Neuropharmacological characterization of local ibogaine effects on dopamine release

Abstract

Local perfusion with ibogaine (10(-6) M-10(-3) M) via microdialysis probes in the nucleus accumbens or striatum of rats produced a biphasic dose-response effect on extracellular dopamine levels. Lower doses (10(-6) M-10(-4) M) produced a decrease while higher doses (5 x 10(-4) M-10(-3) M) produced an increase in dopamine levels. Dihydroxyphenylacetic acid (DOPAC) levels were not effected. Naloxone (10(-6) M) and norbinaltorphimine (10(-6) M-10(-5) M) did not affect dopamine levels, but when co-administered with ibogaine (10(-4) M) blocked the decrease in dopamine levels produced by ibogaine. Ibogaine (10(-3) M) stimulation of dopamine levels in the striatum was calcium independent and not blocked by tetrodotoxin (10(-5) M). Pretreatment with cocaine (15 mg/kg), reserpine (5 mg/kg) or alpha-methyl-para-tyrosine (250 mg/kg) given intraperitoneally significantly reduced ibogaine (10(-3)M) stimulation of striatal dopamine levels. In striatal synaptosomes, both ibogaine and harmaline (10(-7)-10(-4) M) produced dose-dependent inhibition of [3H]-dopamine uptake. These findings suggest that ibogaine has both inhibitory and stimulatory effects on dopamine release at the level of the nerve terminal. It is suggested that the inhibitory effect is mediated by kappa opiate receptors while the stimulatory effect is mediated by interaction with the dopamine uptake transporter.

Apomorphine enhances harmaline-induced tremor in rats

“…However, this compound is also a reversible monoamine oxidase-A (MAO-A) inhibitor, which itself and by its metabolite harmine, enhances dopaminergic transmission in the striatum [17,[33][34][35]. The present results showing that dopaminergic receptor stimulation enhances tremor induced by this agent, suggest that the above striatal mechanism may contribute to this behavior.…”

The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters

“…These competitive inhibitors include several compounds that also inhibit the closely related dopamine and norepinephrine transporters (17, 29). Previous reports suggested that both SERT and DAT were sensitive to inhibition by ibogaine (5, 30). Therefore, we compared the kinetics of ibogaine inhibition of SERT and DAT.…”

Harmaline Tremor: Underlying Mechanisms in a Potential Animal Model of Essential Tremor

“…Activity against MAO-B is negligible 94. Harmaline inhibits synaptosomal GABA uptake (IC 50 47 μM)95 and dopamine uptake (IC 50  = 8.1 μM),96 and increases dopamine release from striatal slices at 6 μM 94. Low doses enhance levodopa-induced stereotypy in mice 97.…”