Effect Of Laterodorsal Tegmental Nucleus Cholinergic Neurons On Heroin-seeking Behavior Induced By Cues In Rats

Objective:The mesolimbic dopaminergic pathway of VTA（Ventral tegmental area）-NAc（Nucleusaccumbens） is critical in drug rewarding and drug relapse.Acetylcholinergic transmission in theVTA or NAc plays an important role in heroin-seeking behavior. The LDTg（Laterodorsaltegmental nucleus） provides a significant proportion of the cholinergic innervation of the VTA.Cholinergic modulation of VTA neurons arises from the LDTg, and little ptojection fromPPT（Pedunculopontine tegmental nucleus）. The goal of these experiments was to examine apotential role for the LDTg cholinergic neurons in the reinstatement of heroin-seeking behavior.Methods:The male SD rats were trained to self-administer heroin under an FR-1schedule for4h per dayfor14days. After14days of heroin withdrawal, rats were placed in stereotaxic apparatus andguided cannulae for microinjections were implanted bilaterally. We assessed the effect ofmicroinjection of Gal, Sco, or Gal combined with Sco into the LDTg on cue-induced heroin-seeking behavior. Then we assessed the effect of microinjection of xanomeline into the LDTg oncue or heroin-induced heroin-seeking behavior before the reinstatement testing, and the effect ofmicroinjection of vu0152100into the LDTg on cue or heroin-induced heroin-seeking behaviorbefore the reinstatement testing.Results:1. We assessed the effect of microinjection of Gal（3μg/μl）, Sco（0.5μg/μl）, or Gal combined withSco into the LDT on cue-induced heroin-seeking behavior, Gal significantly inhibited the activeresponses of heroin self-administration（P<0.05）, There is significant differences between the Galand Gal combined with Sco（P<0.05）.2. The microinjection of xanomeline（1,3,10μg/μl） into the LDTg on cue-induced heroin-seekingbehavior, There is no significant differences between the xanomeline（1μg/μl） and vehicle; there issignificant differences between the active nose-poking responses of xanomeline（3,10μg/μl） andvehicle （P<0.05）. Microinjection of xanomeline（1,3,10μg/μl） into the LDTg on heroin-inducedheroin-seeking behavior, there is significant differences between the active nose-poking responsesof xanomeline and vehicle （P<0.05）. 3. The microinjection of vu0152100（10μg/μl） into the LDTg on cue-induced heroin-seekingbehavior, the active nose-poking responses of vu0152100are significant lower than vehocle’s by0.5h（P<0.05）,and have no no significant differences by1h,1.5h or2h; Microinjection ofvu0152100（10μg/μl） into the LDTg on heroin-induced heroin-seeking behavior, the active nose-poking responses of vu0152100are significant lower than vehocle’s by0.5h and1h（P<0.05）, andhave no no significant differences by1.5h or2h.Conclusions:The microinjection of Gal into the LDTg blocked cue-induced heroin-seeking, while themicroinjection of Sco into the LDTg reversed the inhibitory effect of Gal on drug-seeking behavior.The microinjection of xanomeline and vu0152100into the LDTg inhibited heroin relapse behavior.The results suggest that the LDTg cholinergic M receptors are involved in the cue or heroin-induced heroin-seeking behavior, especially the muscarinic acetylcholine receptor subtype M₄inthe LDTg may regulate the heroin relapse behavior. The results demonstrated that the LDTgcholinergic neurons play an important role in the heroin relapse and addiction.