Norepinephrine Transporter Gene Variation Modulates Acute Response to d-Amphetamine

Dlugos, Andrea; Freitag, Christine M.; Hohoff, Christa; McDonald, J. M.; Cook, Edwin H.; Deckert, Jürgen; Wit, Harriet de

doi:10.1016/j.biopsych.2006.09.031

Cited by 38 publications

(52 citation statements)

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“…In human subjects, there is considerable debate as to the relative importance of dopaminergic and noradrenergic mechanisms in the positive subjective effects of AMPH (Abi-Dargham et al, 2003;Brauer and de Wit, 1997;Dlugos et al, 2007;Jonsson, 1972;Leyton et al, 2007;Lott et al, 2005;Nurnberger et al, 1984;Rothman et al, 2001;Sofuoglu et al, 2009). For example, dopaminergic antagonists have failed to reduce psychostimulant euphoria in most studies (Brauer and de Wit, 1995, 1996Gawin, 1986; but see Gunne et al (1972) and Jonsson (1972)).…”

Section: -Khz Usvs In Relation To Subjective Drug Effects In Humansmentioning

confidence: 99%

“…Moreover, human and animal studies suggest that DA transmission does not contribute to the hedonic impact of psychostimulants, but rather to the incentive salience of reward-related cues (Berridge and Robinson, 1998;Leyton et al, 2005Leyton et al, , 2007. In contrast, several observations point to possible noradrenergic mediation of AMPH euphoria (Dlugos et al, 2007;Rothman et al, 2001;Sofuoglu et al, 2009); although preliminary studies using a-or b-receptor antagonists have been largely negative, only low antagonist doses were used (Brauer and de Wit, 1995;Jonsson, 1972;Nurnberger et al, 1984).…”

Section: -Khz Usvs In Relation To Subjective Drug Effects In Humansmentioning

confidence: 99%

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α- and β-Adrenergic Receptors Differentially Modulate the Emission of Spontaneous and Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Adult Rats

Wright

Dobosiewicz

Clarke

2011

Neuropsychopharmacol

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Amphetamine (AMPH) increases adult rat 50-kHz ultrasonic vocalizations, preferentially promoting frequency-modulated (FM) calls that have been proposed to reflect positive affect. The main objective of this study was to investigate a possible noradrenergic contribution to AMPH-induced calling. Adult male Long-Evans rats were tested with AMPH (1 mg/kg intraperitoneal) or saline combined with various systemic pretreatments: clonidine (α2 adrenergic agonist), prazosin (α1 antagonist), atipamezole (α2 antagonist), propranolol, betaxolol, and/or ICI 118,551 (β1/β2, β1, and β2 antagonists, respectively), nadolol (β1/β2 antagonist, peripheral only), or NAD-299 (5HT(1A) antagonist). In addition, effects of cirazoline (α1 adrenergic agonist) and cocaine (0.25-1.5 mg/kg intravenous) were studied alone. AMPH-induced calling was suppressed by low-dose clonidine and prazosin. Cirazoline and atipamezole did not significantly affect calling rate. Propranolol, without affecting the call rate, dose dependently promoted 'flat' calls under AMPH while suppressing 'trills,' thus reversing the effects of AMPH on the 'call subtype profile.' This effect of propranolol seemed to be mediated by simultaneous inhibition of CNS β1 and β2 rather than by 5HT(1A) receptors. Finally, cocaine elicited fewer calls than did AMPH, but produced the same shift in the call subtype profile. Taken together, these results reveal differential drug effects on flat vs trill vs other FM 50-kHz calls. These findings highlight the value of detailed call subtype analyses, and show that 50-kHz calls are associated with adrenergic α1- and β-receptor mechanisms. These preclinical findings suggest that noradrenergic contributions to psychostimulant subjective effects may warrant further investigation.

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Section: -Khz Usvs In Relation To Subjective Drug Effects In Humansmentioning

confidence: 99%

Section: -Khz Usvs In Relation To Subjective Drug Effects In Humansmentioning

confidence: 99%

α- and β-Adrenergic Receptors Differentially Modulate the Emission of Spontaneous and Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Adult Rats

Wright

Dobosiewicz

Clarke

2011

Neuropsychopharmacol

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“…In addition, potentially functionally relevant variants as well as polymorphisms reported in previous association studies were included ( fig. 1 ): single-nucleotide polymorphism (SNP) 1 (rs35915, -17215A/T); SNP2 (rs28386840, -3081A/T) [26] ; SNP3 (rs unknown, -3083C/T, not included in pharmacogenetic analysis since it is not polymorphic); SNP4 (rs168924, -1014A/G) [27] ; SNP5 (rs2242446, -133T/C) [14,[16][17][18] ; SNP6 (rs36017, 28257G/C) [28] ; SNP7 (rs47958, 36001A/C) [28] , and SNP8 (rs171798, T/C). Linkage disequilibrium (LD) analysis revealed, on the one hand, a high LD between the 4 NET SNPs rs28386840, rs unknown -3083C/T, rs168924 and rs2242446, and on the other hand between the 3 NET SNPs rs36017, rs47958 and rs171798, which led to 2 haplotype blocks of 3 kb and 25 kb, respectively.…”

Section: Selection Of Single-nucleotide Polymorphisms and Genotypingmentioning

confidence: 99%

Norepinephrine and Serotonin Transporter Genes: Impact on Treatment Response in Depression

Baffa¹,

Hohoff²,

Baune³

et al. 2010

Neuropsychobiology

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Background/Aims: The norepinephrine transporter (NET) and serotonin transporter (5-HTT) genes constitute promising candidate genes in major depression. Seven polymorphisms in the promoter, intronic and exonic region of the NET gene, as well as serotonin-transporter-linked promoter region (5-HTTLPR) and 5-HTT rs25531 polymorphisms were analyzed with respect to antidepressant treatment response with particular attention to gender effects and subtypes of melancholic or anxious depression. Methods: 252 unrelated Caucasian patients (f = 142; m = 110) with major depression were genotyped for NET and 5-HTT polymorphisms. Genotype effects on Hamilton Depression Rating Scale score changes over 6 weeks of antidepressant treatment were analyzed using analysis of covariance with repeated measures. Results: There was no effect of any of the 7 investigated NET, or the two 5-HTT polymorphisms, on the overall treatment response. An additional –/CT insertion/deletion (ins/del) polymorphism (rs58532686), however, was significantly associated with melancholic depression, with a better response in 12 patients carrying the deletion. Stratification for anxious versus nonanxious depression revealed a significantly detrimental effect of the less active 5-HTTLPR S allele (p = 0.007) and 5-HTTLPR/5-HTT rs25531 haplotypes on treatment response in patients with anxious depression. Conclusion: The present findings do not support a major impact of the NET and 5-HTT genes on antidepressant treatment response in major depression per se. However, there might be an impact of a –/CT ins/del polymorphism in the enhancer domain of the NET gene on treatment response in melancholic depression, which remains to be functionally investigated in future studies. The observed significant influence of the 5-HTT gene variation on antidepressant treatment in anxious depression points to anxious depression as a potential diagnostic entity of its own, requiring specific diagnostic and therapeutic attention.

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“…In our previous study (Dlugos et al 2007), genotype groups at SLC6A2 locus rs36017 differed on the composite scale positive mood (positive mood=elation-depression; Profile of Mood States [POMS]; Johanson and Uhlenhuth 1980; McNair et al 1971) after 20 mg D-amphetamine in 56 healthy volunteers. Post hoc analyses revealed that this association was due to the elation subcomponent of positive mood (Dlugos et al 2007).…”

Section: Introductionmentioning

confidence: 91%

“…Several polymorphisms in the noncoding and coding regions of SLC6A2 have been studied and found to modulate individual differences in behavior, mood, and drug responses (Brookes et al 2006; Inoue et al 2004; Kim et al 2006, 2008). We previously reported that two highly linked ( D ′=1.0, r 2 =1.0) SLC6A2 polymorphisms were associated with subjective response to acute D-amphetamine in a sample of 56 Caucasian healthy volunteers (Dlugos et al 2007). In the present study, we extended the Caucasian subsample to 159 Caucasian individuals.…”

Section: Introductionmentioning

confidence: 99%

Further evidence of association between amphetamine response and SLC6A2 gene variants

et al. 2009

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Background and rationale We previously found that the intronic norepinephrine transporter gene (SLC6A2) polymorphism rs36017 modulates feelings of elation after administration of 20 mg D-amphetamine in healthy volunteers. Objectives In this study, we further investigated the association between D-amphetamine response and 11 SLC6A2 single-nucleotide polymorphisms (SNPs), including rs36017, in an extended sample of Caucasian young adults. Methods One hundred fifty-nine healthy volunteers participated in a three-session double-blind crossover design receiving either placebo or oral D-amphetamine (10 and 20 mg). Based on our previous results, we examined the associations between levels of self-reported elation and vigor after D-amphetamine administration and SNPs and SNP haplotypes in SLC6A2. Results Consistent with our previous findings, SNPs rs36017 and rs1861647 were associated with significantly higher ratings of elation and vigor after 20 mg D-amphetamine. Ratings of vigor after 20 mg D-amphetamine were also associated with a two-SNP haplotype formed with rs1861647 and rs5569 and a three-SNP haplotype formed with rs36017, rs10521329, and rs3785155. Conclusions These results provide further evidence that genetic variants in the SLC6A2 gene are involved in acute response to D-amphetamine, which may influence progression to amphetamine abuse. Identifying sources of variation in acute drug responses could lead to better prevention and treatment of psychostimulant abuse and may be valuable in the therapeutic use of stimulants.

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Norepinephrine Transporter Gene Variation Modulates Acute Response to d-Amphetamine

Cited by 38 publications

References 50 publications

α- and β-Adrenergic Receptors Differentially Modulate the Emission of Spontaneous and Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Adult Rats

α- and β-Adrenergic Receptors Differentially Modulate the Emission of Spontaneous and Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Adult Rats

Norepinephrine and Serotonin Transporter Genes: Impact on Treatment Response in Depression

Further evidence of association between amphetamine response and SLC6A2 gene variants

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