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Although the function of the kainate receptors in the brain is still not clear, they are increasingly defined as targets in the development of new classes of anti-epileptics. The thienopyrimidines described in this report were tested for their antagonistic effect at the kainate receptor subtypes GluR5 and GluR6. The highest effectiveness was obtained by a 4-ethoxy-thieno[2,3-d]pyrimidin with an IC50 = 68 microM at the GluR6 receptor.

In the last years, numerous studies have been performed on neurobiological mechanisms in alcohol craving. Changes in the hypothalamic cortisol pathway and the leptin metabolism, which is also associated with pharmacological interventions, have been of special interest. With acamprosate and naltrexone two substances exist for pharmacotherapy, but recent results about the efficacy are controversial. The clinical profit of disulfiram has been shown, at least in a subgroup of patients. Besides, there are several promising candidate substances. Current investigations focus on a differentiated pharmacotherapy of alcohol dependence, including psychological and genetic factors.

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal AMPA/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. These were reduced by NBQX, a selective antagonist of AMPA/kainate receptors. However, administration of NMDA receptor antagonists caused no or only a modest decrease in behaviors for secondary hyperalgesia but produced associated motor deficits and supraspinal side effects. We further determined that only secondary mechanical hyperalgesia was reversed by JSTX, a selective antagonist of calcium-permeable AMPA receptor; primary mechanical hyperalgesia and guarding behavior were unchanged. These findings indicate that JSTX influenced a spinal amplification process that leads to secondary hyperalgesia but does not contribute to primary hyperalgesia and guarding after incision. This amplification process likely requires Ca(2) influx through spinal AMPA/KA (but not NMDA) receptors. Behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.

Statins, i.e. HMG-CoA reductase inhibitors, reduce the risk of stroke and may have therapeutic potential for other neurologic diseases, including multiple sclerosis and Alzheimer's disease. In addition to lowering cholesterol levels, statins exert a number of cholesterol-independent (pleiotropic) effects. While endothelial, anti-thrombotic, anti-inflammatory, and immunomodulatory, i.e. peripheral, effects of statins are well known, little is known about the direct effects on neurons. This may be of clinical relevance because some statins are able to cross the blood-brain barrier. Recent experimental studies demonstrate that statins reduce the activity of neuronal glutamate receptors and protect neurons from excitotoxic insults. At higher doses, however, statins may also inhibit neurite sprouting and even induce neuronal apoptosis.

Post-mortem investigations have confirmed that glutamatergic NMDA, AMPA, and kainate receptors are involved in the pathophysiology of schizophrenia. It is still unclear, however, whether the altered number of receptors is caused by the disease itself or the medication. Therefore, animal models were investigated for effects of antipsychotic medication after treatment periods of up to 6 months, the results of which are summarized here. Generally, NMDA receptor binding was found to be increased in striatum and nucleus accumbens after therapy with haloperidol, whereas clozapine only increased the number of receptors in nucleus accumbens. While haloperidol led to an increase in AMPA receptors in the posterior cingulate gyrus, striatum, insular cortex, and n. accumbens, clozapine was found to elevate ligand binding in the anterior cingulate gyrus and infralimbic cortex. Although kainate receptor binding was increased in hippocampus by both antipsychotics, clozapine was significantly more effective. In conclusion, data reveal different effects from the typical neuroleptic haloperidol and the atypical antipsychotic clozapine. The results suggest that post-mortem findings in patients with schizophrenia may at least partially be explained by drug effects and plasticity changes induced by long-term medication with antipsychotics.

Background: Reduction in the excitatory and potentially toxic neurotransmitter glutamate can protect retinal ganglion cells. What are the effects of the antiepileptic drug gabapentin, for which antiglutamatergic effects have been described, and the new substance gabapentin-lactam (GBP-L) on retinal ganglion cell survival after retinal ischemia?, Methods: In 3 groups of 10 rats each, ischemia was induced by elevating the intraocular pressure of the left eye to 120 mmHg for 1 h. Saline, gabapentin (2 x 50 mg/kg intraperitoneally) and GBP-L (2 x 50 mg/kg intraperitoneally) were injected before and 5 h after ischemia. Two weeks later ischemic damage was quantified histologically by counting the number of neurons in the ganglion cell layer. In vitro transmitter release experiments were performed to obtain information on the effect of gabapentin and GBP-L on ischemia-induced glutamate release and the mechanism of action of GBP-L., Results: In the control group 17% of the retinal ganglion cells survived ischemia. GBP-L doubled the number of the surviving cells while gabapentin was not effective in these experiments. In vitro gabapentin and GBP-L reduced ischemia-induced glutamate release by 35.7% and 42.5%, respectively. The blockade of ATP-sensitive potassium channels antagonized the effect of GBP-L completely., Conclusion: GBP-L is neuroprotective in retinal ischemia and diminishes the release of the excitatory neurotoxic amino acid glutamate. The effect of GBP-L might be mediated by ATP-sensitive potassium channels. Also gabapentin reduced glutamate release but was not neuroprotective in vivo.

Several different possibilities concerning pharmacotherapy of alcoholism are discussed on the background of new neurobiochemical findings. Contributions to a new understanding of relapse are made and the complexity of the treatment of patients with double diagnosis is explained.

Excessive smoking is a well know phenomenon in psychiatry. Nicotine, the most important content of cigarette tobacco, interacts with several receptors of neurotransmitters in the CNS: especially the dopaminergic system appears to be relevant in this respect. Nicotine is a potent substance to counteract neuroleptic-induced parkinsonism. On the other hand nicotine is possibly a risk-factor for tardive dyskinesia. Nicotine has enormous therapeutical implications.