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Biomedical subjects

C Fahlke

Publications and source records attributed to C Fahlke.

At least 19 recordsLinked to original sources
PubMed2006

Inverse relationship between central serotonergic neurotransmission and blood pressure in alcohol-dependent male subjects.

Data has accumulated indicating an inverse relation between central serotonergic (5-HT) neurotransmission and blood pressure in hypertensive rats and in healthy individuals. The present study aimed to elucidate whether an inverse relation exists between systolic (SBP) and diastolic (DBP) blood pressure levels and central 5-HT neurotransmission also in a group of alcohol-dependent individuals. Central 5-HT neurotransmission was assessed by using the maximum prolactin (PRL) responses to the 5-HT probe DL-fenfluramine (DL-FEN; 60 mg po) in 17 alcohol-dependent male subjects investigated during a period of on-going alcohol intake. BP was measured immediately before all time points for blood sampling, and readings before DL-FEN administration were used as the subjects resting BP. Results showed that there were inverse correlations between the maximum PRL responses to DL-FEN and the SBP levels (r = -0.57, p < 0.002) and with the DBP levels (r = -0.52, p < 0.05), respectively. The present study suggests the existence of an association between central 5-HT neurotransmission and blood pressure regulation also in alcohol-dependent individuals.

Adult↗
PubMed2006

Personality profile in type I alcoholism: long duration of alcohol intake and low serotonergic activity are predictive factors of anxiety proneness.

The aim of the present study was to further investigate personality profiles in male type I alcohol-dependent subjects (n = 33), in relation to central serotonergic neurotransmission, history of excessive alcohol consumption and present use of tobacco. Central serotonergic neurotransmission was assessed by the prolactin (PRL) response to D-fenfluramine. By using the Temperament and Character Inventory and the Karolinska Scales of Personality, all subjects self-rated their personality profile. The results showed that individuals with low PRL response and long duration of excessive alcohol consumption had significantly higher anxiety proneness, and that years of excessive alcohol consumption was the strongest predictor. Long duration of excessive alcohol consumption thus appears to have an influence on personality traits in male type I alcohol-dependent individuals and these personality traits may therefore be a consequence of, rather than preceding, alcoholism in these individuals.

Adult↗
PubMed2005

Platelet monoamine oxidase B (MAO-B) activity and its relationship to DL-fenfluramine-induced prolactin response in healthy men.

Several techniques are used to assess central serotonergic neurotransmission in man, e.g. challenge tests (hormonal and physiological responses to serotonin active drugs), platelet MAO-B activity as well as brain imaging techniques. Little is known about how these tests relate to each other. The aim of the present study was therefore to investigate if platelet MAO-B activity could be related to hormonal and temperature responses to the serotonin active drug DL-fenfluramine in healthy men. Twelve male subjects without any history of psychiatric disorders or drug abuse/dependencies were recruited. Prior to the challenge with 60 mg DL-fenfluramine, which was given orally, blood for determination of platelet MAO-B activity was drawn. Blood samples for determination of serum prolactin and serum cortisol were drawn at baseline and thereafter every hour for the following six hours. In addition, body temperature was measured at the same time-points. Delta-values were calculated as the difference between the baseline values and the highest (prolactin and cortisol) or lowest value (temperature) thereafter. There was a strong positive correlation (r = 0.75, p < 0.02) between platelet MAO-B activity and Delta-prolactin. No correlations were found to Delta-cortisol, Delta-temperature or any of the baseline values. The results support the notion that the peripheral marker platelet MAO-B activity is related to the function of the central serotonergic neurotransmitter system as assessed by the prolactin response to 60 mg DL-fenfluramin.

Adult↗
PubMed2001

Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram.

The relationship between the effect of citalopram on alcohol intake and central serotonergic neurotransmission, as assessed by prolactin (PRL) response to fenfluramine, was investigated in 17 male heavy drinkers. A positive correlation was obtained, suggesting that the status of central serotonergic neurotransmission in individuals is associated with the treatment response to citalopram. When the group of subjects were divided into those with high and low PRL response (above and below median, respectively) to fenfluramine, those with high PRL response had a significant reduction in alcohol intake during citalopram treatment, whereas those with low PRL response had no such effect. Thus, in subjects with evidence of unimpaired or only slightly impaired central serotonergic neurotransmission (high PRL response) citalopram may have beneficial effect on alcohol consumption, whereas in those with more evidently impaired serotonergic neurotransmission (low PRL response) citalopram treatment may have no effect on or may even increase the alcohol consumption.

Adult↗
PubMed2001

No effect of the cortisol-synthesis inhibitor metyrapone on alcohol drinking: a pilot study.

Two bases for this study were the theory of stress as a provoking factor for high alcohol consumption in human being and findings that the stress hormones stimulate ethanol intake in rats. We therefore investigated whether the cortisol-synthesis inhibitor metyrapone could reduce high alcohol consumption in socially stable subjects who reported drinking mainly for relaxation purposes. Most of the investigated subjects were found to be alcohol dependent (81%), with moderately high levels of intake, yet they had not reported more severe life problems. All subjects reported their daily alcohol consumption during 2-week baseline, medication, and postmedication periods. Sixteen subjects were given 1 g of metyrapone orally daily for 14 days, and 15 subjects received placebo. Morning serum cortisol concentration was assessed four times in the course of the study period. Metyrapone treatment was not found to reduce alcohol consumption more than placebo. Serum cortisol concentrations remained within the laboratory reference interval during the study and did not differ between the study groups. In this study, we found that a cortisol-synthesis inhibitor had no effect on alcohol consumption. One reason may be that cortisol secretion has no role in the maintenance of high alcohol consumption. On the other hand, because this study is the first of its kind, further studies using other doses of treatment and treatment schedules are suggested.

Adult↗
PubMed2001

Ion permeation and selectivity in ClC-type chloride channels.

Voltage-gated anion channels are present in almost every living cell and have many physiological functions. Recently, a novel gene family encoding voltage-gated chloride channels, the ClC family, was identified. The knowledge of primary amino acid sequences has allowed for the study of these anion channels in heterologous expression systems and made possible the combination of site-directed mutagenesis and high-resolution electrophysiological measurements as a means of gaining insights into the molecular basis of channel function. This review focuses on one particular aspect of chloride channel function, the selective transport of anions through biological membranes. I will describe recent experiments using a combination of cellular electrophysiology, molecular genetics, and recombinant DNA technology to study the molecular basis of ion permeation and selection in ClC-type chloride channels. These novel tools have provided new insights into basic mechanisms underlying the function of these biologically important channels.

Animals↗
PubMed2000

Residues lining the inner pore vestibule of human muscle chloride channels.

Chloride channels belonging to the ClC family are ubiquitous and participate in a wide variety of physiological and pathophysiological processes. To define sequence segments in ClC channels that contribute to the formation of their ion conduction pathway, we employed a combination of site-directed mutagenesis, heterologous expression, patch clamp recordings, and chemical modification of the human muscle ClC isoform, hClC-1. We demonstrate that a highly conserved 8-amino acid motif (P3) located in the linker between transmembrane domains D2 and D3 contributes to the formation of a wide pore vestibule facing the cell interior. Similar to a previously defined pore region (P1 region), this segment functionally interacts with the corresponding segment of the contralateral subunit. The use of cysteine-specific reagents of different size revealed marked differences in the diameter of pore-forming regions implying that ClC channels exhibit a pore architecture quite similar to that of certain cation channels, in which a narrow constriction containing major structural determinants of ion selectivity is neighbored by wide vestibules on both sides of the membrane.

Amino Acid Sequence↗
PubMed2000

Subsensitive alpha-2-adrenoceptor function in male alcohol-dependent individuals during 6 months of abstinence.

Postsynaptic alpha-2-receptor function, as assessed by growth hormone (GH) response to clonidine (CLON), has been shown to be downregulated in patients investigated in acute but also in late withdrawal after heavy alcohol intake. The results are however sometimes conflicting. The question whether this changed receptor function is a trait or state marker is not fully investigated so far. A total of seven male patients with alcohol dependence according to DSM-IV were assessed for the postsynaptic alpha-2-receptor function with the CLON/GH test (2.0 microg/kg body weight; i.v.) starting immediately after a period of heavy drinking. Neuroendocrine tests were repeated after 7 days, 2 and 6 months. A total of six healthy males were used as controls. The maximum GH responses to CLON were significantly lower on all four test occasions in the patient group as compared to the controls. Furthermore, in the patient group all neuroendocrine test results showed blunted GH responses to CLON. Thus, patients with downregulated alpha-2-receptor function during acute withdrawal after heavy alcohol intake showed similar subsensitive receptor function abnormality after a prolonged period of abstinence. The findings in this study indicate that alcohol dependent individuals have a persistent subsensitive alpha-2-adrenoceptor function which may constitute a trait factor for alcohol dependence.

Adult↗
PubMed2000

Anabolic androgenic steroids affects alcohol intake, defensive behaviors and brain opioid peptides in the rat.

The present study investigated whether a relationship exists between nandrolone decanoate and voluntary ethanol intake in laboratory rats. Animals were subjected to daily subcutaneous injections with nandrolone decanoate (15 mg/kg) during 2 weeks. One group of animals was tested for voluntary alcohol intake 1 week after the end of the 2-week treatment period and another group received alcohol 3 weeks after the treatment. In addition, assessment of defensive behaviors and immunoreactivity (ir) levels of the brain opioid peptides dynorphin B and Met-enkephalin-Arg-Phe (MEAP) were performed. The nandrolone decanoate-treated animals were significantly more aggressive and showed lower fleeing and freeezing reaction than the oil-treated controls. Treatment with nandrolone decanoate enhanced voluntary alcohol intake, regardless if it was presented 1 or 3 weeks after end of the treatment period. These animals had a decreased activity of dynorphin B-ir in the nucleus accumbens, decreased levels of MEAP-ir in the periaqueductal gray (PAG) and higher levels of MEAP-ir in the hypothalamus compared to controls. In line with previous studies, this suggests that the altered dynorphin B-ir activity may promote the rewarding effects of ethanol and thereby increasing alcohol intake, whereas MEAP-ir may be associated with the ability to control the aggressive reaction. Abuse of nandrolone decanoate may thus constitute a risk factor for increased alcohol consumption and defensive aggression. In human, this constellation of behavioral symptoms is closely related to acts of crimes and violence and is often observed among those abusing anabolic androgenic steroids.

Aggression↗
PubMed2000

Cardiovascular responses to clonidine in alcohol withdrawal: are they related to psychopathology and mental well-being?

The possible relationships between alpha-2-adrenoceptor function, as assessed by blood pressure, heart rate, and sedative responses to clonidine (CLON; 1.5 microg/kg, i.v.), and psychopathology and mental well-being were investigated in 19 patients with alcohol-dependence in the early withdrawal period (days 1 and 7). An age-matched control group was used (n=17). CLON-induced maximum reduction of systolic blood pressure was less day 1 in the alcohol-dependent patients compared to controls. CLON was found to induce less sedation at day 7 compared to day 1 and to controls. No relationships were seen between the parameters for alpha-2-adrenoceptor function and psychopathology and mental well-being. These findings suggest that CLON-induced changes in blood pressures and heart rate reflect the cardiovascular situation in alcohol withdrawal and not aspects of behavior.

Adrenergic alpha-Agonists↗
PubMed2000

Molecular mechanisms of ion conduction in ClC-type chloride channels: lessons from disease-causing mutations.

The muscle Cl- channel, ClC-1, is a member of the ClC family of voltage-gated Cl- channels. Mutations in CLCN1, the gene encoding this channel, cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). The functional characterization of these naturally occurring mutations not only allowed a better understanding of the pathophysiology of myotonia, it also provided important insights into the structure and function of the entire ClC channel family. This review describes recent experiments using a combination of cellular electrophysiology, molecular genetics, and recombinant DNA technology to study the molecular basis of ion permeation and selection in ClC-type chloride channels.

Amino Acid Sequence↗
PubMed2000

Rearing experiences and stress-induced plasma cortisol as early risk factors for excessive alcohol consumption in nonhuman primates.

BACKGROUND: The purpose of this study was to assess the impact of early rearing and stress-induced rise of plasma cortisol collected during infancy as a biological predictors of adult alcohol consumption in nonhuman primates. METHODS: Ninety-seven female and male rhesus macaques (Macaca mulatta) were investigated. They were reared for their first 6 months of life either without mothers or other adults but with constant access to same-aged peers (peer-reared), or as controls with their mothers (mother-reared). When subjects reached 6 months of age, they underwent a series of four sequential weeks of 4-day social separations. Blood was drawn 1 and 2 hr after initiation of the 4-day separation periods, and the plasma was assayed for plasma cortisol concentrations. When the subjects were young adults (approximately 50 months of age), they were tested for voluntary intake of alcohol for 1 hr per day, 4 days a week, during a period of 5 to 7 weeks under normal living conditions. RESULTS: The social separation challenge increased infant plasma cortisol concentrations, with peer-reared subjects exhibiting higher stress-induced cortisol concentrations than mother-reared animals. Subjects that responded to the social separation challenge with high cortisol levels consumed significantly more alcohol per kilogram of body weight as adults than subjects with a low cortisol response to the separation challenge, regardless of rearing condition. In addition, male and peer-reared subjects consumed significantly more alcohol than female and mother-reared subjects, respectively. CONCLUSIONS: These findings suggest that early rearing experiences, such as adult absence, and high plasma cortisol concentrations early in life after a social separation stressor, are useful psychobiological predictors of future high alcohol consumption among nonhuman primates.

Alcohol Drinking↗
PubMed1999

Alcohol responsiveness, hyperreactivity, and motor restlessness in an animal model for attention-deficit hyperactivity disorder.

RATIONALE: Attention-deficit hyperactivity disorder and related pervasive developmental disorders constitute risk factors for adult alcohol abuse and antisocial behaviours, including violent offending. OBJECTIVES: The present study assessed alcohol responsiveness and hyperemotionality in neonatally 6-OHDA-treated rats, which provides an animal model for attention-deficit hyperactivity disorder. METHOD: Male Wistar rats were given intracerebroventricular 6-OHDA (100 microg/5 microl) or vehicle (saline-ascorbic acid) on postnatal day 3. In adulthood, we measured motor activity, defensive behaviours and ethanol responsiveness. RESULTS: 6-OHDA resulted in depletions of brain catecholamine levels. The experimental animals were markedly hyperactive, showed increases in active defensive behaviours (fleeing) and decreases in passive defensive responses (freezing) in response to an sudden auditory signal. In tests for reactivity to the experimenter (i.e. defensiveness to innocuous stimuli), 6-OHDA rats were hyperreactive in comparison to controls. With regard to home cage 6% ethanol and water consumption, there were no differences between experimental and control rats. However, 6-OHDA rats displayed a remarkable resistance to the motor-impairing effect of alcohol (0.5-1.0 g/kg, IP). A similar hyposensitivity to the motor-suppressive effect of diazepam (5.0 mg/kg, IP) was also found. CONCLUSIONS: The present results show that adult rats exposed to 6-OHDA as neonates are motorically restless, unusually prone to respond defensively to innocuous stimuli, and considerably less sensitive to the intoxicating effects of ethanol and diazepam.

Alcohol Drinking↗
PubMed1999

A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.

Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.

Amino Acid Sequence↗
PubMed1999

Regulation of the human skeletal muscle chloride channel hClC-1 by protein kinase C.

1. The regulation of a recombinant human muscle chloride channel, hClC-1, by protein kinase C (PKC) was investigated in human embryonic kidney (HEK 293) cells. 2. External application of 4beta-phorbol esters (4beta-PMA) reduced the instantaneous whole-cell current amplitude over the entire voltage range tested. This effect was abolished when the cells were intracellularly perfused with a specific protein kinase C inhibitor, chelerythine. Inactive 4alpha-phorbolesters did not affect the chloride currents. We conclude that the effect of 4beta-phorbol esters is mediated by protein kinase C (PKC). 3. Activation of PKC resulted in changes in macroscopic current kinetics. The time course of current deactivation determined in the presence and absence of 4beta-phorbol esters could be fitted with the sum of two exponentials and a constant value. In the presence of phorbol esters, the fast time constants and the minimum value of the fraction of non-deactivating current were increased, whereas the voltage dependence of all fractional current amplitudes remained unchanged. PKC-induced phosphorylation had only small effects on the voltage dependence of the relative open probability and the maximum absolute open probability was unaffected by treatment with 4beta-PMA, as shown by non-stationary noise analysis. 4. The kinetic changes indicate that phosphorylation alters functional properties of active channels. Since the absolute open probability is not reduced, the observed macroscopic current reduction implies alterations of the ion permeation process. 5. Phosphorylation by PKC appears to affect ion transfer and gating processes. It is postulated that the phosphorylation site may be located at the cytoplasmic vestibule face of the pore.

Alkaloids↗
PubMed1998

Pore stoichiometry of a voltage-gated chloride channel.

Ion channels allow ions to pass through cell membranes by forming aqueous permeation pathways (pores). In contrast to most known ion channels, which have single pores, a chloride channel belonging to the CIC family (Torpedo CIC-0) has functional features that suggest that it has a unique 'double-barrelled' architecture in which each of two subunits forms an independent pore. This model is based on single-channel recordings of CIC-0 that has two equally spaced and independently gated conductance states. Other CIC isoforms do not behave in this way, raising doubts about the applicability of the model to all CIC channels. Here we determine the pore stoichiometry of another CIC isoform, human CIC-1, by chemically modifying cysteines that have been substituted for other amino acids located within the CIC ion-selectivity filter. The CIC-1 channel can be rendered completely susceptible to block by methanethiosulphonate reagents when only one of the two subunits contains substituted cysteines. Thiol side chains placed at corresponding positions in both subunits can form intersubunit disulphide bridges and coordinate Cd2+, indicating that the pore-forming regions from each subunit line the same conduction pathway. We conclude that human CIC-1 has a single functional pore.

Cadmium↗
PubMed1997

Pore-forming segments in voltage-gated chloride channels.

The ability to differentiate between ions is a property of ion channels that is crucial for their biological functions. However, the fundamental structural features that define anion selectivity and distinguish anion-permeable from cation-permeable channels are poorly understood. Voltage-gated chloride (Cl-) channels belonging to the ClC family are ubiquitous and have been predicted to play important roles in many diverse physiological and pathophysiological processes. We have identified regions of a human skeletal muscle ClC isoform that contribute to formation of its anion-selective conduction pathway. A core structural element (P1 region) of the ClC channel pore spans an accessibility barrier between the internal and external milieu, and contains an evolutionarily conserved sequence motif: GKxGPxxH. Neighbouring sequences in the third and fifth transmembrane segments also contribute to isoform-specific differences in anion selectivity. The conserved motif in the Cl- channel P1 region may constitute a 'signature' sequence for an anion-selective ion pore by analogy with the homologous GYG sequence that is essential for selectivity in voltage-gated potassium ion (K+) channel pores.

Amino Acid Sequence↗