Effects of harman and harmine on naloxone-precipitated withdrawal syndrome in morphine-dependent rats
Introduction
Harman, first isolated from Peganum harmala, and related alkaloids such as harmine and harmaline are agents that have the β-carboline structure (Tse et al., 1991). They are found in medicinal plants and in mammalian tissues, including the central nervous system, liver, platelets, plasma and urine Airaksinen and Kari, 1981, Beck and Faull, 1986. They have also been used in hallucinogenic preparations by South American and African tribes (Holmstedt and Lindgren, 1967). These harmala alkaloids have pharmacological effects including convulsive or anticonvulsive actions (Loew et al., 1985), binding to benzodiazepine receptors Muller et al., 1981, Rommelspacher et al., 1981, tremoregenesis (Lutes et al., 1988) and monoamine oxidase inhibition Fuller et al., 1986, Rommelspacher et al., 1994.
Studies on the occurrence and the properties of β-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds may play a role in processes of substance abuse and dependence. For example, chronic infusion of harman increases voluntary ethanol intake in rats (Adel and Myers, 1994). (Cappendijk et al., 1994) also showed that norharman produced prominent inhibitory effects of the naloxone-precipitated withdrawal syndrome in morphine dependent rats. On the other hand, high plasma levels of these compounds have been found in chronic alcoholics (Rommelspacher et al., 1991) and heroin dependent humans Stohler et al., 1993, Stohler et al., 1995. In a recent study, (Spijkerman et al., 2002) showed that elevated plasma levels of norharman are due to heavy smoking. Although these findings suggest a role of at least some of the β-carbolines in alcoholism and drug dependence, literature investigating the effects of other harmala alkaloids such as harman and harmine on morphine dependence and withdrawal are very limited.
Chronic administration of opiates such as morphine produces tolerance and dependence that limit their clinical use (O'Brien, 1996). The discontinuation of chronic administration of morphine to rodents is associated with excitatory withdrawal signs (Aricioglu-Kartal and Uzbay, 1997). Although the morphine withdrawal syndrome in rodents has been well described Blaesig et al., 1973, Aricioglu-Kartal and Uzbay, 1997, the mechanisms underlying physical dependence to morphine or the morphine withdrawal syndrome are poorly understood. However, indirect evidence suggests that multiple mechanisms may be operating in these processes Koob, 1992, Stolerman, 1992.
The present study was designed to investigate the effects of harman and harmine on naloxone-precipitated withdrawal syndrome in morphine dependent rats. This was done by observing behavioural signs of morphine withdrawal in morphine dependent rats after treatment with harman and harmine.
Section snippets
Animals and Laboratory
All procedures in this study were in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health (USA) and the declaration of Helsinki. Adult male Wistar rats (200–250 g) were used in the study. They were housed in a quiet, temperature (20° ± 2 °C) and humidity (60 ± 3 %) controlled room in which a 12/12 hrs light-dark cycle was maintained (07:00–19:00 light). The rats were fed standard lab chow and tap water ad libitum during the study.
Drugs used in the study
Results
In rats treated for three days with morphine pellets, naloxone (2 mg/kg) precipitated clear signs of abstinence (open bars, Fig. 1, Fig. 2).
Harman (5 and 10 mg/kg) increased significantly the intensity of naloxone- precipitated jumping behaviour in morphine dependent rats [F(2,33) = 42.17; p < 0.05] (Fig. 1A). It decreased significantly the intensity of wet dog shake, writhing, defecation, tremor and ptosis [F(2,33) = 129.9, 37.11, 19.13, H(2,33) = 13.51 and 11.93, respectively; p < 0.05)] (
Discussion
The present study showed that both harman and harmine, β-carbolines, attenuated the intensity of many signs of the naloxone-precipitated morphine withdrawal syndrome in rats. Our findings are in line with the hypothesis that harmala alkaloids may have beneficial effects in morphine withdrawal and support the results of (Cappendijk et al., 1994) who found that norharman, another harmala alkaloid, produced inhibitory effects on naloxone-precipitated withdrawal syndrome in morphine dependent rats.
Conclusion
In conclusion, our results suggest that the β-carbolines harman and harmine have some beneficial effects on naloxone-precipitated withdrawal syndrome in rats. Our observations also indicated that harmine is more effective than harman in reducing the signs of morphine abstinence syndrome or morphine withdrawal.
Acknowledgements
This study has been supported by “Republic of Turkey, Ministry of Defense and Institute of State Planning” (Grant No: MSB-DPT-3; 99K120150).
References (34)
- et al.
Inhibition of morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester
Life Sciences
(1993) - et al.
Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats
Life Sciences
(1997) - et al.
Concentrations of the enantiomers of 5-hydoxymethtryptoline in mammalian urine: implications for in vivo biosynthesis
Biochemical Pharmacology
(1986) - et al.
The inhibitory effect of norharman on morphine withdrawal syndrome in rats: comparison with ibogaine
Behavioural Brain Research
(1994) - et al.
Enhancement of 7-nitro indazole-induced inhibition of brain nitric oxide synthase by norharmane
Nuroscience Letters
(1995) - et al.
MD 240928 and harmaline: opposite selectivity in antagonism of the inactivation of types A and B monoamine oxidase by pargyline in mice
Life Sciences
(1986) - et al.
Beta-carboline binding to imidazoline receptors
Drug and Alcohol Dependence
(2001) Drug abuse: anatomy, pharmacology and function of reward pathways
Trends in Pharmacological Sciences
(1992)- et al.
Tolerance to the tremorogenic effects of harmaline: evidence for altered olivo-cerebellar function
Neuropharmacology
(1988) - et al.
On the neuropharmacology of harman and other β-carbolines
Pharmacology, Biochemistry and Behavior
(1981)
Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo
European Journal of Pharmacology
Harman (1-methyl-β-carboline) is a natural inhibitor of monoamine oxidase type A in rats
European Journal of Pharmacology
Stimulatory effect of harmane and other beta-carbolines on locus coeruleus neurons in anaesthetized rats
Neuroscience Letters
The impact of smoking and drinking on plasma levels of norharman
European Neuropsychopharmacology
The role of beta-carbolines (harman/norharman) in heroin addicts
European Psychiatry
Drugs of abuse: behavioral principles, methods and terms
Trends in Pharmacological Sciences
Increased alcohol intake in low alcohol drinking rats after chronic infusion of the β-carboline harman into the hippocampus
Pharmacology, Biochemistry and Behavior
Cited by (41)
A review on β-carboline alkaloids and their distribution in foodstuffs: A class of potential functional components or not?
2021, Food ChemistryCitation Excerpt :Competition experiments against [3H]2-BFI (I2 receptor ligand, 2-(2-benzofuranyl)-2-imidazoline) indicated that βCs recognized the components of the imidazoline I2 receptor with the order of potency (KiH in nM): norharman > harmalol > harmaline ≫ harmine > harman in brain, while in liver, the order was harmine > harmaline ≫ harmalol > harman ≫ norharman (Miralles et al., 2005). Moreover, βCs prevented the stimulating effect of naloxone on 3,4-dihydroxyphenylalanine synthesis in morphine-dependent rats which indicated they might be useful in the treatment of opioid withdrawal syndrome in humans (Aricioglu-Kartal, Kayır, & Tayfun Uzbay, 2003; Miralles et al., 2005). βCs are expected to be new anticancer drugs because of their cytotoxic activity.
Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross-sectional study of 11,912 consumers
2021, Journal of Affective Disorders Reportsβ-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats
2020, Pharmacology Biochemistry and BehaviorEffect of harmane, an endogenous β-carboline, on learning and memory in rats
2013, Pharmacology Biochemistry and BehaviorCitation Excerpt :Harmane has a number of effects on the central nervous system function pointing to its importance as a neuromodulator. Previous studies has been shown that treatment with harmane has a profound anti-allodynic effect in both mononeuropathic and acute pain; anxiolytic and antidepressant effect and it has been found to have a modulatory role on both in vivo and in vitro morphine withdrawal syndrome (Aricioglu et al., 2003; Aricioglu and Altunbas, 2003; Aricioglu and Utkan, 2003; Aricioglu-Kartal et al., 2003). In general, memory function, as measured by changes in an animal's behavior is determined some time after learning, which reflects many processes, including the acquisition, consolidation and retrieval of memory (Abel and Lattal, 2001).
Developments in harmine pharmacology - Implications for ayahuasca use and drug-dependence treatment
2012, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :It has been suggested that β-carbolines may represent novel targets for opiate dependence therapeutics due to reported modulation of some behavioural effects of morphine by I2-BS ligands (Sanchez-Blazquez et al., 2000). Harmine (5 and 10 mg/kg) attenuated the intensity of most signs of morphine withdrawal in the rat (Aricioglu-Kartal et al., 2003). These findings were extended by Miralles et al. (2005), who also investigated a series of β-carbolines for binding affinities at I1-BS and I2-BS, in addition to the effects of norharman on the behavioural and biochemical effects of opiate withdrawal.