Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure

ABSTRACTAdolescence is a time of significant brain development, and exposure to nicotine during this period is associated with higher subsequent rates of dependence. Chronic nicotine exposure alters expression of nicotinic acetylcholine receptors (nAChRs), changing the pattern of nicotine responsiveness. We used quantitative autoradiography to measure three major subtypes of nAChRs after chronic nicotine exposure by osmotic minipump in adult and periadolescent rats. Comparison of control animals at the two different ages revealed that periadolescents express consistently greater numbers of α4β2⁎ nAChRs compared to the same brain regions of adults. Similar but less pronounced increases in α7 nAChRs were found in control periadolescent rats compared to adults. Binding of [125I]α-conotoxin MII (largely to α6⁎ nAChRs) did not systematically differ between adults and periadolescents. The response to chronic nicotine exposure also differed by age. Up-regulation of α4β2⁎ nAChRs was prominent and widespread in adult animals; in periadolescents, α4β2⁎ up-regulation also occurred, but in fewer regions and to a lesser extent. A similar pattern of response was seen with α7 receptors: adults were more responsive than periadolescents to nicotine-induced up-regulation. In adult animals, chronic nicotine exposure did not cause up-regulation of α6⁎ nAChRs; binding was down-regulated in three regions. Unlike the other subtypes, the response of α6⁎ nAChRs to chronic nicotine was greater in periadolescents, with more regions showing greater down-regulation compared to adults. These differences in receptor expression and regulation between age groups are likely to be important given the unique vulnerability of adolescents to nicotine-induced behavioral changes and susceptibility to drug abuse

Y Chromosome Lineages in Men of West African Descent

The early African experience in the Americas is marked by the transatlantic slave trade from ∼1619 to 1850 and the rise of the plantation system. The origins of enslaved Africans were largely dependent on European preferences as well as the availability of potential laborers within Africa. Rice production was a key industry of many colonial South Carolina low country plantations. Accordingly, rice plantations owners within South Carolina often requested enslaved Africans from the so-called “Grain Coast” of western Africa (Senegal to Sierra Leone). Studies on the African origins of the enslaved within other regions of the Americas have been limited. To address the issue of origins of people of African descent within the Americas and understand more about the genetic heterogeneity present within Africa and the African Diaspora, we typed Y chromosome specific markers in 1,319 men consisting of 508 west and central Africans (from 12 populations), 188 Caribbeans (from 2 islands), 532 African Americans (AAs from Washington, DC and Columbia, SC), and 91 European Americans. Principal component and admixture analyses provide support for significant Grain Coast ancestry among African American men in South Carolina. AA men from DC and the Caribbean showed a closer affinity to populations from the Bight of Biafra. Furthermore, 30–40% of the paternal lineages in African descent populations in the Americas are of European ancestry. Diverse west African ancestries and sex-biased gene flow from EAs has contributed greatly to the genetic heterogeneity of African populations throughout the Americas and has significant implications for gene mapping efforts in these populations

Differential molecular and genetic short-term and long-term effects of chronic nicotine exposure on adolescent and adult rats

Adolescence is a time of significant brain development, and exposure to nicotine during this period is associated with higher subsequent rates of dependence. Chronic nicotine exposure alters expression of nicotinic acetylcholine receptors (nAChRs), changing the pattern of nicotine responsiveness. I used quantitative autoradiography to measure three major subtypes of nAChRs after chronic nicotine exposure by osmotic minipump in adult (PN60-70) and periadolescent (PN28-30) rats. Comparison of control animals at the two different ages revealed that periadolescents express consistently greater numbers of α4β2* nAChRs compared to the same brain regions of adults. Similar but less pronounced increases in α7 nAChRs were found in control periadolescent rats compared to adults. Binding of [125I]α-conotoxin MII (largely to α6* nAChRs) did not systematically differ between adults and periadolescents. The response to chronic nicotine exposure also differed by age. Up-regulation of α4β2* nAChRs was prominent and widespread in adult animals; in periadolescents, α4β2* up-regulation also occurred, but in fewer regions and to a lesser extent. A similar pattern of response was seen with α7 receptors: adults were more responsive than periadolescents to nicotine-induced up-regulation. In adult animals, chronic nicotine exposure did not cause up-regulation of α6* nAChRs; binding was down-regulated in three regions. Unlike the other subtypes, the response of α6* nAChRs to chronic nicotine was greater in periadolescents, with more regions showing greater down-regulation compared to adults. These differences in receptor expression and regulation between age groups are likely to be important given the unique vulnerability of adolescents to nicotine-induced behavioral changes and susceptibility to drug abuse. I used whole genome microarray analysis to determine the effects of nicotine on gene expression in the ventral tegmental area. I examined brains immediately after two weeks of nicotine or saline, and also four weeks after termination of nicotine exposure. After identifying genes with a significant age x treatment interaction, I employed template matching to find specific patterns of expression across age and treatment. Of those genes that were transiently regulated (up- or down-regulated immediately following the end of nicotine treatment, but back to saline baseline 30 days later), two-thirds were specific to adult animals, while only 30% were specific to adolescents and 4% were shared across the two ages. In contrast, significant genes that were persistently regulated (altered following nicotine treatment and still altered 30 days later) were more likely (59%) to be adolescent associated, with only 32% in adults and 8% shared. The greatest number of significant genes was late-regulated (no change immediately after nicotine, but regulated 30 days later). Again, most were in adolescents (54%), compared to adults (10%) or shared (36%). Pathway analysis revealed that adolescent-specific genes were over-represented in several biological functions and canonical pathways, including nervous system development and function and long-term potentiation. Furthermore, adolescent-specific genes formed extensive interaction networks, unlike those specific for adults or shared between the two age groups. This age-specific expression pattern may relate to the heightened vulnerability of adolescents to the effects of addictive drugs. In particular, the propensity of adolescents to show persistent alterations in gene expression corresponds to the persistence of drug dependence among smokers who began their habit as adolescents. These findings support a model whereby adolescent brains are uniquely vulnerable to long-term changes in gene expression in the brain's reward pathway caused by early exposure to nicotine

Y Chromosome Lineages in Men of West African Descent

The early African experience in the Americas is marked by the transatlantic slave trade from ~1619 to 1850 and the rise of the plantation system. The origins of enslaved Africans were largely dependent on European preferences as well as the availability of potential laborers within Africa. Rice production was a key industry of many colonial South Carolina low country plantations. Accordingly, rice plantations owners within South Carolina often requested enslaved Africans from the so-called ‘‘Grain Coast’’ of western Africa (Senegal to Sierra Leone). Studies on the African origins of the enslaved within other regions of the Americas have been limited. To address the issue of origins of people of African descent within the Americas and understand more about the genetic heterogeneity present within Africa and the African Diaspora, we typed Y chromosome specific markers in 1,319 men consisting of 508 west and central Africans (from 12 populations), 188 Caribbeans (from 2 islands), 532 African Americans (AAs from Washington, DC and Columbia, SC), and 91 European Americans. Principal component and admixture analyses provide support for significant Grain Coast ancestry among African American men in South Carolina. AA men fromDC and the Caribbean showed a closer affinity to populations from the Bight of Biafra. Furthermore, 30–40% of the paternal lineages in African descent populations in the Americas are of European ancestry. Diverse west African ancestries and sexbiased gene flow from EAs has contributed greatly to the genetic heterogeneity of African populations throughout the Americas and has significant implications for gene mapping efforts in these populations

Partitions of Y chromosome molecular variance.

<p> <b>Φ_ST = Within populations; Φ_CT = Among groups; Φ_SC = Among populations within groups; %V = Percent of the variance.</b></p

Expansion Times of West African Y Chromosome Groups.

<p>Expansion Times of West African Y Chromosome Groups.</p

Estimates of European paternal ancestry (%) in African descent populations in the Americas.

<p>Estimates of European paternal ancestry (%) in African descent populations in the Americas.</p

Maps showing location of (A) 5 populations in the Americas and (B) 12 West African populations sampled in the study.

<p>Maps showing location of (A) 5 populations in the Americas and (B) 12 West African populations sampled in the study.</p

Plot of the first two principal components of a Y chromosome genetic distance matrix estimated for 17 populations.

<p>Plot of the first two principal components of a Y chromosome genetic distance matrix estimated for 17 populations.</p

Summary of Y chromosome diversity and frequency of YAP and M89 alleles.

<p><b>Note</b>. n = number of Y-chromosomes, <i>k</i> = observed number of haplotypes, H = haplotype diversity, <i>h</i> = allelic diversity, MPD = mean pairwise differences of haplotypes.</p