ly-379268 and Heroin-Dependence

Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 microg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 microg of LY379268 into the NAc core had no effect, while a higher dose (3.0 microg) decreased this reinstatement. Injections of LY379268 (3.0 microg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.

Topics: Amino Acids; Animals; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Conditioning, Operant; Dose-Response Relationship, Drug; Enzyme Activation; Extinction, Psychological; Heroin; Heroin Dependence; Male; Narcotics; Nucleus Accumbens; Rats; Rats, Long-Evans; Receptors, Metabotropic Glutamate; Secondary Prevention; Self Administration

In humans, drug-associated stimuli can provoke heroin relapse during abstinence. In rats, cues paired with heroin self-administration reinstate heroin seeking in a relapse model. The neurobiological mechanisms involved in this reinstatement, however, are largely unknown. Here, we determined the effect of LY379268, an mGluR2/3 agonist that decreases evoked glutamate release, on cue-induced reinstatement of heroin seeking. Systemic injections of LY379268 attenuated reinstatement of heroin seeking induced by exposure to a discrete tone-light cue that was previously paired with heroin infusions during self-administration training. In contrast, LY379268 had no effect on heroin self-administration. Results indicate that glutamate plays an important role in cue-induced reinstatement of heroin seeking and suggest that mGluR2/3 agonists should be considered for the treatment of opiate relapse.

Topics: Amino Acids; Animals; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Conditioning, Operant; Cues; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Extinction, Psychological; Heroin; Heroin Dependence; Male; Narcotics; Rats; Rats, Long-Evans; Self Administration

The environmental context previously associated with opiate use plays an important role in human relapse, but the neuronal mechanisms involved in context-induced drug relapse are not known. Using a rat relapse model, we determined the effect of a group II metabotropic glutamate receptor agonist [LY379268 ((-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid)] on contextual cue-induced reinstatement of heroin seeking. LY379268, which acts centrally to reduce evoked glutamate release, was injected systemically or directly into the ventral tegmental area (VTA), a brain area involved in opiate reward and conditioned drug effects. Rats were trained to self-administer intravenous heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of lever responding, LY379268 was injected systemically or into the VTA, and nonreinforced responding was determined in the extinction context or the drug context. Exposure to the heroin-associated context induced robust reinstatement of drug seeking, and this effect was attenuated by systemic or intra-VTA injections of LY379268. Results indicate that glutamate transmission in the VTA plays an important role in contextual cue-induced relapse to heroin seeking.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cues; Extinction, Psychological; Glutamic Acid; Heroin Dependence; Injections; Male; Rats; Rats, Long-Evans; Receptors, Metabotropic Glutamate; Recurrence; Substantia Nigra; Ventral Tegmental Area