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Bettina Platt

Publications and source records attributed to Bettina Platt.

11 recordsLinked to original sources
PubMed2006

Differential effects of cannabis extracts and pure plant cannabinoids on hippocampal neurones and glia.

We have shown previously that the plant cannabinoid cannabidiol (CBD) elevates intracellular calcium levels in both cultured hippocampal neurones and glia. Here, we investigated whether the main psychotropic constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC) alone or in combination with other cannabis constituents can cause similar responses, and whether THC affects the responses induced by CBD. Our experiments were performed with 1 microM pure THC (pTHC), with 1 microM pure CBD (pCBD), with a high-THC, low CBD cannabis extract (eTHC), with a high-CBD, low THC cannabis extract (eCBD), with a mixture of eTHC and eCBD (THC:CBD=1:1) or with corresponding 'mock extracts' that contained only pTHC and pCBD mixed in the same proportion as in eTHC, eCBD or the 1:1 mixture of eTHC and eCBD. We detected significant differences in neurones both between the effects of pTHC and eTHC and between the effects of pCBD and eCBD. There were also differences between the Ca(2+) responses evoked in both neurones and glia by eTHC and mock eTHC, but not between eCBD and mock eCBD. A particularly striking observation was the much increased response size and maximal responder rates induced by the mixture of eTHC and eCBD than by the corresponding 1:1 mixture of pTHC and pCBD. Our data suggest that THC shares the ability of CBD to elevate Ca(2+) levels in neurones and glia, that THC and CBD interact synergistically and that the cannabis extracts have other constituents yet to be identified that can significantly modulate the ability of THC and CBD to raise Ca(2+) levels.

Animals↗
PubMed2005

Cannabidiol-induced intracellular Ca2+ elevations in hippocampal cells.

The phytocannabinoid cannabidiol (CBD) is at the forefront of therapeutic cannabinoid research due to its non-psychotropic properties. Research supports its use in a variety of disorders, yet the cellular mechanisms of its action remain unclear. In this study, the effect of CBD upon Ca2+ homeostasis in hippocampal cells was characterised. CBD (1 microM) elevated intracellular Ca2+ ([Ca2+]i) by approximately +45% of basal Ca2+ levels in both glia (77% responders) and neurones (51% responders). Responses to CBD were reduced in high excitability HEPES buffered solution (HBS), but not affected in low excitability/low Ca2+ HBS. CBD responses were also significantly reduced (by 50%) by the universal Ca2+ channel blocker cadmium (50 microM) and the L-type specific Ca2+ channel blocker nifedipine (20 microM). Interestingly, intracellular store depletion with thapsigargin (2 microM) had the most dramatic effect on CBD responses, leading on average to a full block of the response. Elevated CBD-induced [Ca2+]i responses (>+100%) were observed in the presence of the CB1 receptor antagonist, AM281 (1 microM), and the vanilloid receptor antagonist, capsazepine (CPZ, 1 microM). Overall, our data suggest that CBD modulates hippocampal [Ca2+]i homeostasis via intracellular Ca2+ stores and L-type VGCC-mediated Ca2+ entry, with tonic cannabinoid and vanilloid receptor signalling being negatively coupled to this pathway.

Animals↗
PubMed2005

Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine.

Homocysteine (HCY) is a sulphur-containing amino acid, which has been linked to neurodegenerative diseases such as Alzheimer's disease, and is widely reported to enhance vulnerability of neurons to oxidative, excitotoxic and apoptotic injury via perturbed calcium homeostasis, activation of N-methyl-D-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors. The present study was undertaken to investigate the effects of HCY on long-term potentiation (LTP) and synaptic transmission after chronic 4-week systemic exposure to HCY in adult rats, and possible longer-term effects of HCY 4 weeks after exposure had ended. Contrary to expectation, LTP was enhanced, not retarded after chronic HCY exposure relative to controls. Basic synaptic transmission was not affected at this time point. However, after the 4-week wash out period, a decrease in speed of basic synaptic transmission emerged, and LTP was still partially enhanced, particularly for time points >30 min post-tetanus. In summary, we provide first evidence for sustained HCY-induced changes in hippocampal plasticity and a slow-onset disruption in synaptic transmission. These changes may reflect the suggested (excito-)toxicity of HCY and its putative contribution to neurodegenerative disease.

Animals↗
PubMed2003

Presynaptic group I metabotropic glutamate receptors modulate synaptic transmission in the rat superior colliculus via 4-AP sensitive K(+) channels.

1. Group I metabotropic glutamate receptors (mGluRs) are thought to be important modulators of neuronal function in the superior colliculus (SC). Here, we investigated the pharmacology and signalling mechanisms underlying group I mGluR-mediated inhibition of neuronal excitability and synaptic transmission in the rat SC slice. 2. The group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) potently depressed synaptically evoked excitatory postsynaptic potentials (EPSPs), currents (EPSCs), and action potentials in a dose-dependent manner (IC50: 6.3 microm). This was strongly reduced by the broad-spectrum antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mm, approximately 95% reduction), by the mGluR1 antagonist LY367385 (100 microm, approximately 80% reduction) but not by the mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 1-100 microm). 3. The putative mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 500 microm) also inhibited EPSPs. Interestingly, CHPG's actions were not blocked by MPEP, but LY367385 (100 microm) reduced the effect of CHPG by 50%. 4. Inhibition induced by DHPG was independent of phospholipase C (PLC)/protein kinase C pathways, and did not require intact intracellular Ca2+ stores. It was not abolished but enhanced by the GABAA antagonist bicuculline (5 microm), suggesting that DHPG's action was not due to facilitated inhibition or changes in neuronal network activity. 5. The K+ channel antagonist 4-aminopyridine (4-AP, 50-100 microm) converted the inhibitory effect of DHPG into facilitation. Paired-pulse depression was strongly reduced by DHPG, an effect that was also prevented by 4-AP. 6. Our data indicate that group I agonists regulate transmitter release, presumably via an autoreceptor in the SC. This receptor may be involved in adaptation to repetitive stimulation via a non-PLC mediated pathway.

4-Aminopyridine↗
PubMed2003

Glutamate receptor function in learning and memory.

The contribution of glutamate to synaptic transmission, plasticity and development is well established; current evidence is based on diverse approaches to decipher function and malfunction of this principal transmitter. With respect to learning and memory, we are now able to identify more specifically the role played by the three main glutamate receptor classes in learning and memory: centre stage is clearly the NMDA receptor, with overwhelming evidence proving its involvement in the actual learning process (encoding), throughout the animal kingdom. This is discussed with respect to many different types of learning. Evidence for the contribution of the AMPA receptors (AMPARs) is less clear-cut due to the general problem of specificity: block of AMPARs will shutdown neuronal communication, and this will affect various components essential for learning. Therefore, the role of AMPARs cannot be established in isolation. Problems of interpretation are outlined and a specific involvement of AMPARs in the regulation of neuronal excitation related to learning is proposed. Metabotropic glutamate receptors (mGluRs) may contribute very little to the actual acquisition of new information. However, memory formation appears to require mGluRs, through the modulation of consolidation and/or recall. Overall, mGluR functions seem variable and dependent on brain structure and learning task.

Animals↗
PubMed2003

Sometimes you see them, sometimes you don't: IPSCs in the rat superficial superior colliculus.

Superficial superior colliculus (SSC) neurones were voltage-clamped and the current-voltage relationship of synaptically evoked currents analyzed in vitro. A strong interplay between excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) was identified. Glutamate receptor antagonists not only fully blocked EPSCs but IPSCs were also frequently reduced by the specific d,l,-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist (by 66.9%), indicative of glutamate-driven inhibitory projections. The GABA(A )receptor antagonist bicuculline enhanced EPSCs and either abolished or reduced (by 79.3%) IPSCs. The GABA(C) receptor antagonist 1,2,5,6-tetrahydro-(pyridin-4-yl)methylphosphinic acid decreased IPSCs in 80% of cells tested (by 24.1%), but had no effect on EPSCs. Varying the recording conditions influenced postsynaptic currents. At a holding potential of -60 mV, IPSCs were generally produced with intracellular chloride concentrations of both 5 and 10 mM (total n=24/30). However, with perforated-patch recordings using gramicidin, IPSCs were less frequently encountered (n=5/21), suggesting a higher intracellular chloride concentration in a large proportion of SSC neurones. Further assessment of experimental conditions revealed that two frequently used sodium channel blockers, QX-314 (bromide salt, intracellular) or tetrodotoxin (extracellular), shifted the IPSC reversal potential towards more positive values. Hence, IPSCs were not encountered at -60 mV in their presence. The level of stimulation intensity (minimal or maximal) did not influence IPSC production in these conditions. Thus, the current study describes the pharmacological properties of PSCs in the SSC and highlights the impact of experimental conditions on synaptic transmission, which requires consideration for past and present data reported in this preparation.

Animals↗
PubMed2003

Cannabinoids: mechanisms and therapeutic applications in the CNS.

Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and anti-oxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.

Animals↗
PubMed2002

Gamma-aminobutyric acid-induced calcium signalling in rat superior collicular neurones.

Ionotropic gamma-aminobutyric acid (GABA) receptors are known to mediate excitation in neonatal neurones as a crucial developmental factor. In the present study we employed calcium imaging techniques with the calcium indicator Fura-2-AM to study the pharmacology of GABA-induced calcium responses in cultures prepared from neonatal rat superficial superior colliculus (SC), after immunocytochemical labelling confirmed the presence of GABA(C) rho(1) subunits in 35% of neurones. Rises in neuronal intracellular calcium were obtained in response to GABA and also to the subtype-specific GABA(A) agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. However, the GABA(C) agonist cis-4-aminocrotonic acid induced calcium response only at unspecifically high concentrations (500 microM). Co-application of GABA antagonists revealed that both GABA(A&C) agonists' actions could be blocked by the GABA(A) antagonist bicuculline but not the GABA(C) antagonists 1,2,5,6-tetrahydro-(pyridin-4-yl) methylphosphinic acid. This suggests that activation of GABA(A) but not GABA(C) receptors contributes to excitatory GABA responses and related calcium signals in neonatal SC neurones.

Animals↗
PubMed2002

No spatial working memory deficit in beta-amyloid-exposed rats. A longitudinal study.

Two experiments are described assessing whether long-term intraventricular or intrahippocampal administration of beta-amyloid protein 1-40 (beta A1-40) affects spatial working memory in rats monitored in a longitudinal study using the open-field water maze. A delayed matching-to-position procedure (DMTP) was employed in which platform locations were semi-randomly altered between days but were kept constant over the four trials on each day. Intertrial intervals (ITIs) were either 30 s or 1 h between Trials 1 and 2 (all other intervals = 30 s), with Trial 2 performance being an index for spatial working memory. Animals were trained before and tested repeatedly at various intervals after application of various compounds (see below) in five successive test sessions (TSs). In Experiment 1, beta A1-40 was applied after a challenge with long-term oral exposure to aluminium (Al; as 0.1% sulfate in drinking water). This in itself did not affect spatial working memory at any delay, despite of the more than 6 months of intake. beta A1-40 administered alone via intracerebroventricular (icv) minipumps (20 micrograms in 250 microliters) led to a small increase in latencies to find the platform, which recovered to control levels 3 months after minipumps were exhausted. Application of beta A1-40 in Al-exposed animals led to a subtle and progressive decline in working memory. This deterioration was reversed by the nootropic compound nefiracetam, which had no effect on the Al only group. In Experiment 2, well-trained rats were bilaterally implanted with intra-hippocampal minipumps containing beta A1-40 or reverse sequence beta A40-1. This did not impair spatial working memory in the DMTP task, measured either directly after minipumps were exhausted, or 2 weeks later. When intraperitoneally (i.p.) injected with a low concentration of the muscarinic antagonist scopolamine (0.2 mg/kg), a dose that was not effective alone, animals in the beta A1-40 group were amnesic. These data suggest that intra-hippocampal beta A1-40 administration alters cholinergic transmission, but these alterations may be mild and thus do not lead to obvious working memory deficits in a DMTP task in well-trained animals.

Administration, Oral↗
PubMed2002

Long-term study of chronic oral aluminum exposure and spatial working memory in rats.

The authors report an effort to advance animal models that mimic the cognitive decline of Alzheimer's disease. Rats were trained and repeatedly tested in a spatial delayed matching-to-position paradigm in the water maze, with the location of the submerged platform changing between, but not within, days. After Trial 1 (random search) and intertrial intervals of 30 s or 1 hr, memory was tested in Trial 2. Young rats quickly acquired this task and were repeatedly tested after different intervals over 7 months, with a slight increase in performance toward the end of testing, but no difference in latencies between delays. Oral long-term treatment of 1 group with 0.1% aluminum caused no delay-dependent working memory deficit. This testing protocol may enable between- and within-subject long-term assessment of spatial working memory before and after drug treatment and may prove useful in animal models of progressive cognitive decline.

Administration, Oral↗