Sedation outcomes for remimazolam, a new benzodiazepine.

Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is expected to be safe and effective for a wide range of patients undergoing intravenous sedation for dental procedures. The aim of this literature review was to evaluate clinical and sedation outcomes for remimazolam, including method of administration, level of sedation at the dose required, and clinical adverse events. An electronic literature search of databases was conducted, and eight articles were selected for inclusion in this review. Onset time from drug administration to optimal sedation level was faster for remimazolam (around 1.5-6.4 min) than for midazolam. Recovery time was significantly shorter for remimazolam than for midazolam and propofol. A study comparing various doses of remimazolam with midazolam found no significant difference in safety. Comparison of a remimazolam group with a propofol group showed that incidences of hypotension (13.0% vs 42.9%, respectively) and respiratory depression (1.1% vs 6.9%, respectively) were significantly lower for remimazolam. Remimazolam appears to be an ideal sedative.

In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats.

GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GABA released from the neuron. Therefore, we hypothesised that glutamic acid decarboxylase (GAD) which generates GABA in accumbal GABAergic neurons, at least partly determines the GABA receptor subtype-mediated GABAergic tonus. To (in)validate this hypothesis, in vivo microdialysis was used to study the effects of an intra-accumbal infusion of the GAD inhibitor l-allylglycine (allylglycine) on the accumbal dopamine efflux of freely moving rats. The intra-accumbal infusion of allylglycine (50.0, 250.0 and 500.0 nmol) dose-dependently increased the accumbal dopamine levels. The co-administration of tetrodotoxin (720 pmol) suppressed the allylglycine (500.0 nmol)-induced dopamine efflux. The intra-accumbal infusion of GABA(B) receptor agonist baclofen (2.5 and 5.0 nmol) inhibited the allylglycine (500.0 nmol)-induced dopamine efflux. The baclofen's effects were counteracted by GABA(B) receptor antagonist saclofen (10.0 nmol). Neither GABA(A) receptor agonist (muscimol: 25.0 and 250.0 pmol) nor antagonist (bicuculline: 50.0 pmol) altered the allylglycine (250.0 and 500.0 nmol)-induced dopamine efflux. The present study provides in vivo neurochemical evidence that newly synthesised GABA that exerts an inhibitory tonus on the accumbal dopaminergic activity, acts at the level of GABA(B) receptors, but not GABA(A) receptors. The present study also shows that there is an allylglycine-insensitive GABA pool that release GABA exerting an inhibitory control of the accumbal dopaminergic activity, at the level of GABA(A) receptors. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Dopamine D1-like receptors play only a minor role in the increase of striatal dopamine induced by striatally applied SKF38393.

We studied the effects of the intra-striatal infusion of Ca(2+)-free medium on the intra-striatal injection of 0.5 µg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca(2+)-insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca(2+)-sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D1-like receptors play only a very limited role in these processes. The present study underlines our previous notion that the effects of SKF38393 cannot simply be ascribed to the dopamine D1-like receptor stimulation (Saigusa et al., 2009): in fact, the present study clearly reveals that SKF38393 is not at all selective in that respect.

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopamine pool and the alpha-methyl-para-tyrosine-sensitive cytosolic dopamine pool. Given the similarities between dexamphetamine and SKF38393, we hypothesized that both types of pool also contribute to the striatally applied SKF38393-induced dopamine efflux. Using in vivo microdialysis technique, we analysed the contribution of these pools to the SKF38393-induced striatal dopamine efflux in freely moving rats. The increase of dopamine efflux induced by 1.5 microg SKF38393 was largely prevented by either reserpine (5mg/kg i.p., given 24h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2h earlier), showing that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the SKF38393-induced increase in striatal dopamine efflux. The sum of the amounts of dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was greater than 100%, namely 137.6% of the basal dopamine level and 143.9% of the SKF38393-induced dopamine level, suggesting that striatally applied SKF38393 promotes the redistribution of dopamine from vesicles to the cytosol, and vice versa. The finding that the combined treatment of reserpine and alpha-methyl-para-tyrosine only inhibited the SKF38393-induced striatal dopamine efflux till 86.0% of the control, is ascribed to the notion that SKF38393 can also inhibit the re-uptake of dopamine. The latter conclusion has far-reaching consequences for studies in which the effects of SKF38393 are simply ascribed to its dopamine D1 receptor stimulation capacity.

The reboxetine-induced increase of accumbal dopamine efflux is inhibited by l-propranolol: a microdialysis study with freely moving rats.

In vivo microdialysis was used to study the effects of the locally applied selective noradrenaline uptake inhibitor reboxetine on the baseline noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. The effects of intra-accumbal infusion of the beta-adrenoceptor antagonist l-propranolol on the reboxetine-elicited noradrenaline and dopamine efflux in the nucleus accumbens were also analysed. The intra-accumbal infusion of reboxetine (1.2 and 12 pmol) significantly increased both the accumbal noradrenaline efflux and the accumbal dopamine efflux. The intra-accumbal infusion of the chosen doses of l-propranolol (300 and 1200 pmol) did not alter the accumbal noradrenaline and dopamine efflux. The l-propranolol treatment did not affect the reboxetine-elicited accumbal noradrenaline efflux, but it significantly inhibited the reboxetine-elicited increase of accumbal dopamine efflux. The doses mentioned are the total amount of drug over the infusion period that varied across the drugs (60 or 120 min). The present study shows that the intra-accumbal infusion of selective noradrenaline uptake inhibitor reboxetine increases noradrenaline as well as dopamine efflux in the nucleus accumbens of freely moving rats. This study also indicates that inhibition of accumbal beta-adrenoceptors prevented the increase of the reboxetine-induced accumbal dopamine efflux. It is suggested that the reboxetine-induced increase of the endogenous accumbal noradrenaline activates among others accumbal beta-adrenoceptors that, in turn, stimulate the accumbal release of dopamine.