Chronic Benzodiazepine Administration: From the Patient to the Gene

Abstract

Chronic benzodiazepine administration is associated with the development of tolerance and dependence. To evaluate the cellular mechanisms for these phenomena the authors developed a mouse model of chronic benzodiazepine exposure. The benzodiazepine agonists lorazepam, alprazolam, and clonazepam produced tolerance in this system, which was associated in each case with benzodiazepine and GABAA receptor downregulation. After discontinuation, a syndrome that included increased motor activity and receptor upregulation occurred with each of these compounds. A benzodiazepine antagonist, flumazenil, and an inverse agonist, FG 7142, were associated with receptor upregulation and increased activity during chronic administration. In contrast, a partial agonist (Ro16-6028) did not produce tolerance or receptor changes. Similar results were obtained in a culture system for clonazepam, flumazenil, and FG 7142. The increase in receptor binding after lorazepam discontinuation may be due to enhanced receptor synthesis. Changes in gene expression for GABAA receptor subunits also occur with chronic lorazepam administration, and they follow alterations in binding.

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

“…(1990) these data suggest that PK11195 administration can at tenuate both tolerance and discontinuation phenom ena. In addition, these results support a relationship between tolerance and discontinuation, as has been postulated in a number of neurotransmitter receptor systems (Miller 1991).…”

“…However, in view of the unknown nature of the networks involved in convul sant effects and the potential subtype-specifIc effects of GABAA receptors, it is plausible that receptor up regulation may be linked to convulsant sensitivity. It should also be pointed out that changes in receptor binding may not always reflect changes in receptor func tion (Miller 1991).…”

Positive Association between the GABRA5 Gene and Unipolar Recurrent Major Depression

“…The GABAa receptors have modulatory sites for benzodiazepines. It was found that the benzodiazepine alprazolam has a high antidepressant efficiency [ 17], and its chronic application in treatment down-regulates GABAa receptors [18]. This suggests that these receptors could be implicated in the pathophysiology of depression.…”

The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

“…The effects of benzodiazepine discontinua tion include sleep disturbances, recurrence of anxiety, and rarely seizures [1], all of which can also be associated with excitatory neuro transmission [17], Animal models of benzodi azepine discontinuation are characterized by increased locomotor activity and reduced sei zure threshold, again consistent with excitatory-mediated events [3], Such effects have also been noted to be consistent with the 'inverse agonist' class of benzodiazepines [ 13,22], Given the extensive regional overlap of glutamate and GABAa receptor ionophores in the brain [23,24], it is not surprising that interactions between the two receptor families exist. Several studies indicate that glutamate agonists, and NMDA in particular, promote GABA release in a number of brain regions [12, 17.…”

“…A number of studies indicate that discontinuation is accompanied by recep tor upregulation; whether receptor phenomena account for discontinuation symptoms re mains uncertain [2,3]. However, several ex periments using a variety of benzodiazepine ligands indicate an apparent correlation be tween discontinuation effects and receptor upregulation [4][5][6], That is, compounds which produce discontinuation effects demonstrate upregulation, and those without behavioral ef fects do not demonstrate changes in binding.…”