DBI binds to receptors that sit on nerve-cell surfaces and are responsive to a tiny but important chemical messenger, or neurotransmitter, called GABA. The roughly one-fifth of all nerve cells in the brain that are inhibitory mainly do their job by secreting GABA, which binds to receptors on nearby nerve cells, rendering those cells temporarily unable to fire any electrical signals of their own.
These receptors come in many different types and subtypes, not all of which are responsive to benzodiazepines. But until now, exactly what this means has remained unclear. The researchers used single-nerve-cell-recording techniques to show that within a GABA-secreting nerve-cell cluster called the thalamic reticular nucleus, DBI has the same inhibition-boosting effect on benzodiazepine-responsive GABA receptors as do benzodiazepines.
In another seizure-prone mouse strain in which that site is intact but the gene for DBI is missing, the scientists saw diminished inhibitory activity on the part of benzodiazepine-responsive GABA receptors. Re-introducing the DBI gene to the brains of these mice via a sophisticated laboratory technique restored the strength of the GABA-induced inhibition.
This suggested that some naturally occurring benzodiazepine-like substance was being displaced from the benzodiazepine-binding site by the drug. In DBI-gene-lacking mice, the blocking agent had no effect at all.
Huguenard, Christian and their colleagues also showed that DBI has the same inhibition-enhancing effect on nerve cells in an adjacent thalamic region — but also that, importantly, no DBI is naturally generated in or near this region; in the corticothalamic circuit, at least, DBI appears to be released only in the thalamic reticular nucleus. But, he said, by finding out exactly which cells are releasing DBI under what biochemical circumstances, it may someday be possible to develop agents that could jump-start and boost its activity in epileptic patients at the very onset of seizures, effectively nipping them in the bud.
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This is particularly problematic given that use is more common among older age groups. Benzodiazepines are also sold as street drugs, can impair driving and are associated with overdose. Continued use even at low dose for a few weeks can lead to physiological dependence tolerance and withdrawal.
Tolerance means that, over time, the effect of the drug wears off and a higher dose is needed for the same effect. When the drug is stopped , users can experience severe withdrawal symptoms such as insomnia, irritability, tension, panic attacks, tremor, sweating, poor concentration, nausea, palpitations, headache, muscle aches and sometimes even seizures and psychotic reactions.
Long-term use is generally not recommended because of the known side effects. But withdrawal can be difficult since the initial symptoms for which the drug was prescribed might return, made worse by the symptoms from the withdrawal itself. Some people are therefore reluctant to stop the drug.
For these reasons, withdrawal should be gradual and guided by clinicians, who can help patients cope with any symptoms. Up to the mids, barbiturates were widely used to treat insomnia and anxiety.
But the incidence of dependence, severe withdrawal reactions, overdose and death had become a great concern. In the quest for a safer alternative , American chemist Leo Sternbach created the first compound in the benzodiazepines class of drugs, methaminodiazepoxide. This led to the release of diazepam Valium in , considered to be safer than barbiturates. Over the next decade, it became the most prescribed drug in the United States.
Negative effects were slow to be recognised and widely acknowledged. This took nearly two decades after the description of the withdrawal syndrome. Only then did prescription rates begin to fall. The good news is there is now greater caution and questioning about the potential unintended effects of new drugs. Despite the clear evidence and widespread acceptance that benzodiazepines cause harm, they have a legitimate place in therapeutics , such as in acute emergencies.
Yet despite international and national guidelines recommending that the use of benzodiazepines should be limited to two to four weeks , these drugs continue to be prescribed beyond these time frames. The reasons for this are complex. As the largest medical workforce, GPs have the greatest contact with patients and therefore prescribe the most medications. They are often seen as responsible for the benzodiazepine problem. But GPs may not always be the initiator. They often take over the care of patients who have been started on benzodiazepines by psychiatrists or during hospital admissions.
Psychiatrists commonly prescribe these medications as an add-on to antidepressant treatment to reduce anxiety and to increase the likelihood that patients will adhere to treatments and respond early.
Today there is a broad spectrum of people and contexts where benzodiazepines are used, from the clearly legitimate short-term situations in known patients to deliberate drug misuse and sale in people with chaotic and sometimes aggressive behaviour. Further, with an increasingly internationally networked world, benzodiazepines can now be purchased on the internet without a prescription.
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