Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice.
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).
['Borrelli|Kristyn N|KN|', 'Langan|Carly R|CR|', 'Dubinsky|Kyra R|KR|', 'Szumlinski|Karen K|KK|', 'Carlezon|William A|WA|', 'Chartoff|Elena H|EH|', 'Bryant|Camron D|CD|http://orcid.org/0000-0003-4505-5809']
D000818:Animals D015259:Dopamine Agents D004305:Dose-Response Relationship, Drug D005260:Female D034441:Heterogeneous-Nuclear Ribonucleoproteins D008124:Locomotion D008297:Male D008474:Medial Forebrain Bundle D008694:Methamphetamine D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D012201:Reward D012646:Self Administration D012653:Self Stimulation
Methamphetamine Addiction Genetics Sensitization Intracranial self-stimulation (ICSS) Behavioral genetics Forward genetics Mouse Psychostimulants QTL