Effect of acute and subchronic administration of desipramine and venlafaxine on abuse liability of heroin in rats
Opioids and antidepressants are frequently used for the treatment of various pain conditions. A combination of both drug classes may be more effective than either treatment used alone and may result in an opiate-sparing effect. The aim of this study was to investigate if motivational-neutral antidepressants with analgesic properties may affect abuse liability of heroin in rats. The effect of venlafaxine and desipramine was investigated with aid of two behavioural techniques; an intravenous drug self-administration (IVSA) and a conditioned place preference (CPP). Because some effects of antidepressants occurs with prolonged administration, effects of both, acute and sub-chronic administration of antidepressants were assessed. To determine whether antidepressants affect reinforcing properties of heroin, male Long-Evans rats were trained to press a lever in order to receive heroin (0.05 mg/kg/infusion) under a fixed ratio (FR) or a progressive ratio (PR) schedule. A control group was trained in a FR food-reinforced operant procedure. The effect of antidepressants on operant responding for heroin and food was assessed both during acquisition and, in separate groups of rats, during maintenance (i.e., after acquisition) of self-administration behaviour. Daily treatment with venlafaxine (10 mg/kg i.p.) before the operant session attenuated the acquisition of responding for heroin, but not for food. However, when tested during the maintenance phase in rats showing stable responding, acute treatment with venlafaxine only marginally affected operant responding for heroin under a FR10 schedule of reinforcement, and neither acute nor subchronic (once daily during 4 weeks) venlafaxine treatment affected responding under a PR schedule. Thus, daily treatment with an antidepressant attenuates the acquisition of heroin IVSA in a behaviourally specific manner, while having only marginal effects on maintenance of heroin IVSA. Desipramine (10 mg/kg/i.p.) also attenuated the maintenance of heroin intake under FR but not under PR schedule. However desipramine suppressed responding for food, questioning specificity of its effect. To determine whether effect observed in IVSA experiments was due to an antidepressant-induced attenuation of the rewarding effect of heroin, the CPP paradigm has been used. Antidepressants were administered to the male Sprague-Dawley rats prior to the conditioning sessions or prior to the expression test after conditioning, respectively. In additional experiments both antidepressants were administered for two weeks prior to conditioning, or for one week prior to the expression test, respectively. When tested alone, heroin (0.05 – 3.16 mg/kg i.p.) produced a dose-dependent CPP, whereas the antidepressants (1 – 21.5 mg/kg i.p.) produced neither a CPP nor a conditioned place aversion (CPA). For both antidepressants (10 mg/kg i.p.), neither acute nor repeated pretreatment affected acquisition or expression of heroin (0.5 mg/kg) CPP. Thus, the CPP study does not support the hypothesis that the previously observed attenuation of acquisition of heroin IVSA by venlafaxine is due to an attenuation of the rewarding effect of heroin. Because venlafaxine attenuated specifically the acquisition and maintenance of heroin IVSA under the FR, but not maintenance under the PR schedule it may be supposed that venlafaxine can delay the development of heroin addiction, however it has no effect on already existing addiction. Decrease in heroin but not in food intake indicated that venlafaxine to some extent can “stabilise” circuits engaged in reward and motivation. Because venlafaxine is effective in treatment of obsessive-compulsive disorder, it can in principle, display some effects on craving, which is a compulsive drug seeking and taking. On the other hand, venlafaxine did not affect the CPP produced by heroin. Because heroin possesses very high abuse liability, a moderate modulating effect of venlafaxine on it’s reinforcing/rewarding properties might be too weak to be observed across different experimental conditions. Alternatively, the modulation of acquisition of heroin IVSA in the previous study may be related to mechanisms that cannot be modelled with the CPP paradigm. Desipramine attenuated the maintenance of heroin intake under FR schedule, however the observed effect was not specific and the question if desipramine may affect abuse liability of heroin remains open. It is noteworthy that in the present study no indication for an enhanced intake of heroin was found. Therefore, it can be postulated that adding an antidepressant drug, such as venlafaxine, to an opioid for the treatment of pain would not be expected to enhance the abuse liability of the opioid (if anything, the combination might reduce abuse liability).
info:eu-repo/classification/ddc/570, Biowissenschaften, Biologie, Missbrauch, Sucht, Analgetika, Antidepressiva, Abhängigkeit, Operantes Verhalten, Opioiden, Verstärker, Belohnung, Abuse, Addiction, Analgesics, Antidepressants, Dependence, Operant behaviour, Opioids, Reinforcement, Reward
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