Anxiolytic effects

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

Kwok MH, Huen MSY, Wang HY, et al. Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem Pharmacol 2002 64 1415-1424. 

Viola H, Wasowski C, Levi de Stein M, et al. Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Med 1995 61 213-216. 

The answer is d. (Hardman, p 564.) A long-acting benzodiazepine, such as diazepam, is effective in blocking the secobarbital withdrawal symptoms. The anxiolytic effects of bus pi rone take several days to develop, obviating its use for acute severe anxiety... 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

A number of medications used in the treatment of anxiety have effects on serotonin neurotransmission (Ch. 13). These medications include tricyclic antidepressant medications, SSRIs, and monoamine oxidase inhibitors (MAOIs). However, because these medications take weeks to exert their full anxiolytic effects, it is unlikely that blocking the reuptake (and thus increasing synaptic levels) of either serotonin or norepinephrine selectively is responsible for their anxiolytic properties — rather it is suspected that the therapeutic effects are due to changes in gene expression, protein levels, and eventually changes in synaptic connections between neurons. 

CRH and its receptors have generated increasing interest as a target for medications. In addition to the pituitary, CRH receptors have been localized to the cortex, the nuclei of the amygdala, the LC, and regions of the hypothalamus. It has also been reported that CRH increases LC activity, and that local injection of CRH into the LC increases behavioral responses consistent with increased anxiety [105]. Furthermore, CRH antagonists have been repeatedly shown to have anxiolytic effects in animal models. 

Pregabalin produced anxiolytic effects similar to lorazepam, alprazolam, and venlafaxine in acute trials. Sedation and dizziness were the most common adverse effects, and the dose should be tapered over 1 week upon discontinuation. 

BZs with a long t1/2 may be dosed once daily at bedtime and may provide nighttime hypnotic and anxiolytic effects the next day. 

The onset of anxiolytic effects requires 2 weeks or more maximum benefit may require 4 to 6 weeks. 

A new HP-TLC method has been applied for the quantitative analysis of flavonoids in Passiflora coerulea L. The objective of the experiments was the separation and identification of the compound(s) responsible for the anxiolytic effect of the plant. Samples were extracted with 60 per cent ethanol or refluxed three times with aqueous methanol, and the supernatants were employed for HPTLC analysis. Separation was performed on a silica layer prewashed with methanol and pretreated with 0.1 M K2HP04, the optimal mobile phase composition being ethyl acetate-formic acid-water (9 1 l,v/v). It was established that the best extraction efficacy can be achieved with 60 - 80 per cent aqueous methanol. The HPTLC technique separates 10 different flavonoids, which can be used for the authenticity test of this medicinal plant [121],... 

Nicotine reduces anxiety in humans, more so in females than males (Stewart et al. 1997). Similar to nicotine, the nicotinic channel activator ABT-418 has anxiolytic effects (Brioni et al. 1994). Nicotine reduces anxiety and right hemisphere EEG activation in subjects watching a stress-inducing movie (Gilbert et al. 1989). Conversely, smoking cessation is commonly associated with increases in anxiety and dysphoria (West and Hajek 1997). 

The anxiolytic effects of nicotine are evident in EEG changes. While subjects watched a stress-inducing movie, higher doses of nicotine reduced anxiety and reduced right hemisphere EEG activation (Gilbert et al. 1989). 

Alternative pharmacological approaches Clonidine, an o2 adrenergic agonist, has been employed as adjunctive therapy to assist in smoking cessation. However, results have been mixed or the effects small (Gourlay et al. 1994 Hilleman et al. 1993 Franks et al. 1989). Buspirone (BuSpar) is a 5-HTlA partial agonist with anxiolytic effects. It has been tested as a treatment for smoking cessation because anxiety is a prominent feature of nicotine withdrawal (Farid and Abate 1998). To date, results have been mixed and more controlled research is needed. 

Cognitive effects Animal studies There is an extensive literature that deals with the effects of ginseng on memory, learning, and behavior (Gillis 1997 Wang et al. 1995). However, ginseng extract (G115) failed to show anxiolytic effects in an animal model (Petkov et al. 1987)... 

Valerian extracts show sedative and anxiolytic effects. Whereas passionflower and chamomile have relatively specific anxiolytic effects, valerian shows more general sedative effects, but all effects occur in a dose-dependent manner (Della Logia et al. 1981 Leuschner et al. 1993). The sedative effects of valerian extract are moderate when compared to diazepam and the neuroleptic chlorpromazine (Leuschner et al. 1993). However, valepotriates reverse the anxiogenic effects of diazepam withdrawal in rats in the elevated plus maze. This effect is dose dependent, effective at 12 mg/kg but not 6 mg/kg. Interestingly, the fragrant valerian compound bornyl acetate has sedative effects in mice, but only when inhaled (Buchbauer et al. 1992). 

There are a few members of the passionflower family (Passifloraceae) that have psychotropic effects. The one most studied is Pass flora incarnata, although some work has been done on Pass flora coerulea and Passiflora edulis. P. incarnata is a colorful, flowering plant with five white or lavender petals, a purple or pink corona, and five brightly colored stamen (Gruenwald et al. 1998). The parts of the plants used for medicinal effect are the whole plant or aerial parts. It is native to the mid- to southeastern United States. Passionflower has a history with Native Americans as a poultice to treat bruises, and as a tea for sedative/anxiolytic effects (Kowalchick and Hylton 1987). It is one of the most common herbs commercially available in Britain (Tyler 1994). 

Sedative and anxioiytic effects A number of flavonoids have been shown to bind to benzodiazepine receptors and have anxiolytic effects (Medina et al. 1997). The anxiolytic effects of chrysin were examined in mice (Wolfman et al. 1994). Chrysin (1 mg/kg IP) reduces behavioral measures of anxiety (elevated-plus maze) in a manner similar to diazepam (0.3-0.6 mg/kg), which was reversed by pretreatment with a benzodiazepine antagonist, Ro 15-1788. The anxiolytic effect is not likely due to sedation because there is no concurrent reduction in motor activity at the doses used. Unlike diazepam, chrysin does not produce muscle relaxation at higher doses. 

The sedative and anxiolytic effects of passionflower were examined in two other animal behavioral assays (staircase test, light/dark box choice test). Both anxiolytic and sedative effects occur, as well as potentiation... 

Despite neuropharmacolgical and animal data to support sedative and anxiolytic effects of passionflower, there have not been any such controlled studies in humans. Two studies have been published that examined the effects of combined herbal extracts on anxiety, including passionflower (Bourin et al. 1997). Although there were significant and experimentally controlled effects, a combined herbal treatment confounds the ability to selectively identify the effects of passionflower. A second controlled study was similarly confounded by the use of a three-herb combination (Gerhard et al. 1991). 

Cognitive effects A study of the effects of chiysin on memory was performed in the rat (Salgueiro et al. 1997). Chrysin does not have any amnestic effects on either acquisition or retention in three tests of memory (inhibitory avoidance, shuttle avoidance, and habituation to an open field), even at higher doses than required to produce anxiolytic effects. The cognitive effects of passionflower have not been examined in humans. 

Other serotonergic drugs that are direct receptor agonists or antagonists have been found to have anxiolytic effects (Stahl 1998 Bonhomme and Esposito 1998). A novel class of anxiolytic drugs called azapirones act as partial agonists at 5-HTlA receptors (Yocca 1990). Clinically, they are represented by BuSpar, which was approved for use in 1986 (Eison... 

AS 1990). Several 5-HTlA agonists have been found to produce anxiolytic effects in animal models and in human clinical trials (File et al. 1996 Krummel and Kathol 1987 Goldberg and Finnerty 1979). Furthermore, they have antidepressant effects they augment the antidepressant effects of serotonin reuptake inhibitors, and they decrease the therapeutic latency (Bouwer and Stein 1997 Artigas et al. 1996 Sussman 1998 Rickels et al. 1991 Wieland and Lucki 1990 Jenkins et al. 1990 Fabre 1990). However, results have not been uniformly positive, such as in refractory severe depression (Sussman 1998 Fischer et al. 1998)... 

Although several putative anxiolytic herbs are discussed in chapter 6, a select few are discussed here because of their similarity to antidepressant medications in terms of neuropharmacological activity, and because of the close relationship between depression, anxiety, and their pharmacological treatment in general. Whereas the anxiolytic herbs discussed previously have anxiolytic effects through more-general CNS depressant actions, the ones discussed here seem to have more-specific actions, particularly on serotonin. 

Two studies have been done to date that address ginger s anxiolytic effects in an animal model (Hassenohrl et al. 1996, 1998). Unfortunately, both of these employ a combined treatment of ginger and Ginkgo biloba so they do not allow for differentiation of effects. The combination had diazepamlike effects in an animal model of anxiety (elevated-plus maze) (Hassenohrl et al. 1996). These effects were dose dependent and tripha-... 

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