Comparative neurobiological effects of ibogaine and MK-801 in rats
Introduction
Ibogaine is a plant-derived compound that has gained attention as a possible medication for treating substance use disorders (reviewed by Popik et al., 1995b). Evidence for the ‘anti-addictive’ properties of ibogaine has come from both preclinical and human studies. In rats, pretreatment with ibogaine decreases the self-administration of cocaine and morphine (Glick et al., 1991, Cappendijk and Dzoljic, 1993, Glick et al., 1994). The drug also alleviates withdrawal symptoms in morphine-dependent animals (Glick et al., 1992, Popik et al., 1995a; although see Sharpe and Jaffe, 1990). In a recent clinical investigation, Sheppard (1994) found that a single ibogaine treatment completely prevented the appearance of withdrawal symptoms in opiate addicts. Collectively, such findings support the utility of ibogaine as a treatment for drug addiction.
Despite extensive research, the precise mechanism responsible for the anti-addictive properties of ibogaine is enigmatic. It is well established that the drug binds with low μM potency to multiple neuronal targets in the brain including sigma-2 receptors (Bowen et al., 1995, Mach et al., 1995), serotonin (5-HT) and dopamine (DA) transporters (Mash et al., 1995a, Staley et al., 1996), μ and κ opioid receptors (Deecher et al., 1992, Pearl et al., 1995), and N-methyl-d-aspartate (NMDA) ion channels (Popik et al., 1994, Sweetnam et al., 1995). However, the role of these various binding sites in mediating specific actions of ibogaine has not been resolved. Biodistribution studies in rats show that brain levels of ibogaine range from 10 to 20 μM when measured 1 h after acute administration of 50 mg/kg, p.o. (Staley et al., 1996) or 40 mg/kg, i.p. (Hough et al., 1996). Thus the interaction of ibogaine with μM-affinity binding sites appears to be functionally relevant in vivo.
Recently some investigators have speculated that the anti-addictive properties of ibogaine might involve antagonist activity at NMDA-coupled ion channels, similar to the effects of MK-801 (Mash et al., 1995b, Popik et al., 1995a, Chen et al., 1996). This hypothesis has important implications since MK-801 is reported to block the long-term neuroadaptive changes associated with chronic administration of opioids, ethanol, and psychomotor stimulants (Karler et al., 1989, Trujillo and Akil, 1991, Wu et al., 1993). Ibogaine inhibits the binding of [3H]MK-801 in brain membrane preparations (Popik et al., 1994, Sweetnam et al., 1995). Similar to MK-801, ibogaine blocks depolarizations evoked by NMDA in cultured hippocampal neurons and in intact motorneurons (Mash et al., 1995b, Popik et al., 1995a, Chen et al., 1996). Studies in mice show that ibogaine cross-generalizes to MK-801 as a discriminative stimulus and antagonizes NMDA-induced lethality (Popik et al., 1995a, Chen et al., 1996). Thus, ibogaine appears to exhibit MK-801-like properties in a variety of in vitro and in vivo assay systems.
With respect to the preceding discussion, it seems appropriate to further evaluate the NMDA antagonist properties of ibogaine. In the present work, we compared the acute effects of ibogaine and MK-801 on central DA metabolism and stress hormone secretion. We examined the actions of ibogaine and MK-801 on these particular neurobiological endpoints for several reasons. First, the essential role of DA neurons in mediating the addictive properties of abused drugs is well accepted (Wise and Bozarth, 1987, Koob and Bloom, 1988). Second, stress hormones, particularly hormones of the hypothalamic–pituitary–adrenal (HPA) axis, are known to modulate the acute and long-term effects of abused drugs (Piazza and Le Moal, 1996, Piazza and Le Moal, 1997). It seems feasible therefore that the anti-addictive effects of ibogaine might involve changes in DA function and/or activity of the HPA axis. Finally, the effects of ibogaine on DA metabolism and neuroendocrine secretion have recently been studied, and this provides a convenient starting point for comparison to MK-801 (Ali et al., 1996, Baumann et al., 1997).
Section snippets
Animals
Adult male CD rats (250–350 g) from the National Center for Toxicological Research (NCTR) breeding colony were used in these studies. Animals were housed two per cage under controlled conditions (lights on: 06:00–18:00 h) with free access to food and water. The housing facilities were fully accredited by the American Association of the Accreditation of Laboratory Animal Care, and experiments were carried out in accordance with Institutional Animal Care and Use Committee of the NCTR.
Experimental procedures
Rats
Effects of ibogaine and MK-801 on DA metabolism
The control levels of DA, DOPAC, and HVA in the cortex, striatum, and olfactory tubercle (from saline-treated rats) are shown in Table 1. The effect of ibogaine on DA metabolism in these brain regions is illustrated in Fig. 1. For the sake of clarity, the data in Fig. 1 are expressed as a percentage of the control values shown in Table 1. DA was significantly decreased in all three regions when assessed 30 min after ibogaine injection: cortex (F[2,17]=4.51, P<0.025), striatum (F[2,17]=42.50, P
Discussion
In the present study, acute ibogaine administration decreased brain tissue levels of DA along with concomitant increases in the DA metabolites, DOPAC and HVA. The drug also caused dose-related increases in plasma corticosterone and prolactin. It is noteworthy that ibogaine-induced reductions in brain DA and elevations in plasma prolactin were apparent after 10 mg/kg, i.p. (Fig. 1, Fig. 3), a dose which is lower than the typical anti-addictive dose of 40 mg/kg, i.p. (Glick et al., 1991, Glick et
References (41)
- et al.
Neuroendocrine and neurochemical effects of acute ibogaine administration: a time course evaluation
Brain Res.
(1996) - et al.
Ibogaine and its congeners are sigma-2 receptor-selective ligands with moderate affinity
Eur. J. Pharmacol.
(1995) - et al.
Ibogaine modulates cocaine responses which are altered due to environmental habituation: in vivo microvoltammetric and behavioral studies
Pharmacol. Biochem. Behav.
(1994) - et al.
Ibogaine block of the NMDA receptor: in vitro and in vivo studies
Neuropharmacology
(1996) - et al.
Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies
Brain Res.
(1992) - et al.
Effects and aftereffects of ibogaine on morphine self-administration in rats
Eur. J. Pharmacol.
(1991) - et al.
Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor
Neuropharmacology
(1992) - et al.
Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effect of dopamine release in the nucleus accumbens and striatum
Brain Res.
(1994) - et al.
Blockade of ‘reverse tolerance’ to cocaine and amphetamine by MK-801
Life Sci.
(1989) - et al.
Ibogaine possesses a selective affinity for sigma2 receptors
Life Sci.
(1995)
Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study
Eur. J. Pharmacol.
Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats
Brain Res.
Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin
Life Sci.
Properties of ibogaine and its principle metabolite, 12-hydroxyibogamine, at the MK-801 binding site of the NMDA receptor complex
Neurosci. Lett.
CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs
Trends Pharmacol. Sci.
Radioligand binding study of noribogaine, a likely metabolite of ibogaine
Brain Res.
Characterization of the effects of the acute and repeated administration of MK-801 on the release of adrenocorticotropin, corticosterone and prolactin in the rat
Eur. J. Pharmacol.
Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications
Brain Res. Rev.
Ibogaine antagonizes cocaine-induced locomotor stimulation in mice
Life Sci.
A preliminary investigation of ibogaine: case reports and recommendations for further study
J. Subst. Abuse Treat.
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