the first contact with various compounds; inhibition and facilitation of olfactory recognition were evaluated as the persistence in investigation 30 min and the decrease in investigation 120 min after pharmacological manipulations, respectively. Systemic injection of CCK-8, of a selective CCK-A agonist, or of non-peptide CCK-B antagonists (CI-988 and LY-262691) enhanced olfactory recognition. In contrast, the CCK-B selective agonist BC 264 and the tetrapeptide CCK-4 both disrupted it. Taken together with previous evidence of the detrimental effect of the non-peptide CCK-A antagonist devazepide on olfactory recognition, these results confirm and extend the hypothesis that there is a balance between CCK-A-mediated facilitative effects and CCK-B-mediated inhibitory effects on memory retention.

Cloning of Rat Parkin cDNA and Distribution of Parkin in Rat Brain

Abstract: The rat parkin cDNA sequence was characterized after screening a rat hypothalamus cDNA library with a 32P‐labeled probe containing the entire open reading frame of the human parkin cDNA. This sequence encompasses 1,576 bp and contains a single open reading frame that encodes a 465‐amino acid protein. The rat parkin amino acid sequence exhibits a very striking homology to the human and mouse parkin, with 85 and 95% identity, respectively. Both the N‐terminal ubiquitin and the ring‐IBR (in between ring)‐ring finger domains appear to be highly conserved among rat, human, and mouse parkin. An affinity‐purified polyclonal antibody (ASP5p) was generated with a synthetic peptide corresponding to amino acids 295‐311 of the parkin sequence, which is identical in the three species. Western blotting revealed that ASP5p recognizes a single 52‐kDa band, which corresponds to the molecular mass of the parkin protein. Immunostaining with ASP5p showed that parkin is principally located in the cytoplasm of neurons that are widely distributed in the rat brain. Parkin‐immunoreactive neurons abound in structures that are specifically targeted in Parkinsons disease, e.g., subtantia nigra, but are also present in unaffected structures, e.g., cerebellum. Furthermore, parkin‐enriched glial cells can be detected in various nuclei of the rat brain. Thus, the role of parkin may be much more global than previously thought on the basis of genetic findings gathered in cases of early‐onset parkinsonism.