Duncan P. Taylor

Dopamine and antianxiety activity.

Clinical trials have indicated that buspirone (Buspar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam. Until recently it has been thought that antianxiety drugs must alter benzodiazepine receptor binding in vitro. However, buspirone lacks any structural similarity to te benzodiazepines and does not interact with the benzodiazepine/gamma-aminobutyric acid (GABA) axis. Specifically, buspirone neither stimulates nor inhibits [3H]benzodiazepine binding, does not affect the influence o GABA or halide anions on benzodiazepine binding, and does not interfere with GABA binding or uptake. Behavioral testing has revealed that buspirone does not produce muscle weakness, does not control seizures, does not potentiate the impairment of psychophysiological function or lethality produced by administration of CNS depressants, does not produce sedation/hypnosis and does not appear to possess any abuse potential or liability for physical dependence. Thus, buspirone has been termed an anxioselective agent. Buspirone appears to only interact with the dopaminergic system with reasonable potency and exhibits properties of both a dopamine agonist and a dopamine antagonist. This suggests that dopamine is implicated in the etiology and expression of anxiety. A discussion of this implication is presented with a review of the clinical efficacy of nonbenzodiazepine drugs, especially dopamine agonists and dopamine antagonists, in the management of anxiety. In addition, neuropharmacological studies which have investigated the role of dopamine in animal models of anxiety are considered. Finally, the multiplicity of dopamine receptors and their regional localization in the brain are considered in the formulation of an hypothesis which features a role for the dopaminergic agents in the pharmacotherapy of anxiety.

Buspirone, a new approach to the treatment of anxiety.

Anxiety has historically been treated by agents with a sedative component to their action. In the last decade or so it has been determined that γ‐aminobutyric acid (GABA) receptors may mediate the anxiolytic actions of the benzodiazepines, propanediol carbamates, barbiturates, and ethanol. However, inasmuch as these drugs have additional pharmacological properties (sedation, muscle relaxation, seizure control), the search for an anxioselective drug was continued. Buspirone appears to be such a drug. Clinical studies have clearly demonstrated the efficacy of buspirone in the treatment of generalized anxiety disorder without the ancillary pharmacology of earlier anxiolytics. Buspirone does not act on the GABA receptor. Rather, its most salient interaction with neurotransmitter receptors occurs at the 5‐HT1A serotonin receptor. This action is supported by studies focused on receptor binding, anatomical localization, biochemistry, neurophysiology, and animal behavior. The recognition that action at 5‐HT1a receptors may be a viable approach to the pharmacotherapy of anxiety is evidenced by the number of other agents of this class under development by a number of pharmaceutical companies.— Taylor, D. P. Buspirone, a new approach to the treatment of anxiety. FASEB J. 2: 2445‐2452; 1988.

Serotonin Agents in Anxiety

The side effects and unwanted or unnecessary ancillary pharmacological properties of benzodiazepine anxiolytic drugs resulted in a continuing search for new agents with improved profiles of activity. Buspirone was the first novel drug to emerge from this search in almost thirty years. Investigations into its mechanism of action revealed a key role for serotonin in the pharmacotherapy of anxiety. A variety of serotonergic agents are now in preclinical and clinical development as anxiolytics, including 5-HT1A partial agonists, 5-HT2 antagonists, and 5-HT3 antagonists. In addition to the new drugs which will be developed as a consequence of these investigations, their clinical efficacy will prompt the development of new animal models of psychopathology, leading us ever closer to a full understanding of the neurobiological substrates of anxiety. In addition, deployment of these new agents in the armamentaria of the clinician and the basic scientist will lead to new insights into the treatment of other disorders and the biochemical mechanisms by which the effects of these drugs are obtained.

Pharmacology and Neurochemistry of Trazodone

Trazodone possesses a different pharmacological profile from that of conventional antidepressants. It is not a monoamine oxidase inhibitor, and it is not active in the major behavioral tests used to identify antidepressant activity. In addition to its antidepressant activity, the behavioral pharmacology of trazodone includes analgesic, antianxiety, and sedative components. The significant biochemical actions of trazodone are selective inhibition of 5-hydroxytryptamine (5-HT) uptake and interaction with 5-HT2 binding sites. It is not yet known if those two phenomena are related or even clinically relevant. However, in view of the time course of trazodones action, it would seem that these selective effects following chronic administration may constitute its mechanism of antidepressant action.

Unique modulation of central 5-HT2 receptor binding sites and 5-HT2 receptor-mediated behavior by continuous gepirone treatment

The effect of continuous treatment with the selective 5-HT1A agonist gepirone upon 5-HT2-mediated behavior and cortical 5-HT2 receptor binding sites was examined in naive rats or rats receiving noradrenergic (DSP4) or serotonergic (5,7-DHT) lesions. Continuous administration of gepirone in non-lesioned rats for 3, 7, or 14 days enhanced the head shake response to the 5-HT agonist quipazine. This enhancement of 5-HT2-mediated behavior occurred despite concomitant down-regulation of cortical 5-HT2 binding sites. However, 28 days of gepirone administration significantly reduced behavioral responsiveness to quipazine. The gepirone-induced facilitation of 5-HT2-mediated behavior observed after 7 days of continuous treatment was blocked in both DSP4 and 5,7-DHT-lesioned rats. However, both noradrenergic and serotonergic denervation failed to modify the down-regulation of 5-HT2 receptor binding sites produced by continuous gepirone administration. These results suggest that the curious dissociation of behavioral and biochemical indices of 5-HT2 receptor function produced by continuous gepirone treatment may be the result of a dual yet separate action of the drug on central presynaptic noradrenergic and serotonergic mechanisms and postsynaptic 5-HT receptors. Furthermore, the postsynaptic action of gepirone which reduces the maximal number of cortical 5-HT2 receptor binding sites may be the result of gepirones agonist action at postsynaptic 5-HT1A receptors.

H1 antihistamines interact with central sigma receptors

Several antihistamines were evaluated for their ability to interact with sigma, muscarinic and histaminic H1 binding sites in rat brain preparations. All of the antihistamines were able to interact with the sigma site, as well as the other two sites. In addition, tripelennamine was found to elicit sigma-like behaviors when administered to rats. This affinity for the sigma site suggests that the compounds may elicit some of their undesirable CNS side effects via this interaction.

Treatment with trazodone plus phenoxybenzamine accelerates development of decreased type 2 serotonin binding in rat cortex

Abstract Combined administration of phenoxybenzamine with the antidepressant trazodone for four days produced a decrease in rat cerebral cortical type 2 serotonin binding as measured with [3H]spiperone. Trazodone alone had no effect on type 2 serotonin binding or β-adrenergic binding as measured with [3H]dihydrolprenolol, during this same time period.

Buspirone: An anxioselective alternative for the management of anxiety disorders

Buspirone HCl (Buspar) is a novel anxiolytic agent unrelated to the benzodiazepines or other psychotherapeutic agents. Animal studies support an anxioselective profile, i.e. relief of anxiety without sedation, muscle relaxation or anticonvulsant activity. Double-blind clinical studies show buspirone to be effective in the treatment of anxiety and anxiety in the presence of depression. The effects of buspirone on psychomotor function, physical dependence and abuse potential tests are similar to those seen with placebo treatments. Mechanism of action studies indicate activity in a variety of neuronal systems.

THE INTERACTION OF TRAZODONE WITH RAT BRAIN MUSCARINIC CHOLINOCEPTORS

The muscarinic receptor binding of trazodone, a new nontricyclic antidepressant, was compared with established tricyclic antidepressants. The ability to inhibit the binding of [3H]‐quinuclidinyl benzilate in vitro was used for comparing atropine‐like effects. Trazodone was found to have essentially no activity at the muscarinic acetylcholine binding site in comparison to the tricyclic antidepressants.

SYNTHESIS AND EVALUATION OF N-SUBSTITUTED 1-(5-FLUORO-2-PYRIMIDINYL)PIPERAZINE DERIVATIVES AS POTENTIAL ANTI-ISCHEMIC AGENTS

Abstract A number of N-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives were prepared and evaluated for binding to sigma and serotonin 5-HT 1A and 5-HT 2 receptor subtypes as well as for their protection against nitrogen anoxia-induced lethality in rats. Although various compounds exhibited good binding affinity and/or anti-anoxic effects, there was no obvious correlation between their receptor binding and in vivo effects.