Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice

• Published in: Psychopharmacology 2021-07, Vol.238 (7), p.2031-2041
• Main Authors: Borrelli, Kristyn N., Langan, Carly R., Dubinsky, Kyra R., Szumlinski, Karen K., Carlezon, William A., Chartoff, Elena H., Bryant, Camron D.
• Format: Article
• Language: English
• Subjects: Addictions; Analysis; Animals; Behavior; Biomedical and Life Sciences; Biomedicine; Brain stimulation rewards; Dopamine; Dopamine Agents - administration & dosage; Dosage and administration; Dose-Response Relationship, Drug; Female; Females; Forebrain; Genetic aspects; Genotypes; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Identification and classification; Intracranial self-stimulation; Locomotion - drug effects; Locomotion - physiology; Locomotor activity; Male; Medial forebrain bundle; Medial Forebrain Bundle - drug effects; Medial Forebrain Bundle - physiology; Methamphetamine; Methamphetamine - administration & dosage; Methods; Mice; Mice, Inbred C57BL; Mice, mutant strains; Mice, Transgenic; Neurosciences; Operant conditioning; Original Investigation; Pharmacology/Toxicology; Phenotypes; Physiological aspects; Place preference conditioning; Psychiatry; Public health; Reinforcement; Response rates; Reward; Ribonucleoproteins; Self Administration; Self Stimulation - drug effects; Self Stimulation - physiology; Self-stimulation
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05829-4

Rationale Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 ( Hnrnph1 ; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1 +/− ) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1 +/− on innate and MA-modulated reward sensitivity are not known. Objectives We examined innate reward sensitivity and facilitation by MA in H1 +/− mice via intracranial self-stimulation (ICSS). Methods We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5–4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. Results H1 +/− mice displayed reduced normalized maximum response rates in response to MA. H1 +/− females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. Conclusions H1 +/− mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1 +/− females (lower normalized M50 values).