Michael S. Eison

Serotonergic mechanisms in the behavioral effects of buspirone and gepirone

The literature describing the role of serotonin (5-HT) in the mediation of anxiety is a controversial one. Serotonergic involvement in the mechanism of action of two nonbenzodiazepine anxiolytics, buspirone and gepirone, supports a role for serotonin in anxiety. The anticonflict effect of both drugs is blocked by serotonin lesions, and gepirone induces the serotonin syndrome. A shift in the gepirone dose-response curve to the left in serotonin lesioned rats suggests that this may be 5-HT-receptor mediated. Both buspirone and gepirone enhance the acoustic startle response and gepirones effect is attenuated in serotonin lesioned animals. While other components of buspirones mechanism of action may suppress the behavioral expression of its serotonergic interactions, results from these studies suggest that serotonin agonist-like activity may be an important mechanism in the actions of a clinically proven nonbenzodiazepine anxiolytic (buspirone), and anxiolytic candidate (gepirone).

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.

Neuropharmacology of Buspirone

Buspirone is a clinically effective anxiolytic with a unique structure and pharmacology which distinguishes it from the benzodiazepines. It has been termed anxioselective because it lacks anticonvulsant, sedative, or muscle-relaxant properties. Preclinical evidence suggests it lacks potential for abuse or physical dependence and interacts minimally with CNS depressants such as alcohol. Rather than working through traditional benzodiazepine mechanisms, buspirone affects diverse aspects of the brains neurochemical circuitry. For example, it exerts potent influences on the nigrostriatal and mesolimbic dopamine systems, the dorsal raphe serotonergic system, and the locus coeruleus noradrenergic system. Although without direct receptor interaction, potentiation of cholinergically mediated behavior and involvement with GABAergic neurotransmission have also been demonstrated.

Serotonergic mechanisms in anxiety

1. Anatomical, behavioral, neurochemical and electrophysiological evidence collectively support a role for central 5-HT in the modulation of anxiety and the anti-anxiety action of the benzodiazepines. 2. The advent of selective agonists and antagonists for 5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3) has rekindled investigation of the role of 5-HT in anxiety mechanisms. 3. The azapirones represent a new class of agent which possesses affinity for 5-HT1A receptors (partial agonists) and is active in anxiolytic animal models as well as in the clinic (buspirone) 4. While preclinical data supporting the anxiolytic potential of 5-HT2 antagonists remains controversial, a recent clinical study supports ritanserins anxiolytic effects. 5. Several animal models support the anxiolytic potential of the 5-HT3 antagonist odansetron (GR38032F). Confirmation of its therapeutic utility awaits clinical results.

Effects of imipramine and serotonin-2 agonists and antagonists on serotonin-2 and beta-adrenergic receptors following noradrenergic or serotonergic denervation.

The effects of chronic (14 day) administration of the tricyclic antidepressant imipramine, the serotonin-2 (5-HT2) antagonist ketanserin, and the serotonin agonist quipazine on 5-HT2 receptor binding parameters and 5-HT2-mediated behavior were examined in rats with or without prior serotonergic denervation [via 5,7-dihydroxytryptamine (5,7-DHT)] or noradrenergic denervation [via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)]. Chronic administration of imipramine, ketanserin, or quipazine produced a marked reduction in the number of 5-HT2 binding sites which was accompanied by reductions in the 5-HT2-mediated quipazine-induced head shake response. In animals receiving DSP4 or 5,7-DHT lesions and continuous vehicle treatment, beta-adrenergic receptor binding sites were significantly up-regulated while 5-HT2 receptor binding sites did not change. Imipramine normalized the lesion-induced increases in beta-adrenergic binding observed in DSP4 and 5,7-DHT-lesioned rats but failed to down-regulate beta-adrenergic binding sites below non-lesioned control levels. Chronic imipramine, ketanserin, and quipazine reduced quipazine-induced head shakes and down-regulated 5-HT2 binding sites in rats with noradrenergic denervation. While imipramine, ketanserin, and quipazine all down-regulated 5-HT2 binding sites in animals with serotonergic denervation, only imipramines ability to reduce quipazine-induced head shakes was attenuated in 5,7-DHT-lesioned rats. The present results suggest that imipramine-induced down-regulation of 5-HT2 receptors may not involve presynaptic 5-HT mechanisms, and imipramine-induced alterations in 5-HT2 sensitivity as reflected in the quipazine-induced head shake may, in part, be influenced by beta-adrenergic receptors.

The new generation of serotonergic anxiolytics: possible clinical roles.

Serotonin has been implicated in mediating diverse physiologic and psychologic processes. The anatomy and complex pharmacology of brain-serotonin systems enables this neurotransmitter to broadly affect normal and abnormal behaviors. It appears that serotonin plays a role in multiple psychopathologies, including anxiety, depression, mood disorders, aggressive acting out, alcohol-related syndromes, and disinhibitory disorders characterized by impulsivity. It would not be surprising, therefore, if drugs that alter the dynamics of serotonergic neurotransmission prove to be effective in multiple clinical settings. Such agents may treat broad symptom clusters common to multiple nosologic categories. The new generation of serotonergic anxiolytics, including buspirone, gepirone, ipsapirone, and SM-3997, which interact potently with 5-hydroxytryptamine-1A receptors, may prove to be such symptom cluster drugs. There is a scientific rationale for exploring the clinical utility of these agents in anxiety, depression, mood disorders, aggressive syndromes, and alcohol-related disorders.

The nootropic compound BMY-21502 improves spatial learning ability in brain injured rats

Although long-lasting cognitive dysfunction often follows clinical traumatic brain injury (TBI), few pharmacologic regimens have been developed to treat post-traumatic cognitive deficits. We have previously shown that, in the rat, experimental lateral fluid-percussion (FP) brain injury induces a profound impairment in retrograde memory. In the present study, we characterized alterations in the ability of rats to learn a novel task following lateral FP brain injury and examined the potential modulatory effects of the nootropic cognitive enhancer BMY-21502 on post-injury learning. Male Sprague-Dawley rats were subjected to lateral (parasagittal) FP brain injury of moderate severity (2.4 atm) or sham surgery (no injury). On days 7 and 8 post-injury, animals were tested in a Morris water maze for their ability to learn to navigate to a submerged, invisible platform using external visual cues. BMY-21502 (10 mg/kg) or vehicle was administered 30 min prior to the first trial on both days. A highly significant (P < 0.001) impairment in post-injury learning was observed in vehicle-treated brain-injured animals compared with vehicle-treated sham animals. Injured animals treated with BMY-21502 at one week post-injury showed significantly (P < 0.05) improvement in post-injury learning ability compared to injured animals treated with vehicle. Paradoxically, in uninjured control animals BMY-21502 treatment appeared to worsen learning scores. The results of this study indicate that BMY-21502 may be useful for attenuating the dysfunction in learning ability that occurs following TBI.

Use of Animal Models: Toward Anxioselective Drugs

The debilitating psychopathology of anxiety neurosis is particularly amenable to relief by pharmacotherapy. While currently available drugs successfully alleviate the distressing symptoms suffered by anxious patients, they also carry potential liabilities which must be considered in their use. Through the use of predictive animal models, researchers hope to elucidate a set of structure-activity relationships through which anxiolytic, and most particularly anxioselective compounds can be rationally designed. Such models should predict side-effect potential as well as efficacy, so that unwanted ancillary effects of potential anxiolytics can be eliminated by appropriate structural modifications. The state of the art in preclinical testing for anxiolytic potential will be discussed with particular emphasis on the need to design test systems capable of detecting anxiolytic activity in diverse, nontraditional chemical series. The contribution of such methodology to the discovery and development of one anxioselective, non-benzodiazepine anxiolytic, buspirone, will be discussed.

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.

Lack of Withdrawal Signs of Dependence following Cessation of Treatment or Ro-15,1788 Administration to Rats Chronically Treated with Buspirone

Failure to gain weight during withdrawal from chronic regimens of dependence-producing drugs is observed in laboratory rats. Withdrawal from the benzodiazepine anxiolytic agent diazepam, whether induced by cessation of treatment or precipitated by administration of the specific benzodiazepine antagonist Ro-15,1788, is accompanied by weight loss. However, the same withdrawal treatments following a chronic regimen of equal doses of the nonbenzodiazepine antianxiety drug buspirone are not associated with weight loss. Buspirone-treated rats gain weight during withdrawal, suggesting that this novel anxiolytic should lack dependence liability in man.