Neuropharmacology of paroxetine

Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with some neuropharmacologic properties unique among this class of compounds. The findings of early in vitro studies demonstrated the potency of paroxetine at inhibiting 5-HT uptake in rat synaptosomes. Paroxetine also has been shown to be a potent and selective inhibitor of the human serotonin transporter (SERT) and has recently been demonstrated to have moderate affinity for the norepinephrine transporter (NET). Because of the affinity and in vitro selectivity of this SSRI, tritiated paroxetine is now widely used as a marker for SERT in laboratory settings, and its use has advanced our understanding of neurotransmitter function in the brain and periphery. The in vivo pharmacologic properties of paroxetine are well characterized, especially following acute administration. However, the pharmacologic effects of chronically administered paroxetine remain an active area of study. Paroxetine administration in laboratory animals has been shown to be associated with decreased SERT density and function, maintenance of normal firing rates and release of 5-HT, and increased activation of postsynaptic 5-HT receptors. Using a novel ex vivo assay, we have demonstrated that paroxetine exhibits dose-related inhibition of the NET in patients treated for depression. At usual clinical doses (ie, 20 mg/d), paroxetine is a potent and selective inhibitor of the SERT; however, at higher doses (ie, 40 mg/d), paroxetine can exhibit marked NET inhibition. The application of these findings of in vivo NET inhibition by paroxetine in the treatment of mood and anxiety disorders will be informed by further clinical studies.     

Neuropharmacology of alcohol addiction

Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA(A), glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca(2+) channels and G-protein-activated inwardly rectifying K(+) channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcohol-seeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones.     

Neuropharmacology of 5-hydroxytryptamine

This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders.     

Neuropharmacology of addiction--setting the scene

Addiction is a complex disorder, affecting not only the individual addict, but also their family and the community at large. While therapeutic strategies are available for the treatment of some forms of substance abuse/dependence, these are not without problems and are not universally efficacious. Moreover, in some instances (for example, cocaine addiction), there are still no medications specifically registered as treatment options. In this themed issue of the British Journal of Pharmacology, we highlight a number of addictions from a pharmacological perspective, with an emphasis on both mechanism and potential therapeutic approaches that are either under development or reflect preclinical work. As such, the authors endeavour to describe the latest thinking on the neural theory of addiction and corresponding novel pharmacotherapeutic targets, and in this way to set the stage for future advances in research and drug development. In addition, we have also attempted to draw attention to the clinicians' perspective in terms of the interface between basic science and care provision.     

Neuropharmacology of learned flavor preferences

Innate and learned flavor preferences influence food and fluid choices in animals. Two primary forms of learned preferences involve flavor-flavor and flavor-nutrient associations in which a particular flavor element (e.g., odor) is paired with an innately preferred flavor element (e.g., sweet taste) or with a positive post-oral nutrient consequence. This review summarizes recent findings related to the neurochemical basis of learned flavor preferences. Systemic and central injections of dopamine receptor antagonists implicate brain dopamine signaling in both flavor-flavor and flavor-nutrient conditioning by the taste and post-oral effects of sugars. Dopamine signaling in the nucleus accumbens, amygdala and lateral hypothalamus is involved in one or both forms of conditioning and selective effects are produced by D1-like and D2-like receptor antagonism. Opioid receptor antagonism, despite its suppressive action on sugar intake and reward, has little effect on the acquisition or expression of flavor preferences conditioned by the sweet taste or post-oral actions of sugars. Other studies indicate that flavor preference conditioning by sugars is differentially influenced by glutamate receptor antagonism, cannabinoid receptor antagonism and benzodiazepine receptor activation.     

Neuropharmacology of the autonomic vestibular syndrome

It was found during studies on man and experiments on animals that various neuromediator systems of the organism (M-cholinergic, H1-histaminergic, dopaminergic, and opioidergic) are involved in the genesis of VVS. In addition, animal experiments showed that of great importance in the process are different regulatory peptides, in particular, substance P and beta-endorphin. The findings indicate that some neuropeptides may be used in the future in man for VVS prevention. At neuronal level the role of opioid peptides in realization of vestibulovegetative reactions is decoded and a number of possible mechanisms of their action is established. The study of the human hormonal status in VVS revealed complex neuroendocrine changes occurring in the organism. Based on the knowledge of some neurohormonal and neurochemical mechanisms of VVS pathogenesis, a new drug prevention and therapy of seasickness was proposed, efficacy of opioid antagonists naloxone and nalorphine was shown.     

Neuropharmacology of a new psychotropic 2,3-benzodiazepine

1-(3-Chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 51189) is a new analogue of tofisopam. Due to the novel chemical structure this molecule displays a peculiar spectrum of pharmacological activity. In many respects tofisopam and its new analogue differ from the traditional 1,4-benzodiazepines, e.g. in that they possess selective anxiolytic action without muscle relaxant and anticonvulsive activity, as well as they do not show any affinity for the 1,4-benzodiazepine receptors. This new compound exerts more pronounced anxiolytic potency than tofisopam. In addition to its main action it possesses significant antidepressant activity. It attenuates psychomotor agitation and exerts significant antiaggressive effect by reducing both spontaneous and induced aggressiveness. Vegetative responses (rise in blood pressure and heart rate) induced by electric stimulation of the hypothalamus are also inhibited by this compound, while motor functions remain unaffected and no somnolence is induced. The new tofisopam analogue fails to exert any potentiating effect either on ethanol or on barbiturates. GYKI-51189 has a highly favourable therapeutic index and only few side effects. Neither tolerance nor dependence was observed during the chronic toxicological investigations.     

Neuropharmacology of zonisamide,a new antiepileptic drug

• 1.1. Zonisamide readily crosses the blood-brain barrier and is readily absorbed after oral administration with a T_max of about 3 hr.
• 2.2. The half-life of ZNA in epileptic patients is about 28 hr.
• 3.3. Zonisamide has a broader therapeutic range than other antiepileptic drugs.
• 4.4. Neurotoxic, hemapoietic, renal, and liver effects have been minimal in patients participating in controlled clinical studies.
• 5.5. It is effective in several experimental models of epilepsy and in initial clinical trials has been shown to be effective in generalized tonic-clonic, simple, and complex partial seizures.

     

Neuropharmacology of an Extract Derived from Centella asiatica

The hydroalcoholic extract of Centella asiataica L. leaves was subjected to pharmacological screening using various experimental models. The extract was found to show protective action against increase in current electroshock (ICES) and chemoconvulsions, which includes pentylenetetrazol-induced convulsions, pentylenetetrazol-kindled seizures, and strychnine-induced opisthotonus tonic convulsions. It also showed a reduction in formation of lipid peroxidation products, reduction in spontaneous motor activity, potentiation in diazepam withdrawal-induced hyperactivity, hypothermia, and potentiation of pentobarbitone sleeping time. An extract was administered orally to the animals in all the studies. The extract (200 mg/kg body weight) completely inhibited pentylenetetrazol-induced convulsions. In pentylenetetrazol-kindled seizures and strychnine-induced convulsions, the extract showed protection at a dose of 100 mg/kg body weight. The doses of the extract of selected for remaining studies were based on pilot studies, animal model used, and so forth. These findings suggest that C. asiatica extract possesses potential anticonvulsant, antioxidant, and central nervous system depressant actions.     

Niax Catalyst Esn: Subchronic Neuropharmacology and Neurotoxicology

ABSTRACT

NIAX catalyst ESN (a mixture of 95% DMAPN/dimethylamino-proprionitrile and 5% A-99/bis-dimethylaminoethyl ether) was a catalyst used in the production of polyurethane foam which was reported to produce a reversible peripheral neuropathy in workers exposed to it. ESN and its two components were tested by a variety of short term tests for neurologic activity. In vivo (rat and mouse) and in vitro (isolated tissue) assays were employed.

Both ESN and DMAPN at dose levels of 0.25 ml/kg IP (intraperitoneally) produced tremors, convulsions, and cardiovascular effects in rats and mice. At doses as low as 0.01 ml/kg both ESN and DMAPN also induced a loss of micturition reflex in rats. A-99, though more lethal, caused no neurologic or reflex effects at doses up to 1.0 ml/kg. DMAPN was concluded to be the causative agent.     

Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A

Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzón de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolized smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT(2A) receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biological processes responsible for its observed psychological effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.