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Untersuchungen zum Einfluss von Buprenorphin auf das Alkoholtrinkverhalten und das allgemeine Trinkverhalten bei Ratten

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Abstract

Das limbische System beinhaltet mit dem mesolimbischen Teil ein körpereigenes Belohnungszentrum, welches aber auch die Grundlage für Suchterkrankungen bildet. Eine konstante Beteiligung des endogenes Opioidsystems ist bei kurzzeitigem Alkoholkonsum wie auch der Alkoholsucht gesichert. Aus der Therapie von Opioidsuchtpatienten zeigte sich, dass auch Buprenorphin (Bup.) das Alkoholtrinkverhalten beeinflussen könnte. Das Wirkungsprofil von Bup. auf das Alkoholtrinkverhalten wurde nun untersucht. Dazu konnten Wistar-Ratten mittels einer Versuchsbox im Zwei-Taster-Auswahlsystem, freiwillig zwischen Alkohol und Wasser wählen. Nach einer Trainingsphase für einen stabilen Alkoholtrinkpegel, wurden die Tiere in unterschiedlichen Gruppen mit verschiedenen Dosen von Bup. behandelt. Das folgende Trinkverhalten wurde gemessen und miteinander verglichen. Bup. zeigte eine selektive Reduktion des Alkoholtrinkverhaltens, bei gesüßter Lösung sogar mit einem stark signifikanten Effekt. Weiterhin zeigten sich auch Auswirkungen auf das allgemeine Trinkverhalten. Somit kann Bup. über mehrere Wege wirken. Ebenso wird eine funktionelle Verbindung von zwei topographisch verschiedenen Gehirnregionen, dem des Trinkzentrums in der präoptischen Region und dem des mesolimbischen Systems, erkennbar. Da bereits bekannt ist, das Bup. auch andere Rezeptoren (Nociceptin/Orphanin (FQ-NOP) oder Opioid-Rezeptor-Like-1 (ORL-1) Rezeptoren) besetzen kann, liegt die Vermutung nahe, dass diese Rezeptoren an der Wirkung von Bup. beteiligt sein können. Daraus folgt, FQ-NOP- oder ORL-1-Rezeptoren müssen in Kernbereichen enthalten sein, die der Kontrolle des Trinkmechanismuses dienen. Im Umkehrschluss könnte so die senkende Wirkung auf den Alkoholkonsum auch durch FQ-NOP- oder ORL-1-Rezeptoren vermittelt werden, die dann innerhalb des Belohnungszentrums zu finden wären. Das Potential von Bup. das Alkoholtrinkverhalten zu senken, kann einen neuen therapeutischen Ansatz in der Alkoholsuchttherapie bieten.

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Morphine, given acutely, inhibits oxytocin secretion in adult female rats, but chronic intracerebroventricular infusion for five to six days induces tolerance and dependence in the mechanisms regulating oxytocin secretion. One explanation for tolerance could be that there is a loss of opioid receptors. To test this hypothesis cryostat sections of selected brain regions and the pituitary, from six control and six intracerebroventricular morphine-infused rats, were processed for quantitative in vitro receptor autoradiography. [3H]Etorphine or [3H](-)-bremazocine were used as ligands, and DAGO, DPDPE and U50,488H as selective displacers from mu-, delta-, and kappa-receptors, respectively. Control incubations had naloxone determined specificity. The supraoptic nucleus (site of oxytocin-secreting magnocellular perikarya) contained both mu- and kappa-receptors in control rats (mean +/- S.E.M. binding of mu-selective [3H]etorphine was 91.8 +/- 25.4 fmol/mg of tissue, and of kappa-selective [3H](-)-bremazocine was 130.4 +/- 25.6 fmol/mg). Chronic morphine treatment caused a 83.9% decrease in binding in mu-selective conditions (P less than 0.05), but no significant change in kappa-selective binding. In the median preoptic nucleus (which projects to the supraoptic nucleus) mean +/- S.E.M. binding of [3H]etorphine decreased by 77.0% (P less than 0.01) in chronic morphine-treated rats, from the control value of 76.2 +/- 9.8 fmol/mg of tissue. In the posterior pituitary gland (site of the terminals of the oxytocin-secreting magnocellular perikarya) binding with [3H](-)-bremazocine in controls was over 90% lower than in the supraoptic nucleus. No changes followed chronic morphine treatment. Thus chronic morphine exposure reduces the numbers of available mu-receptors in the supraoptic nucleus, and of opioid receptors in the median preoptic nucleus, perhaps accounting for morphine-tolerance in relation to oxytocin secretion.
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The role of opioids, dopamine and serotonin in ethanol (EtOH) reward and preference was investigated in non-deprived, Alcohol-Preferring (P), and genetically heterogenous Wistar rats. Operant responding for ethanol was initiated using sweet-solution substitution procedures. The rats were then trained in 30-min daily sessions to respond for ethanol (10% v/v) versus water under a two-lever, free-choice contingency. All testing was conducted in the absence of water and food deprivation or addition of sweeteners to the ethanol drinking solution. Rats of both strains developed stable preferences in responding for ethanol over water and consumed ethanol at quantities sufficient to produce pharmacologically relevant mean blood alcohol concentrations (P-Rats: 98 +/- 19.6 mg%; unselected Wistars: 41.7 +/- 8.5 mg%). In P-rats, systemic naloxone (NAL; 0.125, 0.25 and 0.5 mg/kg) pretreatments resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference (expressed as percent ethanol of total intake). In contrast, bromocriptine (BRO; 1.0, 2.0 and 4.0 mg/kg) produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. In unselected Wistar rats, NAL and BRO treatments produced changes in ethanol preference patterns similar to those observed in P-rats. However, compared to P-rats, these changes were smaller and not consistently dose dependent. No changes in ethanol preference and water or ethanol intake were observed with methysergide (MET; 2.5, 5.0, 10.0 mg/kg) in either strain of rat. Together, the results suggest a possible involvement of dopaminergic mechanisms in the reinforcing properties of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Angiotensin II infused intravenously into sinoaortic-denervated rats induced drinking and increased glucose utilization in the subfornical organ and pituitary neural lobe in amounts not different from those observed in sham-operated animals. We suggest that inputs from baroreceptors have a negligible influence on glucose metabolism in the subfornical organ during infusion of angiotensin II.
Article
The experiments to be described have been designed in order to: (a) provide new information on the concentrations of opioid kappa receptors in different regions of the brain of the male rats; and (b) to analyze whether the density of brain kappa receptors might be modified by the process of aging. The concentration of kappa receptors was investigated in the hypothalamus, amygdala, mesencephalon, corpus striatum, hippocampus, thalamus, frontal poles, anterior and posterior cortex collected from male rats of 2 and 19 months of age. 3H-bremazocine (BRZ) was used as the ligand of kappa receptors, after protection of mu and delta receptors respectively with dihydromorphine and d-ala-d-leu-enkephalin. The results obtained show that: (1) in young male rats, the number of kappa opioid receptors is different in the various brain areas examined: the hypothalamus and the striatum have a concentration of kappa binding sites which is significantly higher than that found in the mesencephalon and in the amygdala; much lower concentrations of kappa binding sites have been found in the thalamus, the frontal poles, the hippocampus, the anterior and posterior cerebral cortex. (2) Aging exerts little influence on the number of kappa receptors in the majority of the brain structures considered. However in the amygdala and in the thalamus the number of kappa receptors was increased in old animals. To the authors' knowledge, the data here presented are the first ones which suggest that age may increase rather than decrease the number of neurotransmitter receptors in the brain.
Article
Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.
Article
Buprenorphine was studied for its antagonist activity against the specific kappa-opioid agonist U-50,488H in pigeons responding under a multiple schedule of grain presentation and in mice in an antinociception test. U-50,488H decreased rates of responding of pigeons over the dose range (2.5-20 mg/kg i.m.). In the presence of 0.32 mg/kg of buprenorphine, the U-50,488H dose-effect curve was shifted to the right approximately two-fold. Buprenorphine alone (0.01-0.08 mg/kg s.c.) inhibited in mice the abdominal stretching induced by i.p. acetic acid. beta-Funaltrexamine pretreatment blocked the mu-like agonist analgesic effect of buprenorphine and revealed an antagonist action of buprenorphine against 2.5 mg/kg of U-50,488H over the same dose range that it produced antinociception at the mu-receptor. Thus, buprenorphine is a potent kappa-opioid receptor antagonist, producing the kappa-antagonist activity over the same dose range that it produces its mu-mediated partial agonist activity.
Article
An in vivo autoradiographic technique permitted the visualization of discrete neuroanatomical changes in opiate receptor binding as a result of 23-h water deprivation and drinking. Two groups of rats (n = 5) were placed on a 23-h water deprivation schedule for 10 days. On the last day, one group was given access to water for 15 min. These groups, plus a matched ad libitum water control group (n = 5), received an injection of 0.002 mg/kg [3H]diprenorphine ([3H]Dpr) through chronically implanted jugular catheters followed by preparation for opiate receptor autoradiography. Relative cerebral blood flow was estimated non-quantitatively by the injection of 75 microCi/kg iodo-[14C]antipyrene into 3 additional groups identically treated. Results indicated that water-deprivation stress increased [3H]Dpr binding in the claustrum, lateral hypothalamus, amygdala and ventral tegmental area while decreasing binding in the medial frontal cortex, lateral septum, dorsolateral thalamus and central gray. All effects of water deprivation were reversed in animals receiving water. Observations of changes in relative blood flow were shown to have no correlation with changes in opiate receptor binding. It appears that water deprivation stress causes a reduction in opioid release in areas along the mesotelencephalic dopamine pathway which may contribute to a drive state. Water intake may then reduce or otherwise alter the drive state through the release of opioids along these pathways, contributing to the perception of reward.
Article
In summary, the nucleus accumbens, located at the interface of the limbic projections from the amygdala, hippocampus, and cingulate cortex, and receiving extrapyramidal fibers from midbrain DA-containing nuclei, is well situated to form neural circuitry that mediates the behaviorally activating properties of several stimulants. Efferent GABAergic fibers projecting from the nucleus accumbens to the ventral pallidum translate integrated limbic and extrapyramidal information to lower motor circuitry; some of this information appears to be carried by ventral pallidal efferent fibers projecting to the dorsomedial nucleus of the thalamus. It seems very possible that activation of this circuitry by positive reinforcing environmental stimuli, through the release of endogenous DA or opiate compounds, might contribute to motivated behavior. Indeed, environmentally generated locomotor activity can be blocked by disruption of this circuitry following destruction of N. Acc. DA terminals. It is also tempting to speculate that pathological changes in activity within this system might disrupt normal reinforcement contingencies, and contribute to the affective components of both psychiatric and neurologic disease states.
Article
While various methods have been used to initiate ethanol drinking in animals, the development of models in which animals will perform some specific behavior in order to obtain the opportunity to drink ethanol has been fraught with difficulty. In the past several years, new procedures have been developed in which rats, neither food nor fluid deprived, will perform an operant task reinforced by the presentation of ethanol. This paper reviews some of these recent findings and presents new data concerning these models of oral ethanol self-administration as measured in an operant paradigm.
Article
Extracellular single-unit activity was recorded from phasically firing neurohypophyseal neurons (n = 41) in the hypothalamic paraventricular nucleus (PVN) of urethane-anesthetized male rats. Electrical stimulation of the subfornical organ (SFO) produced orthodromic long-duration (n = 18) or short-duration (n = 10) excitation or inhibition (n = 8) of the activity of PVN neurons. The long-duration excitatory response of about half (n = 7) the neurons (n = 15) tested was reversibly abolished by microinjection of the local anesthetic lidocaine into the median preoptic nucleus (MnPO), whereas neither the short-duration excitatory (n = 7) nor inhibitory (n = 6) responses were affected. These results suggest that the SFO efferents through the MnPO to the PVN may transmit the neuromodulatory signals which evoke long-duration increases in the excitability of putative vasopressin (VP)-secreting neurons in the PVN.
Article
The spontaneous food intake of 31 adult humans was investigated with diary self-reports of ingestive behaviors and subjective hunger over 7 consecutive days. Meals were identified, using five different definitions, and their composition of total calories, carbohydrate, fat, and protein was estimated from a computer file of the nutritive value of foods. These data were analyzed by intercorrelating meal sizes with intermeal intervals, estimated stomach contents and self-reported hunger with univariate and multiple correlation techniques. Human feeding was found to be regulated on the basis of preprandial factors; the premeal interval, estimated premeal stomach content, and self-reported hunger significantly correlating with the meal size. These correlations were significant regardless of whether the meal was evaluated as spontaneous or constrained by external factors, but were stronger when the meals occurred without other people being present. The postprandial relationship between the meal size and the duration of the postmeal interval, which is present in nonhuman species, was only present in humans when meals that were eaten alone were considered separately. This suggests that the species differences may be due to the social context of observation. The intake of carbohydrate, fat, and protein was found to have a suppressive effect on subsequent intake and subjective hunger through their contributions to total food energy ingested. Protein, however, was found to suppress subsequent intake and subjective hunger independent of its contribution to total calories, suggesting that the macronutrients have differing satiating properties.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Although the effects of negative reinforcement on human behavior have been studied for a number of years, a comprehensive body of applied research does not exist at this time. This article describes three aspects of negative reinforcement as it relates to applied behavior analysis: behavior acquired or maintained through negative reinforcement, the treatment of negatively reinforced behavior, and negative reinforcement as therapy. A consideration of research currently being done in these areas suggests the emergence of an applied technology on negative reinforcement.
Article
Rats, maintained on free access to both food and water, were trained to press a lever to obtain a 20% sucrose solution. When presentation of the sucrose solution was maintaining responding, low ethanol concentrations were added to the solution. Over 25 sessions, the solution presented as reinforcement was gradually reduced in sucrose concentration until a 10% ethanol solution with no sucrose was presented. Following this initiation procedure, ethanol concentrations up to and including 40% ethanol were found to maintain responding. At the higher ethanol concentrations, the rats consumed doses of ethanol between 0.90 and 0.95 g/kg in the 30-min session. When a concurrent choice between ethanol and water was available in the operant chamber, the rats responded on the lever associated with 10% ethanol presentation. Home cage preference between ethanol and water was found to be altered following the operant ethanol experience with the rats acceptability for 10% ethanol increased prior to the start of the experiment. This initiation procedure provides another manner in which ethanol reinforcement can be instigated in animals that have not been either food- or fluid-deprived. It is hypothesized that mechanisms which may regulate the intravascular and intragastric self-administration of ethanol may also be operating when the oral route is employed.
Article
A survey is given about features of renin synthesis and secretion from juxtaglomerular epithelioid cells that are largely atypical as compared to those of other secretory systems. Renin-producing cells have the capability of reversible metaplastic transformation into vascular smooth muscle cells, their secretory granules are very closely related to lysosomes, and they react paradoxically, i.e. with an inhibition instead of a stimulation of renin secretion, to a rise in intracellular free Ca++. The modes of renin secretion and activation of the enzyme as well as possible mechanisms involved in adjusting the ratio of secreted active to inactive renin to the current needs of the renin-angiotensin system are discussed.
Article
The effect of the i.p. administration of ethanol on the release of dopamine (DA) and on the output of its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, was estimated in the rat by transcerebral dialysis of two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of ethanol (0.25-0.5 g/kg i.p.) stimulated DA release specifically in the n. accumbens and elicited pure behavioral stimulation. Higher doses of ethanol (1.0-2.5 g/kg) elicited sedation and hypnosis and stimulated further DA release and dihydroxyphenylacetic acid and homovanillic acid output in the accumbens and, although less, also in the caudate. High doses of ethanol (5 g/kg i.p.) elicited long-lasting hypnosis and sedation and induced a depression followed by stimulation of DA release in the accumbens. DA release in the caudate was stimulated further. Low doses of apomorphine (0.05 mg/kg s.c.) reversed completely the stimulant effect of 0.5 g/kg of ethanol on behavior and on DA release in the accumbens. Moreover, the stimulation of behavior and of DA release in the accumbens elicited by 0.5 g/kg of ethanol were abolished completely by pretreatment with 700 mg/kg of gamma-butyrolactone, an agent which blocks DA firing and DA release. The results indicate that ethanol preferentially stimulates DA transmission in the mesolimbic system probably by activating the firing activity of mesolimbic DA neurons and provide direct evidence that these changes are involved in the motor stimulant effects of ethanol.
Article
Drinking and feeding were elicited by stimulation of topographically differentiated sites in the rat brain. When stimulated with low current via small electrodes, drinking was elicited from the zona incerta (ZI) feeding from the lateral hypothalamus (LH), and both responses from a restricted portion of the LH dorsolateral to the fornix. With stimulation of sites outside these regions consummatory responses occurred unreliably. Discrete lesions were made at sites of stimulation and resulting axonal degeneration was stained by the Fink and Heimer technique. Although similar connections existed, the main degeneration from drinking sites in the ZI differed from that arising from feeding sites in LH; degeneration from drinking sites coursed in the ZI and in other structures including the nucleus reuniens, ventromedial thalamus, the region ventral to the globus pallidus and the region near the subcommissural organ; degeneration from feeding sites in the LH coursed in the medial forebrain bundle and in the pathways that extend from it. Degeneration from sites dorsolateral to the fornix where both feeding and drinking were elicited was similar to that from feeding sites. These anatomical differences and similarities suggest the existence of two neural systems for drinking, one being closely related to the system for feeding and the other being independent.