Dopamine D2 receptor binding, Drd2 expression and the number of dopamine neurons in the BXD recombinant inbred series: Genetic relationships to alcohol and other drug associated phenotypes

Robert Hitzemann, Barbara Hitzemann, Seth Rivera, John Gatley, Peter Thanos, Lu Lu Siming Shou, Robert W. Williams

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background: It has not been established to what extent the natural variation in dopamine systems contribute to the variation in ethanol response. The current study addresses this issue by measuring D2 dopamine (DA) receptor binding, the expression of Drd2, the number of midbrain DA neurons in the BXD recombinant inbred (RI) series and then compares these strain means with those previously reported for a variety of ethanol and other drug-related phenotypes. Methods: Data were collected for 21 to 23 of the BXD RI strains and the parental strains. D2 DA receptor autoradiography was performed using 125I-epidepride as the ligand [Kanes S, Dains K, Cipp L, Gatley J, Hitzemann B, Rasmussen E, Sanderson S, Silverman S, Hitzemann R (1996) Mapping the genes for haloperidol-induced catalepsy. J Pharmacol Exp Ther 277:1016-1025]. Drd2 expression was measured using the Affymetrix oligoarray system. Immunocytochemical techniques were used to determine the number of midbrain DA neurons [Hitzemann B, Dains K, Hitzemann R (1994) Further studies on the relationship between dopamine cell density and haloperidol response. J Pharmacol Exp Ther 271:969-976]. Results and Conclusions: The range of difference in receptor binding for the RI strains was approximately 2-fold in all regions examined, the core, the shell of the nucleus accumbens (NAc) and the dorsomedial caudate-putamen (CPu); heritability in all regions was moderate - (h2∼0.35). Drd2 expression in forebrain samples from the RI and parental strains ranged 1.5-to 2-fold and h2 was moderate - 0.47. Variation in the number of tyrosine hydroxylase (TH) positive neurons was moderate, 41% and 26% and h2 was low - 0.19 and 0.15 for the ventral tegmental area (VTA) and substantia nigra compacta (SNc), respectively. Significant correlations were found between D2 DA receptor binding and the low dose (1.33 g/kg) ethanol stimulant response. (p <0.002) and between Drd2 expression and conditioned place preference (CPP) (p <0.0005). No significant correlations were detected between ethanol preference and either receptor binding or Drd2 expression; however, a significant correlation was found between preference and Ncam expression. Ncam is approximately 0.2 Mb from Drd2. Overall, the data suggest ethanol preference and CPP are associated with the expression of Drd2 or closely linked genetic loci.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume27
Issue number1
StatePublished - Jan 1 2003

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Dopamine D2 Receptors
Dopaminergic Neurons
Neurons
Dopamine
Ethanol
Alcohols
Phenotype
Pharmaceutical Preparations
Haloperidol
Mesencephalon
Catalepsy
Ventral Tegmental Area
Genetic Loci
Chromosome Mapping
Putamen
Nucleus Accumbens
Tyrosine 3-Monooxygenase
Prosencephalon
Autoradiography
Cell Count

Keywords

  • Conditioned Place Preference
  • Dopamine Receptor
  • Drd2 Expression
  • Genetic
  • Microarray
  • QTL
  • Recombinant Inbred
  • Tyrosine Hydroxylase

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

Dopamine D2 receptor binding, Drd2 expression and the number of dopamine neurons in the BXD recombinant inbred series : Genetic relationships to alcohol and other drug associated phenotypes. / Hitzemann, Robert; Hitzemann, Barbara; Rivera, Seth; Gatley, John; Thanos, Peter; Shou, Lu Lu Siming; Williams, Robert W.

In: Alcoholism: Clinical and Experimental Research, Vol. 27, No. 1, 01.01.2003, p. 1-11.

Research output: Contribution to journalArticle

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abstract = "Background: It has not been established to what extent the natural variation in dopamine systems contribute to the variation in ethanol response. The current study addresses this issue by measuring D2 dopamine (DA) receptor binding, the expression of Drd2, the number of midbrain DA neurons in the BXD recombinant inbred (RI) series and then compares these strain means with those previously reported for a variety of ethanol and other drug-related phenotypes. Methods: Data were collected for 21 to 23 of the BXD RI strains and the parental strains. D2 DA receptor autoradiography was performed using 125I-epidepride as the ligand [Kanes S, Dains K, Cipp L, Gatley J, Hitzemann B, Rasmussen E, Sanderson S, Silverman S, Hitzemann R (1996) Mapping the genes for haloperidol-induced catalepsy. J Pharmacol Exp Ther 277:1016-1025]. Drd2 expression was measured using the Affymetrix oligoarray system. Immunocytochemical techniques were used to determine the number of midbrain DA neurons [Hitzemann B, Dains K, Hitzemann R (1994) Further studies on the relationship between dopamine cell density and haloperidol response. J Pharmacol Exp Ther 271:969-976]. Results and Conclusions: The range of difference in receptor binding for the RI strains was approximately 2-fold in all regions examined, the core, the shell of the nucleus accumbens (NAc) and the dorsomedial caudate-putamen (CPu); heritability in all regions was moderate - (h2∼0.35). Drd2 expression in forebrain samples from the RI and parental strains ranged 1.5-to 2-fold and h2 was moderate - 0.47. Variation in the number of tyrosine hydroxylase (TH) positive neurons was moderate, 41{\%} and 26{\%} and h2 was low - 0.19 and 0.15 for the ventral tegmental area (VTA) and substantia nigra compacta (SNc), respectively. Significant correlations were found between D2 DA receptor binding and the low dose (1.33 g/kg) ethanol stimulant response. (p <0.002) and between Drd2 expression and conditioned place preference (CPP) (p <0.0005). No significant correlations were detected between ethanol preference and either receptor binding or Drd2 expression; however, a significant correlation was found between preference and Ncam expression. Ncam is approximately 0.2 Mb from Drd2. Overall, the data suggest ethanol preference and CPP are associated with the expression of Drd2 or closely linked genetic loci.",
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T2 - Genetic relationships to alcohol and other drug associated phenotypes

AU - Hitzemann, Robert

AU - Hitzemann, Barbara

AU - Rivera, Seth

AU - Gatley, John

AU - Thanos, Peter

AU - Shou, Lu Lu Siming

AU - Williams, Robert W.

PY - 2003/1/1

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N2 - Background: It has not been established to what extent the natural variation in dopamine systems contribute to the variation in ethanol response. The current study addresses this issue by measuring D2 dopamine (DA) receptor binding, the expression of Drd2, the number of midbrain DA neurons in the BXD recombinant inbred (RI) series and then compares these strain means with those previously reported for a variety of ethanol and other drug-related phenotypes. Methods: Data were collected for 21 to 23 of the BXD RI strains and the parental strains. D2 DA receptor autoradiography was performed using 125I-epidepride as the ligand [Kanes S, Dains K, Cipp L, Gatley J, Hitzemann B, Rasmussen E, Sanderson S, Silverman S, Hitzemann R (1996) Mapping the genes for haloperidol-induced catalepsy. J Pharmacol Exp Ther 277:1016-1025]. Drd2 expression was measured using the Affymetrix oligoarray system. Immunocytochemical techniques were used to determine the number of midbrain DA neurons [Hitzemann B, Dains K, Hitzemann R (1994) Further studies on the relationship between dopamine cell density and haloperidol response. J Pharmacol Exp Ther 271:969-976]. Results and Conclusions: The range of difference in receptor binding for the RI strains was approximately 2-fold in all regions examined, the core, the shell of the nucleus accumbens (NAc) and the dorsomedial caudate-putamen (CPu); heritability in all regions was moderate - (h2∼0.35). Drd2 expression in forebrain samples from the RI and parental strains ranged 1.5-to 2-fold and h2 was moderate - 0.47. Variation in the number of tyrosine hydroxylase (TH) positive neurons was moderate, 41% and 26% and h2 was low - 0.19 and 0.15 for the ventral tegmental area (VTA) and substantia nigra compacta (SNc), respectively. Significant correlations were found between D2 DA receptor binding and the low dose (1.33 g/kg) ethanol stimulant response. (p <0.002) and between Drd2 expression and conditioned place preference (CPP) (p <0.0005). No significant correlations were detected between ethanol preference and either receptor binding or Drd2 expression; however, a significant correlation was found between preference and Ncam expression. Ncam is approximately 0.2 Mb from Drd2. Overall, the data suggest ethanol preference and CPP are associated with the expression of Drd2 or closely linked genetic loci.

AB - Background: It has not been established to what extent the natural variation in dopamine systems contribute to the variation in ethanol response. The current study addresses this issue by measuring D2 dopamine (DA) receptor binding, the expression of Drd2, the number of midbrain DA neurons in the BXD recombinant inbred (RI) series and then compares these strain means with those previously reported for a variety of ethanol and other drug-related phenotypes. Methods: Data were collected for 21 to 23 of the BXD RI strains and the parental strains. D2 DA receptor autoradiography was performed using 125I-epidepride as the ligand [Kanes S, Dains K, Cipp L, Gatley J, Hitzemann B, Rasmussen E, Sanderson S, Silverman S, Hitzemann R (1996) Mapping the genes for haloperidol-induced catalepsy. J Pharmacol Exp Ther 277:1016-1025]. Drd2 expression was measured using the Affymetrix oligoarray system. Immunocytochemical techniques were used to determine the number of midbrain DA neurons [Hitzemann B, Dains K, Hitzemann R (1994) Further studies on the relationship between dopamine cell density and haloperidol response. J Pharmacol Exp Ther 271:969-976]. Results and Conclusions: The range of difference in receptor binding for the RI strains was approximately 2-fold in all regions examined, the core, the shell of the nucleus accumbens (NAc) and the dorsomedial caudate-putamen (CPu); heritability in all regions was moderate - (h2∼0.35). Drd2 expression in forebrain samples from the RI and parental strains ranged 1.5-to 2-fold and h2 was moderate - 0.47. Variation in the number of tyrosine hydroxylase (TH) positive neurons was moderate, 41% and 26% and h2 was low - 0.19 and 0.15 for the ventral tegmental area (VTA) and substantia nigra compacta (SNc), respectively. Significant correlations were found between D2 DA receptor binding and the low dose (1.33 g/kg) ethanol stimulant response. (p <0.002) and between Drd2 expression and conditioned place preference (CPP) (p <0.0005). No significant correlations were detected between ethanol preference and either receptor binding or Drd2 expression; however, a significant correlation was found between preference and Ncam expression. Ncam is approximately 0.2 Mb from Drd2. Overall, the data suggest ethanol preference and CPP are associated with the expression of Drd2 or closely linked genetic loci.

KW - Conditioned Place Preference

KW - Dopamine Receptor

KW - Drd2 Expression

KW - Genetic

KW - Microarray

KW - QTL

KW - Recombinant Inbred

KW - Tyrosine Hydroxylase

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