Psychopharmacology & biological narcology

In the norm (i.e., the absence of ethyl alcohol in blood in sober people), sudden local cooling of the skin and soft tissues of different parts of the body from +37°С to +18°С and below (but not below 0°С) causes two-phase changes in blood vessels tone, blood filling, and intensity of blood supply and pain in the cooled tissues. In the first seconds of cooling, the tone of the muscular blood vessels begins to increase and their blood filling decreases, the skin color lightens, and in the cooled area of the body, acute soreness develops. After a few tens of seconds of cooling, spasm in the blood vessels reaches maximum level and their filling with blood decreases to a minimum, the skin turns white, and the soreness becomes severe. These changes persist at their peak for a few minutes, after which they begin to disappear, despite the persisting hypothermia. However, after 10–15 minutes of cooling, hyperemia develops in the hypothermia zone; as a result, the soreness disappears and the skin reddens. Notably, in the norm, sudden cooling of tissues causes irritation of the temperature receptors found in them. The resulting excitation of temperature receptors causes reflex spasm of blood vessels, which has an adaptive value, as it developed for temperature homeostasis of warm-blooded organisms. Acute pain accompanying cold spasm of blood vessels has been found to be due to mechanical squeezing of pain receptors located under the muscular layer in the wall of blood vessels. Conversely, the presence of ethyl alcohol in the blood or, in severe cases, alcohol intoxication changes the dynamics of blood supply in tissues at their sudden cooling: during cooling, blood vessels expand and overflow with blood without the initial phase of spasm and occurrence of pain. Moreover, hyperemia persists throughout and after the cooling period. That is, alcohol intoxication is manifested by the immediate development of hyperemia and skin redness in the cooled area of the body without the initial spasm of blood vessels and appearance of soreness and pallor of the skin in the area of cooling.

BACKGROUND: Clinical observations and animal experiments have shown the lateral specificity of the action of compounds that alter monoaminergic transmission. However, the mechanism of this phenomenon has not yet been studied. AIM: To evaluate the effect of unilateral cortical spreading depression on monoamine metabolism in white outbred mice. MATERIALS AND METHODS: Eighteen sexually mature male white outbred mice were studied. Functional inactivation of the cortex of one of the cerebral hemispheres was induced using unilateral epidural application of 1 × 1 mm filter paper moistened with 25% KCl solution. Then, 15 minutes after exposure, the animals were decapitated. The norepinephrine, dopamine, serotonin, and metabolite (i.e., dioxyphenylacetic (DOPAC), homovanilinic (HVA), and 5-hydroxyindolacetic (5-HIAA) acids) content of the cerebral cortex, hippocampus, olfactory tubercle, and striatum was measured using the HPLC method with an electrochemical detector. RESULTS: The inactivation of the left hemisphere was due to a bilateral decrease in norepinephrine in the hippocampus, an ipsilateral increase in extracellular metabolism of dopamine (HVA and/or HVA/dopamine) in the olfactory tubercle and striatum, and a contralateral increase of dopamine in the cortex and hippocampus. Furthermore, the DOPAC/dopamine ratio in the right olfactory tubercle decreased with left hemisphere inactivation. Right hemisphere inactivation did not cause bilateral effects. With inactivation of the right hemisphere on the inactivation side, norepinephrine in the hippocampus decreased and HVA in the striatum increased. In the left side, with the inactivation of the right hemisphere mice, dopamine in the hippocampus increased, as well as the DOPAC level and DOPAC/dopamine ratio in the olfactory tubercle. Serotonin metabolism (5-HIAA/serotonin) in the right hippocampus and left olfactory tubercle increased only at inactivation of the right hemisphere. CONCLUSIONS: The monoaminergic effects of functional inactivation of the left and right hemisphere cortex in white outbred mice are not mirror-symmetrical.

BACKGROUND: U-49900 is a chemical analog of U-47700. Despite the growing abuse of synthetic opioids, including U-49900, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is a promising model organism in neuroscience often used for the psychopharmacological evaluation of neurotropic drugs. OBJECTIVE: To evaluate the effects of U-49900 on the behavior of adult zebrafish in a new tank. MATERIALS AND METHODS: The effect of the test compound U-49900 at 1, 5, 10, and 25 mg/L concentrations (incubation for 20 minutes) on the behavior of adult zebrafish was assessed using the “new aquarium” test. U-49900 is 3.4-dichloro-N-(2-(diethylamino)cyclohexyl)-N-methylbenzamide and is considered an analog of the synthetic opioid U-47700, causing withdrawal in humans. RESULTS: The psychopharmacological profile of U-49900 at 1, 5, 10, and 25 mg/l concentrations (water immersion) in adult zebrafish was evaluated with the novel tank test. U-49900 at 25 mg/l for 20 min reduced the distance traveled and number of top entries in the novel tank test (p < 0.001 vs. control group), but unaltered other parameters. CONCLUSIONS: Overall, the sensitivity of zebrafish to synthetic non-fentanyl opioids such as U-49900 indicates the possibility of developing high-throughput screening platforms for finding effective therapies for pathological conditions caused by synthetic opioids.

BACKGROUND: The reinforcing systems of the brain are represented by the ventral forbrain dopaminergic bundle, which innervates the emotiogenic structures of the limbic system. Their study shows the reproduction of unconditioned (self-stimulation, self-administration) and conditioned reflex (preference for place, temperature, color) reactions. The quantitative assessment of the brain’s reinforcing systems remains unclear. For self-stimulation of brain structures, the change of the pedal presses in the Skinner chamber and some calculated coefficients are used, for example, the “mismatch coefficient”, which characterizes the temporal characteristics of the pedal pressings. AIM: To develop, test, and substantiate an additional objective quantitative method for assessing the reinforcing systems of the brain, called the “addiction coefficient”, based on an analysis of the effect of three psychoactive compounds (amphetamine, morphine and ethanol) in different doses on self-stimulation of the lateral hypothalamus in rats. MATERIALS AND METHODS: The main method for studying the reinforcing systems of the brain was the reaction of self-stimulation of the lateral hypothalamus in Wistar rats, which was modulated by the administration of psychoactive substances. The psychomotor stimulant amphetamine (phenamine) hydrochloride (0.5, 1, 2, and 4 mg/kg), narcotic analgesic morphine hydrochloride (1, 2, 4, and 8 mg/kg), and ethanol (0.5, 1, 2, and 4 g/kg) administered intraperitoneally were used as inductors of reinforcing. The control was the administration of of 0.9% NaCl solution (0.1, 0.2, 0.4, and 0.8 ml/rat). RESULTS: The use of different controls, characterized by an increase or decrease in the self-stimulation reaction in response to the introduction of 0.9% NaCl solution, showed that calculated coefficients, including the “mismatch coefficient”, can change in different directions and do not objectively reflect the reinforcing effects of pharmacological substances. The proposed “addiction coefficient”, which reflected the component of psychic dependence, changed unidirectionally toward an increase. The degree of this increase can be tens and hundreds of percent of the control and is significantly independent of the initial values of self-stimulation. As expected, the “addiction coefficient” increased most clearly after amphetamine administration and less significantly after morphine and ethanol injections. CONCLUSIONS: The “addiction coefficient” of a psychoactive substance, calculated as the ratio of the increase in pedal presses to the value of the “mismatch coefficient”, is a clear quantitative indicator when assessing the reinforcing properties of psychoactive substances in the self-stimulation reaction of the lateral hypothalamus. The “addiction coefficient” does not significantly depend on the initial level of self-stimulation and is recommended for a comparative assessment of the reinforcing properties of primarily related psychoactive compounds.

BACKGROUND: The search for markers and predictors of complicated forms of alcoholism, which include alcoholic delirium and acute psychotic reactions with hallucinatory and delusional phenomena, is one of the actual problems of modern addiction medicine. AIM: Clinical validation of a model for early detection of patients at high risk of developing complicated alcohol withdrawal syndrome (AWS) based on laboratory diagnostics. SUBJECTS AND METHODS: A prospective, cohort, observational study was performed. The study included 200 patients; 9 were excluded. The included patients were distributed as follows: uncomplicated AWS, 98 patients (51.3%); alcohol delirium, 67 patients (35.1%); and alcohol-induced psychotic disorder, 26 patients (13.6%). Potassium, sodium, calcium, and platelet count were compared between the groups, and the relationships between sex, age, and potassium levels in patients with alcohol delirium were studied. RESULTS: Potassium, sodium, and platelet count were significantly different in patients with alcohol delirium and in those with uncomplicated AWS and alcohol-induced psychotic disorder. Blood calcium levels were significantly different between patients with alcohol delirium and uncomplicated AWS. Women were found to be less sensitive to metabolic disorders that developed as a result of alcohol consumption, as evidenced by lower incidence of delirium. The high prevalence of alcohol delirium among older patients is a consequence of decompensation of metabolic regulation mechanisms. CONCLUSIONS: Predictive model of alcohol delirium, based on the results of blood potassium level study, proved effectiveness in clinical application.