In these experiments, the iboga alkaloid congener, 18-MC, differentially affected the acquisition, expression and reinstatement of a cocaine CPP. It was not surprising that 18-MC blocked the acquisition of a cocaine CPP, as this component has been associated with the direct rewarding properties of a drug, and 18-MC also decreases cocaine self-administration [3
]. However, 18-MC had no effect on CPP expression, and enhanced cocaine-induced reinstatement of CPP following extinction. Contrasting effects on CPP acquisition and expression have been previously reported (e.g.,[2
]), suggesting different neurobiological mechanisms underlie these processes. Still, there is little consensus regarding the precise neurotransmitter systems or brain regions that regulate CPP acquisition, expression and reinstatement [1
These results are consistent with those obtained using ibogaine, the parent compound of 18-MC. Like 18-MC, ibogaine disrupted acquisition of morphine[15
] and amphetamine CPP [11
], without affecting CPP expression [10
]. Furthermore, the two compounds did not elicit an aversion or a preference when administered alone[15
]. The action of both 18-MC and ibogaine may be due to their role as α3β4 nicotinic receptor antagonists [14
]. This nAChR subtype is densely populated along the habenulo-interpeduncular pathway, which has been referred to as an “alternate reward pathway” due to the existence of reciprocal connections between it and the mesolimbic dopamine pathway [13
]. Local injections of 18-MC into the medial habenula or interpeduncular nucleus reduce drug self-administration[5
]. Moreover, the habenulo-interpeduncular pathway has been recently implicated in mediating drug withdrawal [16
An enhanced cocaine-induced reinstatement of CPP by 18-MC probably does not reflect a summation of rewarding properties of 18-MC and cocaine, as 18-MC did not induce a place preference when given alone. One possible interpretation of our findings is that 18-MC behaved as a stressor, classically known to enhance reinstatement of self-administration[17
]. However, it might then be assumed that 18-MC would elicit a conditioned place aversion when delivered alone, which was not the case. Similarly, since 18-MC had no rewarding or aversive effects when tested alone there appear to be no anxiolytic or anxiogenic effects of 18-MC that could influence the results with cocaine. Rather, it is possible that 18-MC diminishes the perceived effect of cocaine and more time was spent on the drug-paired side during reinstatement in order to compensate for this diminished perception. The effect of 18-MC on reinstatement of drug self-administration has not been investigated, nor has ibogaine been tested in this manner. Further research is necessary to determine how 18-MC is able to enhance reinstatement in this model.
The dose of 18-MC used in these experiments, 40 mg/kg, was appropriate as it blocks self-administration of cocaine and morphine and acutely decreases dopamine release from the nucleus accumbens [3
]. It should be noted that the acquisition component of CPP differs from expression and reinstatement of the task in that acquisition is tested in a drug-free state. The terminal half-life of 18-MC in vivo
is approximately 100 minutes [4
]. Since 18-MC was injected 45 minutes prior to the expression and reinstatement phases, it is not possible to rule out state-dependent effects during these phases, except that 18-MC exhibited contrasting effects during these procedures, with no effect on expression but enhancement of cocaine-induced reinstatement. Furthermore, 18-MC administered prior to the reinstatement test did not change locomotor activity, as indicated by the number of crosses among the compartments.
In conclusion, we have found that the iboga alkaloid congener, 18-MC, reduces the acquisition of a cocaine CPP, but has no effect on CPP expression, and actually enhances the cocaine-primed reinstatement of CPP. Although the acquisition, expression and reinstatement of CPP appear to involve separate and different mechanisms, the precise details responsible for their differences remain to be determined.