Tj. De Vries et al., Dopaminergic mechanisms mediating the incentive to seek cocaine and heroinfollowing long-term withdrawal of IV drug self-administration, PSYCHOPHAR, 143(3), 1999, pp. 254-260
Rationale: The neurobiological mechanisms underlying the persistence of dru
g craving in detoxified addicts are still poorly understood. Objective: The
present study was designed to evaluate dopaminergic mechanisms in drug-see
king behaviour following long-term (>3 weeks) extinction of IV drug self-ad
ministration in rats. Methods: To that end, we studied the effects of direc
t and indirect dopamine (DA) agonists on reinstatement of previously exting
uished responding for heroin (50 mu g/kg per injection; 14-15 daily 3-h ses
sions) and cocaine (500 mu g/kg per injection; 10-11 daily 2-h sessions). R
esults: In animals with a cocaine history, priming with cocaine, the select
ive DA reuptake inhibitor GBR-12909 and the DA D-2 receptor agonist quinpir
ole resulted in robust and selective reinstatement of non-reinforced nose p
oking behaviour in the previously drug-paired hole. In contrast, the D-1 ag
onist SKF-82958 failed to reinstate responding and the non-selective DA ago
nist apomorphine even suppressed responding in these animals. In heroin-tra
ined rats, heroin and GBR-12909 strongly reinstated responding, whereas all
direct DA agonists were ineffective. Again, the two highest doses of apomo
rphine decreased responding in these animals. In a parallel study, the abil
ity of DA ligands to express behavioural sensitization in animals pretreate
d with amphetamine or morphine was evaluated. Interestingly, all agonists t
hat reinstated responding in the present study caused expression of locomot
or sensitization and vice verse. Conclusions: The differences between direc
t and indirect agonists indicate a clear, but complex, involvement of DA in
drug-seeking behaviour long after detoxification. Moreover, the results sh
ow an important role of D-2 receptor activation in the persistence of cocai
ne- but not heroin-seeking behaviour. Finally, the results from both studie
s suggest a relationship between drug-induced reinstatement and drug hyperr
esponsiveness in long-term abstinent rats.