harmine and Substance-Withdrawal-Syndrome

Greater prefrontal cortex and anterior cingulate cortex monoamine oxidase A (MAO-A) binding is associated with depressed mood. Substances in cigarette smoke, such as harman, inhibit MAO-A, and cigarette withdrawal is associated with depressed mood. Dysphoria during cigarette withdrawal predicts relapse. It is unknown whether MAO-A binding increases during early cigarette withdrawal.. To measure prefrontal and anterior cingulate cortex MAO-A binding during acute cigarette withdrawal and to assess the relationship with smoking severity, plasma levels of harman, and severity of depression.. Study via positron emission tomography of healthy control and cigarette-smoking individuals.. Twenty-four healthy nonsmoking and 24 otherwise healthy cigarette-smoking individuals underwent positron emission tomography with harmine labeled with carbon 11. Healthy nonsmoking individuals underwent scanning once. Cigarette-smoking individuals underwent scanning after acute withdrawal and after active cigarette smoking. Cigarette smoking was heavy (≥25 cigarettes per day) or moderate (15-24 cigarettes per day).. Tertiary care psychiatric hospital.. An index of MAO-A density, MAO-A V(T), was measured in the prefrontal and anterior cingulate cortices.. In heavy-smoking individuals, prefrontal and anterior cingulate cortex MAO-A V(T) was greater during withdrawal (23.7% and 33.3%, respectively; repeated-measures multivariate analysis of variance, F(1,22) = 25.58, P < .001). During withdrawal from heavy smoking, prefrontal and anterior cingulate cortex MAO-A V(T) was greater than in healthy controls (25.0% and 25.6%, respectively; multivariate analysis of variance, F(2,33) = 6.72, P = .004). The difference in MAO-A V(T) in the prefrontal cortex and anterior cingulate cortex between withdrawal and active, heavy smoking covaried with change in plasma harman levels in the prefrontal cortex and anterior cingulate cortex (multivariate analysis of covariance, F(1,10) = 9.97, P = .01). The change in MAO-A V(T) between withdrawal and active, heavy smoking also covaried with severity of depression (multivariate analysis of covariance, F(1,10) = 11.91, P = .006).. The increase in prefrontal and anterior cingulate cortex MAO-A binding and associated reduction in plasma harman level represent a novel, additional explanation for depressed mood during withdrawal from heavy cigarette smoking. This finding resolves a longstanding paradox regarding the association of cigarette smoking with depression and suicide and argues for additional clinical trials on the effects of MAO-A inhibitors on quitting heavy cigarette smoking.

Topics: Adult; Carbon Radioisotopes; Depression; Diagnosis, Dual (Psychiatry); Female; Gyrus Cinguli; Harmine; Humans; Male; Monoamine Oxidase; Positron-Emission Tomography; Prefrontal Cortex; Severity of Illness Index; Smoking; Substance Withdrawal Syndrome; Tobacco Use Disorder

This study was designed to determine the affinity and binding profile of beta-carbolines for imidazoline I2 receptors and catalytic sites of monoamine oxidase (MAO)-A/B in rat brain and liver. The aim was also directed to assess the in vivo effects of norharman (beta-carboline) and LSL 60101 (I2 ligand) on brain 3,4-dihydroxyphenylalanine (DOPA) synthesis in morphine-dependent rats. Competition experiments against [3H]2-BFI revealed that beta-carbolines recognize the high- and low-affinity components of the brain imidazoline I2 receptor with the rank order of potency (K(iH) in nM): noreleagnine (12)>norharman (20)>harmalol (82)>harmaline (177)>>harmine (630)>harman (700)>>FG-7142 (>100,000). In liver, this rank was different: harmine (51)>harmaline (103)=noreleagnine (103)>>harmalol (1290)>harman (2000)>>norharman (12,382)>>FG-7142 (>100,000). In brain and liver, competition curves for beta-carbolines against [3H]Ro41-1049 (MAO-A) and [3H]Ro19-6327 (MAO-B) were monophasic and resulted in different drug potencies for the two MAO isozymes (higher affinities for MAO-A) and in similar pharmacological profiles in both tissues. In morphine-dependent rats, naloxone (2 mg/kg, 2 h)-precipitated withdrawal increased the synthesis of DOPA in the cerebral cortex and hippocampus (50%). Pretreatment with norharman (20 mg/kg) or LSL 60101 (20 mg/kg) (30 min before naloxone) fully prevented the stimulatory effect of opiate withdrawal on DOPA synthesis. Norharman and LSL 60101 also attenuated the severity of the withdrawal syndrome. The results indicate that beta-carbolines bind with high affinity to imidazoline I2B receptors, and similarly to I2 ligands (LSL 60101) can block the behavioural and biochemical effects of opiate withdrawal.

Topics: Animals; Benzofurans; Binding, Competitive; Brain; Carbolines; Cerebral Cortex; Dihydroxyphenylalanine; Dose-Response Relationship, Drug; Harmine; Hippocampus; Imidazoles; Imidazoline Receptors; Liver; Male; Monoamine Oxidase; Morphine; Morphine Dependence; Naloxone; Norepinephrine; Picolinic Acids; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Drug; Substance Withdrawal Syndrome; Thiazoles; Tritium; Tyrosine 3-Monooxygenase

We examined the effects of ethanol ingestion to rats on levels of the beta-carboline norharman in plasma, brain and liver at the end of ethanol ingestion and 10 h after withdrawal. We also investigated the effect of exogenously administered norharman on the behavioural signs of alcohol withdrawal. Ethanol was given by a liquid diet for 21 days. Norharman plasma levels in alcohol fed rats were significantly elevated compared to both control rats and to rats 10 h after withdrawal. Norharman levels in brains and livers showed a similar pattern. The capacity of the livers of both alcohol-dependent and withdrawal rats to catabolise norharman was significantly reduced compared to control rats. Norharman injected intraperitoneally (6.3 mg/kg) attenuated the behavioural signs of alcohol withdrawal significantly. The mechanism behind the increased norharman levels in alcohol-dependent rats may be inhibition of the synthesis and/or activity of liver enzyme(s) responsible for the breakdown of norharman.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Carbolines; Central Nervous System Depressants; Ethanol; Half-Life; Harmine; Liver; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The effects of the beta-carbolines, harman and harmine, on naloxone-precipitated withdrawal syndrome in morphine-dependent rats were investigated. Two morphine pellets containing 75 mg morphine base were implanted subcutaneously in the scapular area of adult male Wistar rats (200-250 g) under light ether anesthesia. Rats were then assigned to several groups (n = 12 for each group). Seventy-two hours after morphine implantation, harman (5 and 10 mg/kg), harmine (5 and 10 mg/kg) or saline was injected to rats intraperitoneally (ip). After 45 min, a morphine withdrawal syndrome was precipitated by naloxone (2 mg/kg, ip), and morphine withdrawal signs were observed and evaluated for 15 min. Harmine (5 and 10 mg/kg) attenuated significantly the intensity of all signs of morphine withdrawal except for jumping. While jumping behaviour appearing in morphine withdrawal was intensified by harman (5 and 10 mg/kg) treatment, harmine administration did not produce any significant change in the intensity of this sign. Harman attenuated significantly the intensity of wet dog shakes, writhing, defecation, tremor and ptosis. However, it produced no significant changes in the intensity of teeth chattering and diarrhea. Our results suggest that harman and harmine, beta-carbolines, have some beneficial effects on naloxone-precipitated morphine withdrawal syndrome in rats. Findings from the present study also indicated that harmine was more effective than harman on morphine abstinence syndrome.

Topics: Animals; Behavior, Animal; Carbolines; Hallucinogens; Harmine; Injections, Intraperitoneal; Male; Morphine Dependence; Naloxone; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Besides nicotine, other chemicals in tobacco smoke, such as norharman, may contribute to the addictive properties of cigarettes. More specifically, elevated blood plasma levels of norharman may reduce feelings of craving among tobacco-dependent individuals. To test this hypothesis, plasma concentrations of norharman were measured in 38 male smokers (at least 15 cigarettes per day) at three time-points on 3 different days spread over a 4-month period. The first measurement (T0) was conducted in the morning at 8.30 a.m., after 12 hours of smoking abstinence. The T1 and T2 measurements were conducted at 13.00 p.m. and 16.30 p.m., during a period of ad libitum smoking (after the T0 measurement, participants were not restricted in their smoking behaviour). At each of the nine time-points, craving was assessed by means of a shortened version of the Questionnaire of Smoking Urges. The Fagerström Test of Nicotine Dependence was used to obtain an indication of nicotine dependence. The results showed that, after a period of smoking abstinence, craving was stronger in those with a high tobacco dependence than in those with a low tobacco dependence. After resumption of smoking, craving declined to a similar low level in both low and high dependent smokers. Measurements during periods of ad libitum smoking indicate that plasma levels of norharman are related negatively to craving among low nicotine-dependent smokers, but not among high dependent smokers.

Topics: Adult; Carbolines; Circadian Rhythm; Female; Harmine; Humans; Male; Middle Aged; Motivation; Nicotine; Smoking; Smoking Cessation; Substance Withdrawal Syndrome; Tobacco Use Disorder

Studies on the occurrence and properties of b-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone-precipitated withdrawal syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine-dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) = 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.

Topics: Adrenergic alpha-Antagonists; Analgesics, Opioid; Animals; Guinea Pigs; Harmine; Idazoxan; Ileum; In Vitro Techniques; Male; Morphine; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome; Yohimbine

Norharman (20 mg/kg, i.p.) and ibogaine (40 mg/kg, i.p.) significantly attenuated naloxone (4 mg/kg, i.p.)-precipitated withdrawal syndrome in morphine-dependent rats. Several withdrawal signs, such as teeth-chattering, chewing, penile licking and diarrhoea, were decreased by both norharman and ibogaine. In addition, norharman reduced also the withdrawal grooming and rearing. It is concluded that both norharman and ibogaine are inhibitors of withdrawal syndrome in morphine-dependent rats.

Topics: Animals; Arousal; Brain; Carbolines; Harmine; Ibogaine; Male; Morphine; Naloxone; Rats; Rats, Wistar; Receptors, Opioid; Substance Withdrawal Syndrome

1. Rats given a 10-% (v/v) alcohol liquid diet over long periods of time reach high blood alcohol levels of more than 200 mg/dl over several weeks. 2. Repeated discontinuation of the alcohol intake resulted, each time within 8 hr, in several withdrawal reactions including a reduction in exploratory behaviour and tremorogenic activity. 3. The inhibition of exploratory activity was measured in a neutral two-chamber model, both in terms of the number of transits into the open area as well as the time spent in the open space. The differences in exploration remained over the 4 successive withdrawal tests. 4. Rats in alcohol withdrawal were also consistently less active than control animals in the tremor cages equipped with a piezofilm floor, and this despite the presence of a clearly visible tremor in the hindpaws when lifted up. 5. Alcohol withdrawal rats revealed a more frequent tremor activity than controls after a challenge with 5 mg/kg harmine. This effect was independent of the length of the tremor bursts used to quantify harmine-induced tremor starting from the second withdrawal period onwards. 6. With a dose of 10 mg/kg harmine, ceiling effects were reached in both the alcohol withdrawal and control rats and differences between the two groups were only present during the first exposures. 7. Overall, these results indicate that it is possible to quantify some withdrawal reactions at repeated time intervals of alcohol cessation in rats chronically exposed to a 10-% alcohol liquid diet. As a consequence, these withdrawal reactions can be studied in a more systematic way.

Topics: Alcoholism; Animals; Behavior, Animal; Diet; Ethanol; Exploratory Behavior; Harmine; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Tremor

Endogenous substances resulting from interactions between alcohol and possibly opioid metabolites and neurotransmitters (dopamine, indolamines) are mediators of the pathochemical process towards dependence. Beta-carbolines are increased in alcoholics and--according to our own results--in heroin-addicts. Still unclear is the impact of other psychopathological disturbances like states of anxiety or depression; unclear is also, if it has to be interpreted as state, trait or residual marker of the dependence syndrome.

Topics: Adult; Carbolines; Female; Harmine; Heroin Dependence; Humans; Male; Methadone; Substance Withdrawal Syndrome

Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism, aromatic beta-carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC), newly developed radioreceptor assays, and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 +/- 26.6 pg/ml vs. 26.9 +/- 10.7 pg/ml; p less than 0.001) and did not change significantly during a 3-week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis, a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.

Topics: Adolescent; Adult; Alcoholism; Carbolines; Chromatography, High Pressure Liquid; Ethanol; Female; Follow-Up Studies; Harmine; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychopathology; Substance Withdrawal Syndrome

The tremors induced by harmine, LON-954 (N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride) and 5-hydroxytryptophan (5-HTP) were studied in control rats and in rats withdrawn for 16-48 hrs from 6 to 9 days' ethanol administration. The frequencies and the intensities of the tremors were determined electronically. In control rats the frequency spectra of the tremors induced by harmine (20 mg/kg) and LON-954 (10 mg/kg) showed a narrow peak frequency at about 10 Hz. Atropine (1.2 mg/kg) altered neither the frequency nor the intensity of these tremors. 5-HTP (50 mg/kg) when given 3.5 hrs after iproniazid (100 mg/kg) induced tremor with peak frequencies at 6-7 Hz and 12 Hz. In ethanol-withdrawn rats treated with harmine or LON-954 the frequency analysis of tremor revealed a narrow peak frequency at about 12 Hz, which was neither the characteristic frequency of ethanol withdrawal tremor (6 Hz) nor that of harmine or LON-954 (10 Hz). The intensity of both harmine- and LON-954-induced tremor was significantly increased in ethanol-withdrawn rats. The ethanol-withdrawn rats were markedly sensitized to the effect of iproniazid+ 5-HTP, shown by deaths. The peak frequencies of this tremor were the same as those in control rats. The results suggest that harmine-induced tremor involves a dopaminergic-5-HT'ergic imbalance and the tremor induced by LON-954 a dopaminergic-cholinergic imbalance in the brain. The tremor in ethanol-withdrawn rats seems to be mediated by alterations in the activity of the cerebral 5-HT'ergic system.

Topics: 5-Hydroxytryptophan; Alkaloids; Animals; Ethanol; Harmine; Male; Physostigmine; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Tremor; Urea