Gerald Zernig

Widening potential for Ca2+ antagonists: non-L-type Ca2+ channel interaction

In addition to their well characterized interaction with the alpha 1 subunit of the voltage-dependent L-type Ca2+ channel, certain Ca2+ antagonists have been reported to modulate an increasing number of cellular functions as diverse as extrusion of cytotoxic substances, or cleavage of cAMP by phosphodiesterase. Some of these interactions (such as the reversal of multidrug resistance by Ca2+ antagonists for the treatment of lymphoma patients) have already been exploited clinically; some (such as protection of ischemic tissue by Ca2+ antagonists interacting with mitochondrial sites) open new therapeutic issues. In this survey of the non-L-type channel Ca2+ antagonist target structures known to date, Gerald Zernig evaluates the available data and emphasizes common characteristics shared by the seemingly diverse target structures. Research on these sites might help to understand yet unexplained effects of Ca2+ antagonists and possibly lead to the development of novel drugs with higher selectivity for non-L-type Ca2+ channel structures.

Activation of Muscarinic and Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Core Is Necessary for the Acquisition of Drug Reinforcement

Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of ∼10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Our findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

Intravenous administration of ecstasy (3,4-methylendioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo.

The effect of intravenous administration of 3,4-methylendioxymethamphetamine (MDMA), in a range of doses (0.32-3.2 mg/kg) that have been shown to maintain self-administration behaviour in rats, on in vivo acetylcholine release from rat prefrontal cortex and dorsal striatum was studied by means of microdialysis with vertical concentric probes. Intravenous administration of MDMA dose-dependently increased basal acetylcholine release from the prefrontal cortex to 57+/-21%, 98+/-20%, 102+/-7% and 141+/-14% above baseline, at doses of 0.32, 0.64, 1.0 and 3.2 mg/kg, respectively. MDMA also stimulated striatal acetylcholine release at the dose of 3.2 mg/kg i.v. (the maximal increase being 32+/-3% above baseline) while at the dose of 1 mg/kg i.v., MDMA failed to affect basal acetylcholine output. Administration of MDMA also dose-dependently stimulated behaviour. The results of the present study show that MDMA affects measures of central cholinergic neurotransmission in vivo and suggest that at least some of the psychomotor stimulant actions of MDMA might be positively coupled with an increase in prefrontal cortical and striatal acetylcholine release.

A study of the mode and site of action of capsaicin in guinea-pig heart and rat uterus.

Summary1.Capsaicin (CAP) has been shown to exert a selective neurotoxic effect on peptidergic primary afferent neurons. The effect of CAP on the isolated guinea-pig left auricle and papillary muscle preparations and on the isolated rat uterus was used to elucidate its mode and site of action with regard to cellular Ca2+ utilization.2.In the electrically driven left auricle CAP first increased and then decreased the size of the contractions while in the electrically driven papillary muscle CAP caused only a decrease in the contractions. Electrophysiological measurements showed that the initial increase in contraction size coincided with a decrease in the upstroke velocity of the action potential. This membrane-stabilizing effect of CAP seemed also responsible for the decrease in contractile activity.3.The positive inotropic effect of CAP on the left auricle was concentration-dependent (0.03–6.5 μM). The positive inotropic effect of 0.33 μM CAP was reproducible at intervals of 15 min, whereas tachyphylaxis developed at shorter intervals or higher concentrations of CAP. The percent increase in the size of contractions by 0.33 μM CAP was smaller when [Ca2+]e was double but larger when 2.2 μM verapamil or 0.1 mM La3+ was present. The increase in contractions by 0.4–400 μM isoproterenol was greatly reduced by 0.33 μM CAP in a noncompetitive manner. The positive inotropic effect of 2.9 μM glucagon was also inhibited by 0.33 μM CAP.4.In the isolated anoestrous rat uterus 0.03–3.3 μM CAP caused a transient inhibition of the spontaneous contractions similarly to the effect of 2.2 μM verapamil.5.It is concluded that the positive inotropic effect of CAP in the left auricle may be due to an increase in [Ca2+]i which does not result from a transmembraneous influx of Ca2+ but probably from a release of Ca2+ from stores inaccessible to either verapamil and La3+. The negative inotropic effect of CAP and the inhibition of the positive inotropic effects of isoproterenol and glucagon may be explained by an unspecific membrane-stabilizing effect of CAP. A membrane-stabilizing effect may also be responsible for the CAP-induced inhibition of the spontaneous contractions of the rat uterus.

Handbook of alcoholism

Unassisted Emergency Management of Acute Alcohol Intoxication PATIENT CARE Screening and Diagnosis First Contact and Early Intervention Natural History Laboratory Parameters Psychometric Screening Instruments Acute Treatment Acute Alcohol Intoxication Alcohol Withdrawal Syndrome Alcohol-Induced Psychotic Disorders Treatment of Alcohol Abuse and Dependence Overview and Outlook Psychotherapy Pharmacotherapy Adolescent Patients Geriatric Patients Women Primary Care Setting Treatment of Non-Psychiatric Alcohol-Related Disorders Nervous System Liver Gastrointestinal System and Pancreas Cardiovascular System Kidney and Electrolyte Disturbances Immune System Endocrine Disorders Vitamin Deficiencies, Zinc Deficiency, and Anaphylactic Reactions Skin Alcohol Embryopathy RESEARCH Epidemiology Comorbidity Heritability Pathogenesis of Alcoholic Liver Disease Harmful Alcohol Consumption Psychometric Instruments to Evaluate Outcome in Alcoholism Treatment Meta-Analysis of Pharmacotherapeutic Trials Calculating a Meta-Analysis on Your Own Patient-to-Treatment Matching Molecular Pharmacology and Neuroanatomy Behavioral Pharmacology Controversial Research Areas USEFUL DATA AND DEFINITIONS Physicochemical Properties of Ethanol How to Calculate Maximum Blood Alcohol Levels After A Drinking Event Basic Pharmacokinetics of Ethanol Drug Interactions With Alcohol Definitions of a Standard Drink Harmful Alcohol Consumption DSM-IV and ICD-10 Definitions of Alcohol Alphabetical List of Psychometric Instruments Including Validated Translations Useful (Internet) Addresses Abbreviations Used Alcohol of Common Drinks and Unit Conversion Table

Different stereoselective effects of (R)- and (S)-propafenone : clinical pharmacologic, electrophysiologic, and radioligand binding studies

Propafenone is a class 1c antiarrhythmic agent with moderate β‐blocking activity as a result of a structural similarity to β‐adrenoceptor antagonists. In a randomized, double‐blind crossover exercise study, eight healthy volunteers were examined before and 2½ hours after oral administration of 300 mg (R,S)‐, 150 mg (R)‐, and 150 mg (S)‐propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)‐propafenone hydrochloride (− 5.2%; p = 0.045) and half‐dosed (S)‐propafenone hydrochloride (−5.9%; p = 0.013), whereas the (R)‐enantiomer caused no significant changes. There was a significant difference between the effects of (R)‐ and (S)‐propafenone (p = 0.033). In β‐adrenoceptor–binding inhibition experiments with (S)‐(125I)iodocyanopindolol in a sarcolemmaenriched cardiac membrane preparation, the eudismic ratio of (S)‐ over (R)‐propafenone was 54. On the spontaneously beating Langendorff‐perfused guinea pig heart, 3 · 10−6 mol/L of both (R)‐ and (S)‐propafenone resulted in significant changes (p < 0.01) on His bundle conduction (+ 79% ± 27% and + 69% ± 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (−54% ± 10% and −57% ± 8%) and ventricular myocardium (−42% ± 6% and −43% ± 6%), indicating equal effects in sodium channel–dependent antiarrhythmic class 1 activity. Thus (R)‐ and (S)‐propafenone exert different β‐blocking actions but equal effects on the sodium channel–dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of β‐blocking side effects may be attained with optically pure (R)‐propafenone hydrochloride instead of the currently used racemic mixture.

A randomized trial of short psychotherapy versus sustained-release bupropion for smoking cessation.

AIMSnTo compare the efficacy and safety of a novel psychological intervention for smoking cessation called psychodynamic model (PDM) training to an active control condition of sustained-release bupropion.nnnDESIGNnRandomized controlled clinical trial with allocation concealment.nnnSETTINGnPrivate psychiatric practice.nnnPARTICIPANTSnSeven hundred and seventy-nine adult smokers recruited by advertising.nnnINTERVENTIONSnPDM training (n = 366 participants) consisted of a very brief (1.5 days) psychoeducation and a supervised training in autosuggestion techniques (guided imageries) aimed at enhancing self-management, decidedness, assertiveness, security and competence in relationships, natural functions of organs and awareness of bodily functions. Bupropion SR (n = 413) was increased to 150 mg twice daily over 1 week and given over a 8-week period.nnnMEASUREMENTSnTwelve-month continuous abstinence confirmed by exhaled carbon monoxide (CO) of 9 parts per million (p.p.m.) or less at all interviews conducted at 3, 6 and 12 months.nnnFINDINGSnIntention-to-treat analysis revealed Russell standard 12-month continuous abstinence rates of 39.1% in the psychotherapy group versus 12.3% in the bupropion SR group (P < 0.001) with a relative benefit (RB) of 3.16 (2.38-4.26). Completer analysis revealed 12-month continuous abstinence rates of 39.9% in the psychotherapy group versus 22.5% in the bupropion group [P < 0.001; RB 1.78 (1.35-2.34)]. Of note, bupropion abstinence rates were comparable to previous medications/placebo-only comparisons in geographically different samples.nnnCONCLUSIONSnThe 1.5-day psychotherapy exceeded bupropions efficacy, presenting an alternative to pharmacological smoking cessation aids, especially for smokers who reject drugs to treat their substance dependence, at a similar cost (Euro 350) as the bupropion treatment (Euro 355).

Stereoselective binding of niguldipine enantiomers to α1A-adrenoceptors labeled with [3H]5-methyl-urapidil

[3H]5-Methyl-urapidil, a potent antihypertensive derivative of urapidil, binds to alpha 1A-adrenoceptors in rat brain cortex membranes with a dissociation constant (KD) of 0.89 nM and a Bmax of 116 fmol/mg protein. The ligand does not bind to purified liver cell membranes (alpha 1B-adrenoceptors). [3H]5-Methyl-urapidil also labels 5-HT1A receptors in brain membranes (KD: 0.84 nM and Bmax: 235 fmol/mg protein). (+/-)-Niguldipine, a novel 1,4-dihydropyridine with Ca2+-antagonistic as well as alpha 1A-adrenoceptor blocking properties, is a competitive inhibitor of [3H]5-methyl-urapidil binding to alpha 1A-adrenoceptors. In contrast to those for prazosin, the Ki values for niguldipine were highly dependent on the membrane protein concentration, indicating partitioning of niguldipine into hydrophobic compartments unavailable for alpha-adrenoceptor interaction. The extrapolated, true Ki values were as follows: (+/-)-niguldipine: 0.298 nM, (-)-niguldipine: 3.12 nM, (+)-niguldipine: 0.145 nM.

Pharmacotherapy of alcohol dependence

The current pharmacotherapeutic approaches to alcohol dependence, together with the results of a number of clinical trials, are reviewed in this article. Despite the somewhat disappointing clinical results, pharmacotherapeutic interventions did lead to some small, but significant, improvements in alcohol abstinence rates.

Sigma1 Receptor Antagonist BD1047 Enhances Reversal of Conditioned Place Preference from Cocaine to Social Interaction

We have previously shown that only four 15-min social interaction episodes with a male adult conspecific reversed cocaine conditioned place preference (CPP) even despite continuing CPP training with cocaine. In the present study, we investigated if BD1047, a sigma1 receptor antagonist that has been shown to inhibit the expression of cocaine CPP, is able to enhance this effect. BD1047, given as a 10-min pretreatment, dose-dependently (ED50 of 0.0036 mg/kg i.p.) decreased the time spent in the previously cocaine-associated compartment in favour of the time spent in the compartment in which a single social interaction had taken place. Our findings indicate that sigma1 blockade may be used therapeutically to enhance treatment adherence in social interaction-based rehabilitation programs.