Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

Caffino, Lucia; Verheij, Michel M.M.; Que, Lin; Guo, Chao; Homberg, Judith R.; Fumagalli, Fabio

doi:10.1111/adb.12673

Cited by 17 publications

(27 citation statements)

References 53 publications

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“…As we reported previously, 25 no genotype differences were observed during the acquisition of cocaine self‐administration. Under ShA conditions, the daily number of cocaine infusion was higher in SERT −/− versus SERT +/+ rats, leading to a higher total cocaine intake in SERT −/− (172 ± 24 infusions) versus SERT +/+ (81 ± 13 infusions) rats.…”

Section: Resultssupporting

confidence: 72%

“…We have previously investigated glutamate homeostasis in the habenula of SERT −/− rats 25 . It has been established that cocaine enhances the glutamatergic transmission in those neurons projecting from habenula to the rostral tegmental area 26 that, in turn, influence the serotonergic tone via inhibition of the dorsal raphe nucleus 27 .…”

Section: Introductionmentioning

confidence: 99%

“…We evaluated the expression of these molecules in the whole homogenate, which informs us primarily about translational changes, as well as in the postsynaptic density (PSD), which gives us a clue of synaptic localization of receptors and the respective scaffolding proteins. In doing so, we took advantage of unused brain material collected from naïve and ShA and LgA cocaine SERT −/− as well as wild‐type rats in a previous study 25 and examined the glutamate synapse in the ILc and PLc.…”

Section: Introductionmentioning

confidence: 99%

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The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short‐ and long‐access cocaine self‐administration

et al. 2020

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Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT−/−) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine‐seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine‐exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT−/− rats, which compared to wild‐type (SERT+/+) rats show increased ShA and LgA intake short‐access (ShA) and long‐access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT−/− rats, we observed a sharp increase in glial glutamate transporter 1 (GLT‐1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA‐induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed.

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Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short‐ and long‐access cocaine self‐administration

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“…Fourth, in mice, cocaine elicited increased Neurotensin expression in the ventral striatum 67 , but deletion of the Nts gene had no effect on locomotion 68 . Finally, although less specific to motor disturbances, GRIN2B has been associated with cocaine dependence at both the genetic and transcriptomic levels, in rodents 69 and in patients 70 , and thus, it is a possible top candidate gene for cocaine misuse according to a recent meta-analysis of genome-wide expression data 71 . We were unable to find any published report of associations between the other CIH-associated genes and either motor function or cocaine response.…”

Section: Discussionmentioning

confidence: 99%

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

et al. 2020

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Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = −0.965 and −2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.

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“…Entering this effect size (based on the previously obtained SD), together with an alpha value of 0.05 and a power of 0.80, into G*power (version 3.1), revealed a minimum number of 13-14 rats per genotype. Because of the substantially smaller SD typically observed in our molecular studies (e.g., Caffino et al, 2019Caffino et al, , 2020, the number of animals in the AMPH-naive groups that were not exposed to self-administration were reduced to 6. All animals tested were treated as independent values; there were no technical replicates.…”

Section: Data and Statistical Analysismentioning

confidence: 99%

Hypersensitivity to amphetamine's psychomotor and reinforcing effects in serotonin transporter knockout rats: Glutamate in the nucleus accumbens

Caffino

Verheij

Roversi

et al. 2020

British J Pharmacology

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Background and Purpose Amphetamine (AMPH) use disorder is a serious health concern, but, surprisingly, little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down‐regulation increases the motor response to cocaine, as well as moderate (as measured during daily 1‐h self‐administration sessions) and compulsive (as measured during daily 6‐h self‐administration sessions) intake of this psychostimulant. Here, we sought to investigate whether these findings generalize to AMPH and the underlying mechanisms in the nucleus accumbens. Experimental Approach In serotonin transporter knockout (SERT−/−) and wild‐type control (SERT+/+) rats, we assessed the locomotor response to acute AMPH and i.v. AMPH self‐administration under short access (ShA: 1‐h daily sessions) and long access (LgA: 6‐h daily sessions) conditions. Twenty‐four hours after AMPH self‐administration, we analysed the expression of glutamate system components in the nucleus accumbens shell and core. Key Results We found that SERT−/− animals displayed an increased AMPH‐induced locomotor response and increased AMPH self‐administration under LgA but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits, and their respective postsynaptic scaffolding proteins as function of SERT genotype and AMPH exposure (baseline, ShA, and LgA), specifically in the nucleus accumbens shell. Conclusion and Implications We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.

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Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

Cited by 17 publications

References 53 publications

The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short‐ and long‐access cocaine self‐administration

The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short‐ and long‐access cocaine self‐administration

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

Hypersensitivity to amphetamine's psychomotor and reinforcing effects in serotonin transporter knockout rats: Glutamate in the nucleus accumbens

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