Biomedical subjects
C L Melchior
Publications and source records attributed to C L Melchior.
A conditioning model of alcohol tolerance.
Tolerance to several effects of ethanol can be learned in a classical conditioning paradigm. In the conditioning model of tolerance, a response compensatory in nature to the effect of ethanol develops in association with the cues that signal the presence of ethanol. Tolerance produced by this procedure (environment-dependent tolerance) differs in several respects from tolerance produced in a paradigm in which learning would not be expected to play a significant role (environment-independent tolerance). Depletion of norepinephrine in the brain blocks the development of both types of tolerance, whereas depletion of serotonin enhances the rate of development of environment-dependent tolerance, but inhibits the development of environment-independent tolerance. Cued alterations in the volume of distribution for ethanol are an important factor in the tolerance displayed in the classical conditioning paradigm. It has been suggested that the conditioned compensatory response comprises the physiological response underlying "craving" for ethanol. This implies that an extinction procedure would be an effective treatment for the prevention of relapse.
Vasopressin maintenance of ethanol tolerance requires intact brain noradrenergic systems.
We have demonstrated that the mammalian antidiuretic hormone, arginine vasopressin (AVP), will maintain functional tolerance to the hypnotic effect of ethanol in mice, beyond the time in which such tolerance normally dissipates. However, when mice are made tolerant to ethanol and then injected intraventricularly with 6-hydroxydopamine (6-OHDA), AVP is no longer effective in maintaining tolerance. The action of AVP was attenuated by a dose of 6-OHDA which significantly lowered brain norepinephrine, but not dopamine levels, suggesting that the maintenance of ethanol tolerance by AVP may require the presence of intact noradrenergic pathways in brain.
Commentary on ethanol tolerance.
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TIQs block the development of environment dependent tolerance to ethanol.
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Modification of environmentally cued tolerance to ethanol in mice.
Tolerance to the hypnotic and hypothermic effects of ethanol in mice develops with multiple injections. The tolerance to both of these effects of ethanol can be reduced by testing the animals in a novel environment, suggesting that the tolerance may be learned. Tolerance to the hypothermic effect of ethanol develops more rapidly than tolerance to the hypnotic effect. Disruption of the brain catecholamine systems, with either 6-hydroxydopamine or alpha-methyl-p-tyrosine slows the rate of development of tolerance to the hypnotic effect of ethanol. Intraventricular injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine, increases initial sensitivity to ethanol-induced narcosis and facilitates the development of tolerance to the hypnotic effects of ethanol. Tolerance to the hypothermic effect of ethanol in a familiar environment is unaffected by either of the neurotoxins or by alpha-methyl-p-tyrosine. However, initial sensitivity to the temperature-lowering effect of ethanol is increased by 6-hydroxydopamine and decreased by alpha-methyl-p-tyrosine administration. Learning may be an important factor in development of tolerance to ethanol under some conditions and tolerance produced under these conditions can be modified by disruption of central catecholamine systems.
Half-lives and actions of intracerebrally injected isoquinolines.
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Interaction of salsolinol and tetrahydropapaveroline with catecholamines.
Formation of aberrant amine metabolites, tetrahydroisoquinolines (TIQs) has been hypothesized to account for some of the effects of ethanol. These compounds have been shown to interact with catecholamine neurons in a variety of ways by in vitro techniques. The most interesting facet of these alkaloids, however, is the fact that they cause an increase in preference for and voluntary consumption of ethanol when administered into the ventricle of the rat in exceedingly low amounts. Investigation of the neurochemical effects in vivo of two of the TIQs tetrahydropapaveroline (THP) and salsolinol, indicates that they influence several aspects of presynaptic catecholamine function when examined acutely. The mechanism of action responsible for the radical long-lasting behavioral effects of these substances has yet to be defined.
Alcohol drinking: abnormal intake caused by tetrahydropapaveroline in brain.
Tetrahydropapaveroline (THP), a dopamine-dopaldehyde condensation product, was delivered directly into the cerebral ventricle of rats automatically every 15 minutes for 12 days. The animals were given access to both water and ethylalcohol, the latter being presented in 12 concentrations from 3 to 30 percent. Within 3 to 6 days of the start of the infusion of THP, the rats, which normally rejected alcohol, drank alcohol solutions in increasingly excessive amounts; this was accompanied by symptoms that were similar to those of withdrawal and intoxication. These results provide evidence that an abnormal metabolite in the brain may produce the addictive state caused by alcoholic beverages.
Preference for alcohol evoked by tetrahydropapaveroline (THP) chronically infused in the cerebral ventricle of the rat.
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Differential actions on voluntary alcohol intake of tetrahydroisoquinolines or a beta-carboline infused chronically in the ventricle of the rat.
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Genetic differences in ethanol drinking of the rat following injection of 6-OHDA, 5,6-DHT or 5,7-DHT into the cerebral ventricles.
The preference characteristics for ethanol of four different strains of rats were determined in a two-choice situation by offering water and ethanol in a concentration which was increased from 3 to 30% over a 12-day test sequence. Using stereotaxic procedures, 50 mug 5,6-dihydroxytryptamine (5,6-DHT), 200 mug 6-hydroxydopamine (6-OHDA) or 100 mug 5,7-dihydroxytryptamine (5,7-DHT) were then injected acutely into the lateral cerebral ventricle in a 20 mul volume. Rats of the Sprague-Dawley strain increased their ethanol preference following the lesioning of the serotonergic system by 5,6-DHT, whereas similar destruction of catecholaminergic neurons by 6-OHDA markedly suppressed ethanol intake; Long-Evans rats displayed a similar trend in ethanol drinking patterns. However, animals of the Holtzman strain manifested the increased drinking after 5,6-DHT, but showed no suppression of drinking following 6-OHDA. The preference of rats of the Wistar strain was unaffected by 5,6-DHT but attenuated by 6-OHDA. 5,7-DHT had little or no effect on ethanol consumption in any of these strains. These findings thus suggest that genetic factors are an important determinant in an animal's response to a drug that affects 5-HT or NE systems in the brain, particularly when ethanol selection is investigated.
Dietary tryptophan and the selection of ethyl alcohol in different strains of rats.
Rats of three different strains were tested systematically for their selection of water or ethanol offered in a two-choice situation. In order that preference-aversion curves could be derived, the concentrations of ethanol were increased in strength from 3 to 30% over an 11 or 12 day test sequence. L-tryptophan was added to the rat's diet in 1% or 3% mixtures for a predetermined interval beginning before or during a test for ethanol preference. Given to female hooded rats of the Royal Victoria strain, excess tryptophan elevated the ethanol preference threshold and significantly increased ethanol intake according to the dose administered. However, in male hooded rats of the Long-Evans strain, tryptophan augmented only slightly the selection of ethanol. Male Sprague-Dawley rats, an albino strain, were unaffected by the addition of this essential amino acid to their diet. Although tryptophan may exert its effect on ethanol intake through an alteration in the metabolism of cerebral serotonin, such an effect seems to be dependent upon the strain of rat tested.
Alcohol drinking in the rat after destruction of serotonergic and catecholaminergic neurons in the brain.
Rats were offered solutions of ethyl alcohol that were increased in strength from 3-30% concentration over a 12 day interval. Then, 50 mug 5,6-dihydroxytryptamine (5,6-DHT), 200 mug 6-hydroxydopamine (6-OHDA), or 100 mug 5, 7-dihydroxytryptamine (5,7-DHT) were injected acutely into the lateral cerebral ventricle in a 20 mul volume. The selection of ethyl alcohol was enhanced following the lesioning of serotonergic neurons by 5,6-DHT in terms of preference-aversion curves as well as the gm/kg intakes. Conversely, a similar destruction of dopamine and norepinephrine containing neurons by 6-OHDA marked suppressed alcohol preference and the overall intake of this fluid. 5,7-DHT had an intermediary effect of alcohol intake. These findings support the concept that the selection or rejection of alcohol may depend on an imbalance in the neuronal activity of either monoaminergic system in the brain of the rat.
Feeding and body temperature in the rat: diencephalic localization of changes produced by excess calcium ions.
In the unanesthetized rat, Ca++ ions in solutions ranging from 2.6 to 112.0 mM in excess of the normal level in CSF were applied at different sites in the brain and by three separate procedures, Colonic temperature was monitored and in certain experiments, the amount of food pellets and water consumed was measured simultaneously following the administration of excess Ca++ ions. An infusion into the lateral cerebral ventricle of excess calcium in a volume of 5.0 mul produced a concentration-dependent hypothermia, This fall in temperature was not attenuated by a prior intraventricular infusion of mecamylamine and often enhanced by atropine. Depending on the site, a microinjection of excess Ca++ ions in a volume of 0.5 to 1.0 mul directly into the hypothalamus produced hypothermia or feeding. The sites of maximum sensitivity at which excess calcium caused a decline in temperature were clustered in the caudal hypothalamus, whereas those at which calcium elicited feeding were distributed widely in caudo-lateral, medial and rostral hypothalamic areas. Push-pull perfusions at a rate of 20 to 25 mul per min for 10 to 20 min at homologous sites caused similar responses but the cation concentration required to evoke feeding or hypothermia was significantly less than that of either microinjection or intraventricular infusion. These findings demonstrate species continuity in the rat concerning anatomical localization of the postulated set-point mechanism for body temperature. Several different pathways in the feeding system are affected by an alteration in the hypothalamic level of calcium.
Dopamine release within forebrain sites perfused with tetrahydroisoquinolines or tryptoline in the rat.
The localized effect of amine-aldehyde condensation products on the endogenous release of dopamine (DA) was examined in dopaminergic-rich areas of the brain. In the unanesthetized rat, dopaminergic stores were labeled by 14C-dopamine (1.0 microCi) microinjected in a volume of 1.0 microliters into the caudate nucleus, tuberculum olfactorium, nucleus accumbens or other contiguous sites within the ventral forebrain. Subsequently, each labeled site was locally perfused with an artificial CSF, by means of push-pull cannulae, at a rate of 25.0 microliters per min. Two tetrahydroisoquinolines, tetrahydropapaveroline and 4,6,7-TH-tetrahydroisoquinoline, as well as the tetrahydro-beta-carboline, tryptoline, significantly enhanced the release of 14C-DA when each alkaloid metabolite was perfused in a concentration of 250 nanograms per min. Tetrahydroisoquinoline was without effect on the local kinetics of 14C-DA, whereas salsolinol had an intermediary action on DA release. These findings suggest that an alkaloid conjugate when given in the cerebral ventricle could exert its central effects by way of a dopaminergic mechanism in the telencephalon.
Behavioral and biochemical effects of intracerebrally injected alkaloids.
Tetrahydroisoquinolines and beta-carbolines, substances which may form in the brain following the ingestion of alcohol, could be responsible for some of the behavioral effects of alcohol. When certain of these alkaloids are infused into the brain of the rat they induce an enhanced consumption of alcohol in a free-choice situation, both during infusion and for months after the cessation of infusion. In investigating the possible mechanism behind this permanent change in preference for alcohol, it does not appear that the post-synaptic side of the catecholamine neurons is involved. Likely candidates for future investigation include the pre-synaptic side of the catecholamine neurons and the serotonergic and opiate systems.
Temperature in mice after ethanol: effect of probing and regain of righting reflex.
The handling involved in rectally probing a mouse in order to measure body temperature is a stress which results in an increase in body temperature. However, after an injection of ethanol the fall in body temperature caused by ethanol is exacerbated by probing. In mice, decreases in temperature following probing are ethanol-dose dependent and can be generated on both the falling and rising phases of the ethanol induced change in temperature. The effect of probing can be observed when the mice are under the hypnotic influence of ethanol, and regain of righting reflex itself is followed by a fall in temperature. The resumption of motor activity in undisturbed mice following an hypnotic dose of ethanol also is accompanied by a fall in temperature. Therefore, the drop in temperature observed in any of these procedures which involve moving the mice may be attributable to the disruption of heat conservation rather than a stress interaction.