Int Rev Neurobiol
-
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. As of yet, neurochemical mechanisms underlying schizophrenia remain unknown. To date, the most widely considered neurochemical hypothesis of schizophrenia is the dopamine hypothesis, which postulates that symptoms of schizophrenia may result from excess dopaminergic neurotransmission particularly in striatal brain regions, along with dopaminergic deficits in prefrontal brain regions. ⋯ As compared to dopaminergic agents, NMDA antagonists induce negative and cognitive symptoms of schizophrenia, as well as positive symptoms. Treatment studies with NMDA modulators, such as glycine, d-serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Finally, genetic linkage and in vivo neurochemical studies in schizophrenia highlight potential etiological mechanisms giving rise to glutamatergic/NMDA dysfunction in schizophrenia.
-
Recent epidemiological studies and advances in understanding of brain cannabinoid function have renewed interest in the long-recognized association between cannabinoids and psychosis. This chapter presents evidence supporting and refuting the association between cannabinoids and psychosis. Cannabinoids can induce acute transient psychotic symptoms or an acute psychosis in some individuals. ⋯ Nevertheless, in the absence of known causes of schizophrenia, the role of component causes such as cannabis exposure (exogenous hypothesis) is important and warrants further study. There is also tantalizing evidence from postmortem, neurochemical, and genetic studies suggesting CB1 receptor dysfunction (endogenous hypothesis) in schizophrenia that warrants further investigation. Further work is necessary to identify those factors that place individuals at higher risk for cannabinoid-related psychosis, to identify the biological mechanisms underlying the risks and to further study whether CB1 receptor dysfunction contributes to the pathophysiology of psychotic disorders.
-
Stroke is a major risk factor for developing acquired epilepsy (AE). Although the underlying mechanisms of ischemia-induced epileptogenesis are not well understood, glutamate has been found to be associated with both epileptogenesis and ischemia-induced injury in several research models. This chapter discusses the development of an in vitro model of epileptogenesis induced by glutamate injury in hippocampal neurons, as found in a clinical stroke, and the implementation of this model of stroke-induced AE to evaluate calcium's role in the induction and maintenance of epileptogenesis. ⋯ The permanent epileptiform phenotype expressed as SREDs that resulted from glutamate injury was found to be dependent on the presence of extracellular calcium. The "epileptic" neurons manifested elevated intracellular calcium levels when compared to control neurons, independent of neuronal activity and seizure discharge, demonstrating that alterations in calcium homeostatic mechanisms occur in association with stroke-induced epilepsy. Findings from this investigation present the first in vitro model of glutamate injury-induced epileptogenesis that may help elucidate some of the mechanisms that underlie stroke-induced epilepsy.
-
Pain is a common problem of patients with multiple sclerosis (MS) and may be due to central/neuropathic or peripheral/somatic pathology. Rarely MS may present with pain, or pain may herald an MS exacerbation, such as in painful tonic spasms or Lhermitte's sign. In other patients, pain may become chronic as a long-term sequela of damage to nerve root entry zones (trigeminal neuralgia) or structures in central sensory pathways. ⋯ The pathophysiology of pain in MS may be linked to certain plaque locations which disrupt the spinothalamic and quintothalamic pathways, abnormal impulses through motor axons, development of an acquired channelopathy in affected nerves, or involve glial cell inflammatory immune mechanisms. At this time, the treatment of pain in MS employs the use of antiepileptic drugs, muscle relaxers/antispasmodic agents, anti-inflammatory drugs, and nonpharmacological measures. Research concerning cannabis-based treatments shows promising results, and substances which block microglial or astrocytic involvement in pain processing are also under investigation.
-
Status epilepticus (SE) is a medical and neurological emergency requiring prompt and aggressive treatment, particularly for elderly individuals in whom comorbid conditions may increase the severity of consequences in SE. Generalized convulsive status epilepticus (GCSE) is the most common and life-threatening type of SE. It may be overt or subtle in its presentation. ⋯ Analysis of data on elderly patients with overt GCSE from a Veterans Affairs cooperative study revealed that success rates of first-line treatment were 71.4% for phenobarbital, 63.0% for lorazepam, 53.3% for diazepam followed by phenytoin, and 41.5% for phenytoin alone. In elderly patients with subtle GCSE, success rates for first-line treatment were 30.8% for phenobarbital, 14.3% for lorazepam, 11.8% for phenytoin, and 5.6% for diazepam followed by phenytoin. Because each drug has advantages and disadvantages, the choice of which agent to use as first-line treatment depends on individual patient characteristics.