Pharmacology Biochemistry and Behavior, Vol. 63, No. 3, pp. 457–464, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/99/$–see front matter PII S0091-3057(99)00038-6 457 Ibogaine Enhances the Expression of Locomotor Sensitization in Rats Chronically Treated With Cocaine KAREN K. SZUMLINSKI, ISABELLE M. MAISONNEUVE AND STANLEY D. GLICK Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY 12208 Received 26 June 1998; Revised 11 December 1998; Accepted 22 December 1998 SZUMLINSKI, K. K., I. M. MAISONNEUVE AND S. D. GLICK. Ibogaine enhances the expression of sensitization in rats chronically treated with cocaine. PHARMACOL BIOCHEM BEHAV 63(3) 457–464, 1999.—Pretreatment (19 h) with the putative antiaddictive agent, ibogaine, has been shown previously to potentiate cocaine-induced locomotion in rats. The present study demonstrates that the magnitude of this effect of ibogaine is dependent on the previous cocaine history of the animal, on the time following ibogaine treatment, and on the number of ibogaine treatments. Compared to rats with no previ- ous cocaine experience, ibogaine pretreatment (40 mg/kg, IP, 19 h earlier) markedly enhanced the expression of locomotor sensitization in response to a cocaine challenge injection (7.5 mg/kg) in rats that were chronically treated with cocaine (15 mg/ kg, IP, daily for 5 days). Tolerance to cocaine-induced locomotor sensitization appeared to occur in vehicle-pretreated chronic cocaine controls. Following a second series of identical treatments (beginning 3–4 days after the initial treatment se- ries), locomotor responding to the cocaine challenge was further enhanced by a second ibogaine injection in chronically co- caine-treated animals. Twenty-four hours later, when animals were challenged again with cocaine in the absence of any fur- ther ibogaine pretreatment, the effect of ibogaine had dissipated. Consistent with previous studies from this laboratory, these data demonstrate that ibogaine can enhance sensitivity to the psychomotor stimulant effect of cocaine. The results of the present study further indicate that the extent of this effect depends on the animal’s history of exposure to both ibogaine and cocaine. © 1999 Elsevier Science Inc. Ibogaine Cocaine Locomotor activity Sensitization Rats THE naturally occurring indole alkaloid, ibogaine, is being cur- rently investigated for its antiaddictive properties (7,16,45). Both human anecdotal reports and preclinical studies indicate that a single dose of ibogaine can produce prolonged (from 1 day to several weeks) decreases in the self-administration of a wide variety of drugs of abuse [including, cocaine (7,14,16), morphine (16,18,49), nicotine (49), and alcohol (45)]; repeated ibogaine dosing may further prolong these effects (7,15,16,18,31). The neural mechanism(s) underlying ibogaine’s antiaddictive effects are unclear. Receptor binding studies demonstrate that ibogaine binds with moderate affinity to kappa opioid recep- tors (10,17), the NMDA subtype of glutamate receptor (17,43), and the serotonin transporter (36), all of which may contribute to this drug’s mechanism of action. Noribogaine [(12); hydrox- yibogamine], the only known metabolite of ibogaine (19), also appears to have affinity for these same receptors (40). Addi- tionally, in in vivo microdialysis studies, ibogaine affects the dopaminergic responses in the nucleus accumbens to various drugs of abuse (e.g., cocaine, amphetamine, morphine, and nic- otine), and the latter actions may mediate effects of ibogaine on the rewarding properties of abused drugs (30,55,56). Ibogaine affects drug-induced locomotor behavior, an ef- fect mediated presumably by the mesencephalic dopamine systems (2,56). The effects of ibogaine on locomotion appear to depend on a number of factors. These include: the type and dose of drug administered [e.g., (32,41)], the species studied (3,48), the sex of the animal (39), and the time after ibogaine injection (4,28,32,35). The previous drug history of the animal is also important. For example, ibogaine produces greater de- creases in morphine-induced locomotion in rats chronically treated with morphine, compared to acutely treated animals (41). Recently, it was reported that ibogaine has differential Requests for reprints should be addressed to Stanley D. Glick, Department of Pharmacology and Neuroscience (A-136), Albany Medical Col- lege, 47 New Scotland Avenue, Albany, NY 12208.