Alteration of neuroinflammation detected by 18F-GE180 PET imaging in place-conditioned rats with morphine withdrawal

Background Accumulating evidence indicates that neuroinflammation (NI) significantly contributes to drug addiction, but the conversion of NI after drug withdrawal is not clear. Here, we conducted 18F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of NI during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with 18F-GE180. Methods Twelve male adult Sprague–Dawley rats were subjected to morphine withdrawal by the administration of naloxone, and six of them were used to model conditioned place aversion (CPA). 18F-GE180 PET imaging was performed for 11 rats on the last day of the morphine treatment phase and for 10 rats on the response assessment phase of the behavior conditioning procedure. A 18F-GE180 template was established for spatial normalization of each individual image, and the differential 18F-GE180 uptakes between the drug withdrawal (DW) group and the drug addiction (DA) group, the CPA group and the DA group, and the CPA group and the DW group were compared by a voxel-wise two-sample t test using SPM8. Results Both the DW group and the CPA group spent less time in the conditioning cage during the post-test phase compared with the pretest phase, but only the difference in the CPA group was significant (63.2 ± 34.6 vs. − 159.53 ± 22.02, P < 0.005). Compared with the DA group, the uptake of 18F-GE180 increased mainly in the hippocampus, visual cortex, thalamus and midbrain regions and decreased mainly in the sensory-related cortices after the administration of naloxone in both the DW and CPA groups. Increased 18F-GE180 uptake was only observed in the mesolimbic regions after conditioned aversion compared with the DW group. Conclusion In morphine-dependent rats, Neuroinflammation (NI) became more severe in the addiction-involved brain regions but remitted in the sensory-related brain regions after the administration of naloxone, and this NI induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory.

Confirmation of a Causal Taar1 Allelic Variant in Addiction-Relevant Methamphetamine Behaviors

Sensitivity to rewarding and reinforcing drug effects has a critical role in initial use, but the role of initial aversive drug effects has received less attention. Methamphetamine effects on dopamine re-uptake and efflux are associated with its addiction potential. However, methamphetamine also serves as a substrate for the trace amine-associated receptor 1 (TAAR1). Growing evidence in animal models indicates that increasing TAAR1 function reduces drug self-administration and intake. We previously determined that a non-synonymous single nucleotide polymorphism (SNP) in Taar1 predicts a conformational change in the receptor that has functional consequences. A Taar1m1J mutant allele existing in DBA/2J mice expresses a non-functional receptor. In comparison to mice that possess one or more copies of the reference Taar1 allele (Taar1+/+ or Taar1+/m1J), mice with the Taar1m1J/m1J genotype readily consume methamphetamine, express low sensitivity to aversive effects of methamphetamine, and lack sensitivity to acute methamphetamine-induced hypothermia. We used three sets of knock-in and control mice in which one Taar1 allele was exchanged with the alternative allele to determine if other methamphetamine-related traits and an opioid trait are impacted by the same Taar1 SNP proven to affect MA consumption and hypothermia. First, we measured sensitivity to conditioned rewarding and aversive effects of methamphetamine to determine if an impact of the Taar1 SNP on these traits could be proven. Next, we used multiple genetic backgrounds to study the consistency of Taar1 allelic effects on methamphetamine intake and hypothermia. Finally, we studied morphine-induced hypothermia to confirm prior data suggesting that a gene in linkage disequilibrium with Taar1, rather than Taar1, accounts for prior observed differences in sensitivity. We found that a single SNP exchange reduced sensitivity to methamphetamine conditioned reward and increased sensitivity to conditioned aversion. Profound differences in methamphetamine intake and hypothermia consistently corresponded with genotype at the SNP location, with only slight variation in magnitude across genetic backgrounds. Morphine-induced hypothermia was not dependent on Taar1 genotype. Thus, Taar1 genotype and TAAR1 function impact multiple methamphetamine-related effects that likely predict the potential for methamphetamine use. These data support further investigation of their potential roles in risk for methamphetamine addiction and therapeutic development.

Alteration of Neuroinflammation Detected by 18F-GE180 PET Imaging in Place-Conditioned Rats with Morphine Withdrawal

Background: Accumulating evidence indicates that neuroinflammation significantly contributes to drug addiction, but the conversion of neuroinflammation after drug withdrawal is not clear. Here, we conducted 18F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of neuroinflammation during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with 18F-GE180.Methods: Twelve male adult Sprague-Dawley rats were subjected to morphine withdrawal by the administration of naloxone, and six of them were used to model conditioned place aversion (CPA). 18F-GE180 PET imaging was performed for 11 rats on the last day of the morphine treatment phase and for 10 rats on the response assessment phase of the behavior conditioning procedure. A GE180 template was established for spatial normalization of each individual image, and the differential 18F-GE180 uptakes between the drug withdrawal (DW) group and the drug addiction (DA) group, the CPA group and the DA group, and the CPA group and the DW group were compared by a voxel-wise two-sample t-test using SPM8. Results: Both the DW group and the CPA group spent less time in the conditioning cage during the posttest phase compared with the pretest phase, but only the difference in the CPA group was significant (63.2 ± 34.6 vs. -159.53 ± 22.02, P < 0.005). Compared with the DA group, the uptake of 18F-GE180 increased mainly in the hippocampus, visual cortex, thalamus and midbrain regions and decreased mainly in the sensory-related cortices after the administration of naloxone in both the DW and CPA groups. Increased 18F-GE180 uptake was only observed in the mesolimbic regions after conditioned aversion compared with the DW group. Conclusion: In morphine-dependent rats, neuroinflammation became more severe in the addiction-involved brain regions but remitted in the sensory-related brain regions after the administration of naloxone, and this neuroinflammation induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory.

Sensory neurons expressing the atypical olfactory receptor guanylyl cyclase D are required for the acquisition of odor preferences by mice in diverse social contexts

ABSTRACTAnimals use social communication to learn important information from conspecifics that can guide appropriate behavioral choices. For example, during the social transmission of food preference (STFP), conspecific semiochemicals detected by mouse olfactory sensory neurons (OSNs) expressing the atypical olfactory receptor guanylyl cyclase D (GC-D+ OSNs) promote the acquisition of food preferences in the recipient animal, mitigating the risk of ingesting food contaminated with toxins or pathogens. However, it is unclear if GC-D+ OSNs mediate preference learning outside this specific context. Here, we report that GC-D+ OSNs are required for the acquisition of odor preferences by both adult and juvenile mice, and that GC-D-dependent preference could be formed for conditionally aversive odors. We used a two-choice olfactory behavioral test to assess odor preferences in adult Gucy2d +/+, +/- and -/- mice that encountered novel odors together with GC-D+ OSN stimuli (guanylin family peptides), during social investigation of a live conspecific, or during suckling as pups. Gucy2d +/+ and +/-mice (which express functional GC-D), but not Gucy2d -/- littermates, successfully acquire a preference for the demonstrated odor in any of these behavioral paradigms. Mice could even acquire a GC-D-dependent preference for odors to which they had recently formed a conditioned aversion. Together, these results demonstrate that GC-D+ OSNs mediate the acquisition of socially-transmitted odor preferences in different social and experiential contexts and at different life stages.