Separating analgesia from reward within the ventral tegmental area

Abstract

Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses to noxious stimuli, and presumably contributes to the addictive liability of strong analgesics. VTA dopamine neurons are activated via cholinergic afferents and microinjection of carbachol (cholinergic agonist) into VTA is rewarding. Here, we evaluated regional differences within VTA in the capacity of carbachol to suppress rats' affective response to pain (vocalization afterdischarges, VADs) and to support conditioned place preference (CPP) learning. As carbachol is a non-specific agonist, muscarinic and nicotinic receptor involvement was assessed by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into VTA prior to carbachol treatment. Unilateral injections of carbachol (4 μg) into anterior VTA (aVTA) and posterior VTA (pVTA) suppressed VADs and supported CPP; whereas, injections into midVTA failed to effect either VADs or CPP. These findings corroborate the hypothesis that the neural substrates underlying affective analgesia and reward overlap. However, the extent of the overlap was only partial. Whereas both nicotinic and muscarinic receptors contributed to carbachol-induced affective analgesia in aVTA, only muscarinic receptors mediated the analgesic action of carbachol in pVTA. The rewarding effects of carbachol are mediated by the activation of both nicotinic and muscarinic receptors in both aVTA and pVTA. The results indicate that analgesia and reward are mediated by separate cholinergic mechanisms within pVTA. Nicotinic receptor antagonism within pVTA failed to attenuate carbachol-induced analgesia, but prevented carbachol-induced reward. As addictive liability of analgesics stem from their rewarding properties, the present findings suggest that these processes can be neuropharmacologically separated within pVTA.

The antero-posterior heterogeneity of the ventral tegmental area

“…An inflexion point was observed between the rewarding and aversive effects of cocaine, around À5.5 mm from the bregma, which neuroanatomically correspond to the location of the interpeduncular nucleus below the VTA. This transition point is similar to the one that was more recently observed between the lack or presence of conditioned place preference after intra-VTA carbachol administration (Schifirnet et al, 2014).…”

“…Some discrepancies are however present concerning the ability of carbachol to induce conditioned place preference into the aVTA Schifirnet et al, 2014), which may be related to the definition of ''aVTA''. Indeed, a recent study proposed the presence of an aVTA (supporting carbachol conditioned place preference), a mid-VTA (lacking such conditioned response) and a pVTA (supporting carbachol conditioned place preference) along the VTA antero-posterior axis (Schifirnet et al, 2014). However, it may be difficult to discriminate aVTA from lateral hypothalamus effects with very rostral injection sites.…”

“…Furthermore, the administration of carbachol into the pVTA also induces locomotor activity, conditioned place preference and c-Fos expression in several brain regions Ikemoto et al, 2003;Schifirnet et al, 2014). Some discrepancies are however present concerning the ability of carbachol to induce conditioned place preference into the aVTA Schifirnet et al, 2014), which may be related to the definition of ''aVTA''.…”

“…Furthermore, the administration of carbachol into the pVTA also induces locomotor activity, conditioned place preference and c-Fos expression in several brain regions Ikemoto et al, 2003;Schifirnet et al, 2014). Some discrepancies are however present concerning the ability of carbachol to induce conditioned place preference into the aVTA Schifirnet et al, 2014), which may be related to the definition of ''aVTA''. Indeed, a recent study proposed the presence of an aVTA (supporting carbachol conditioned place preference), a mid-VTA (lacking such conditioned response) and a pVTA (supporting carbachol conditioned place preference) along the VTA antero-posterior axis (Schifirnet et al, 2014).…”

“…Experiments on tail shocks' thresholds inducing vocalizations also showed aVTA/pVTA differences in the control of such responses. The microinjection of the cholinergic agonist carbachol into the pVTA strongly increased the shock intensity necessary to elicit a vocalization (Schifirnet et al, 2014), which was prevented by either nicotinic (mecamylamine) or muscarinic (atropine) antagonists. No influence was observed at more anterior levels (designed in this article as ''midVTA''), and an increase in the shock intensity eliciting vocalization was again observed more rostrally (designed in this article as ''aVTA'') but in this case only mecamylamine prevented it.…”