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Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice.

ABSTRACT: To identify addiction genes, we evaluate intravenous self-administration of cocaine or saline in 84 inbred and recombinant inbred mouse strains over 10 days. We integrate the behavior data with brain RNA-seq data from 41 strains. The self-administration of cocaine and that of saline are genetically distinct. We maximize power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci are identified in the genome-wide association study. A transcriptome-wide association study highlights the Trpv2 ion channel as a key locus for cocaine self-administration as well as identifying 17 additional genes, including Arhgef26, Slc18b1, and Slco5a1. We find numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2, an ionotropic cannabinoid receptor, for the response to cocaine.

SUBMITTER: Khan AH

PROVIDER: S-EPMC10530068 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice.

Khan Arshad H AH Bagley Jared R JR LaPierre Nathan N Gonzalez-Figueroa Carlos C Spencer Tadeo C TC Choudhury Mudra M Xiao Xinshu X Eskin Eleazar E Jentsch James D JD Smith Desmond J DJ

Cell reports 20230722 8

To identify addiction genes, we evaluate intravenous self-administration of cocaine or saline in 84 inbred and recombinant inbred mouse strains over 10 days. We integrate the behavior data with brain RNA-seq data from 41 strains. The self-administration of cocaine and that of saline are genetically distinct. We maximize power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique sign ...[more]

PMID: 37481717

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Project description:RationaleInitial sensitivity to drugs of abuse often predicts subsequent use and abuse, but this relationship is not always observed in human studies. Moreover, studies examining the relationship between initial locomotor sensitivity and the rewarding and reinforcing effects of drugs in animal models have also been equivocal. Understanding the relationship between initial drug effects and propensity to continue use, potentially resulting in the development of a substance use disorder, may help to identify key targets for prevention and treatment.ObjectivesWe examined intravenous cocaine self-administration in a set of mouse strains that were previously identified to be at the phenotypic extremes for cocaine-induced locomotor activation to determine if initial locomotor sensitivity predicted acquisition, extinction, dose response, or progressive ratio (PR) breakpoint.MethodsWe selected eight inbred mouse strains based on locomotor sensitivity to 20 mg/kg cocaine. These strains, designated as low and high responders, were tested in an intravenous self-administration paradigm that included acquisition of 0.5 mg/(kg*inf) under a FR1 schedule, extinction, re-acquisition, dose response to 0.125, 0.25, 0.5, 1, and 2 mg/(kg*inf), and progressive ratio.ResultsWe observed overall differences in self-administration behavior between high and low responders. Low responders self-administered less cocaine and had lower breakpoints under the PR schedule. However, we also observed strain differences within each group. Self-administration in the low responder, LG/J, more closely resembled the behavior of the high-responding group, and the high responder, P/J, had self-administration behavior that more closely resembled the low-responding group.ConclusionsWe conclude that acute cocaine-induced locomotor activation does predict self-administration behavior, but in a strain-specific manner. These data support the idea that genetic background influences the relationship among addiction-related behaviors.

Project description:Early-life adversity increases the risk for emotional disorders such as depression and schizophrenia. Anhedonia, thought to be a core feature of these disorders, is provoked by our naturalistic rodent model of childhood adversity (i.e., rearing pups for one week in cages with limited bedding and nesting, LBN). Drug use and addiction are highly comorbid with psychiatric disorders featuring anhedonia, yet effects of LBN on drug-seeking behavior and the reward and stress-related circuits that underlie it remain unknown. Here we examined the effects of LBN on cocaine intake and seeking, using a battery of behavioral tests measuring distinct aspects of cocaine reward, and for comparison, chocolate intake. We also examined activation of neurons within the pleasure/reward and stress circuits following cocaine in LBN and control rats. Early-life adversity reduced spontaneous intake of palatable chocolate, extending prior reports of sucrose and social-play anhedonia. In a within-session cocaine behavioral economic test, LBN rats self-administered lower dosages of cocaine under low-effort conditions, consistent with a reduced hedonic set-point for cocaine, and potentially anhedonia. In contrast, cocaine demand elasticity was not consistently affected, indicating no major changes in motivation to maintain preferred cocaine blood levels. These changes were selective, as LBN did not cause an overt anxiety-like phenotype, nor did it affect sensitivity to self-administered cocaine dose, responding for cocaine under extinction conditions, cocaine- or cue-induced reinstatement of cocaine seeking, or locomotor response to acute cocaine. However, high Fos expression was seen after cocaine in both reward- and stress-related brain regions of LBN rats, including nucleus accumbens core, central amygdala, and lateral habenula. In contrast, hypothalamic orexin neuron activation after cocaine was significantly attenuated in LBN rats. Together, these findings demonstrate enduring effects of early-life adversity on both reward- and fear/anxiety-related neural circuits, as well as anhedonia-like reductions in consumption of natural and drug rewards.

Project description:BackgroundCocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors, with allosteric modulators showing particular promise.MethodsWe evaluated the capacity of group I metabotropic glutamate receptors to induce functional responses in ex vivo striatal slices from rats with (1) acute cocaine self-administration, (2) chronic cocaine self-administration, and (3) 60 days cocaine self-administration withdrawal by Western blot and extracellular recordings of synaptic transmission.ResultsWe found that striatal group I metabotropic glutamate receptors are the principal mediator of the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine-induced cAMP responsive-element binding protein phosphorylation. Both acute and chronic cocaine self-administration blunted group I metabotropic glutamate receptor effects on cAMP responsive-element binding protein phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect that was maintained 60 days after chronic cocaine self-administration withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic cocaine self-administration blunted group I metabotropic glutamate receptor stimulation of extracellular signal-regulated protein kinases 1/2 and cAMP responsive-element binding protein. Interestingly, the group I metabotropic glutamate receptor antagonist/inverse-agonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride, led to a specific increase in cAMP responsive-element binding protein phosphorylation after chronic cocaine self-administration, specifically in the nucleus accumbens, but not in the striatum.ConclusionsProlonged cocaine self-administration, through withdrawal, leads to a blunting of group I metabotropic glutamate receptor responses in the striatum. In addition, specifically in the accumbens, group I metabotropic glutamate receptor signaling to cAMP responsive-element binding protein shifts from an agonist-induced to an antagonist-induced cAMP responsive-element binding protein phosphorylation.

Dataset Information

Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice.

Publications

Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice.

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