Livia Alleva

SK channels control the firing pattern of midbrain dopaminergic neurons in vivo

A vast body of experimental in vitro work and modelling studies suggests that the firing pattern and/or rate of a majority of midbrain dopaminergic neurons may be controlled in part by Ca2+‐activated K+ channels of the SK type. However, due to the lack of suitable tools, in vivo evidence is lacking. We have taken advantage of the development of the water‐soluble, medium potency SK blocker N‐methyl‐laudanosine (CH3‐L) to test this hypothesis in anaesthetized rats. In the lateral ventral tegmental area, CH3‐L iontophoresis onto dopaminergic neurons significantly increased the coefficient of variation of their interspike intervals and the percentage of spikes generated in bursts as compared to the control condition. The effect of CH3‐L persisted in the presence of a specific GABAA antagonist, suggesting a direct effect. It was robust and reversible, and was also observed in the substantia nigra. Control experiments demonstrated that the effect of CH3‐L could be entirely ascribed to its blockade of SK channels. On the other hand, the firing pattern of noradrenergic neurons was much less affected by CH3‐L. We provide here the first demonstration of a major role of SK channels in the control of the switch between tonic and burst firing of dopaminergic neurons in physiological conditions. This study also suggests a new strategy to develop modulators of the dopaminergic (DA) system, which could be of interest in the treatment of Parkinsons disease, and perhaps other diseases in which DA pathways are dysfunctional.

Involvement of the brain histaminergic system in addiction and addiction-related behaviors: a comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence.

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence.

Therapeutic potential of histaminergic compounds in the treatment of addiction and drug-related cognitive disorders.

Addiction is a behavioral disorder characterized by the compulsive seeking and taking of drugs despite serious negative consequences. In particular, the chronic use of drugs impairs memory and cognitive functions, which aggravates the loss of control over drug use and complicates treatment outcome. Therefore, cognitive enhancers targeting acetylcholine have been proposed to treat addiction. Interestingly, histamine H(3) receptor (H(3)R) antagonists/inverse agonists stimulate acetylcholine transmission in different brain areas, facilitate memory in animal models and can reverse learning deficits induced by drugs such as scopolamine, dizocilpine and alcohol. Moreover, several studies found that compounds capable of activating the histaminergic system generally decrease the reinforcing effects of drugs, namely alcohol and opioids, in preclinical models of addiction. Finally, several H(3)R antagonists/inverse agonists increase histamine in the brain and have proven to be safe in humans. However, no studies have yet investigated the therapeutic potential of cognitive enhancing H(3)R antagonists/inverse agonists in the treatment of addiction in humans. The present review first describes the impact of addictive drugs on learning processes and cognitive functions that play an important role for addicts to remain abstinent. Second, our work briefly summarizes the relevant literature describing the function of histamine in learning, memory and drug addiction. Finally, the potential therapeutic use of histaminergic agents in the treatment of addiction is discussed. Our review suggests that histaminergic compounds like H(3)R antagonists/inverse agonists may improve the treatment outcome of addiction by reversing drug-induced cognitive deficits and/or diminishing the reinforcing properties of addictive drugs, especially opioids and alcohol.

Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers

So far, small conductance Ca(2+)-activated K(+) channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K(i)=293nM) approximately 100-fold higher than the tertiary compound laudanosine (K(i) approximately 30muM) and similar to the charged compound dequalinium (K(i)=221nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets.