Jautrumas etanoliui ir kitiems hedoniniams dirgikliams paauglystės gyvūnų modelyje: poveikis prevencijos moksliniams tyrimams? (2010)

Dev Psychobiol. 2010 Apr;52(3):236-43.

Spear LP, Varlinskaja EI.

Šaltinis

Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University, State University of New York, Binghamton, NY 13902-6000, USA. [apsaugotas el. paštu]

Abstraktus

Age-related patterns of sensitivity to appetitive and aversive stimuli seemingly have deep evolutionary roots, with marked developmental transformations seen during adolescence in a number of relatively ancient brain systems critical for motivating and directing reward-related behaviors. Using a simple animal model of adolescence in the rat, adolescents have been shown to be more sensitive than their adult counterparts to positive rewarding effects of alcohol, other drugs, and certain natural stimuli, while being less sensitive to the aversive properties of such stimuli. Adolescent-typical alcohol sensitivities may be exacerbated further by a history of prior stress or alcohol exposure as well as by genetic vulnerabilities, permitting relatively high levels of adolescent alcohol use and perhaps an increased probability for the emergence of abuse disorders. A number of potential (albeit tentative) implications of these basic research findings for prevention science are considered.

Raktiniai žodžiai: adolescence, neurobehavioral, animal models, rat, alcohol, drugs of abuse, aversive drug effects, rewarding drug properties, stressors, chronic alcohol, prevention
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Įvadas

Adolescence is the developmental transition between immaturity and maturity that is characterized by puberty and the hormonal and physiological changes leading to sexual maturation, along with other hormonal changes and a considerable growth spurt. Recent research has also led to the recognition that the brain undergoes marked alterations during adolescence—changes that are transforming our understanding of adolescent-typical behaviors. Intriguingly, these hormonal, physiological, neural, and behavioral transformations characteristic of the transition from immaturity to maturity seem to have been notably conserved during evolution, with numerous similarities in the nature of these adolescent-typical alterations seen across mammalian species (see Spear, 2010, for further discussion). The length of this developmental transition is generally proportional to the lifespan of the species although, given that no one event signals the onset or offset of adolescence, it is difficult to determine the precise timing of adolescence in any given species. For instance, although the 1-month-old rat is clearly in the adolescent period, with postnatal days (P) 28–42 conservatively defined as prototypic adolescence in rats, early harbingers of adolescence may be seen as early as P22–23 in females, with some adolescent-typical trails lasting until P55 or so among male rats (see Spear, 2000, for discussion).

The similarities across adolescents of different species in biological and behavioral features support the judicious use of animal models of adolescence when examining neural and environmental contributors to adolescent-characteristic functioning. Of course, the full complexity of human brain and behavioral function during adolescence (or at any other stage in life, for that matter) cannot be completely modeled in other species, and hence the validity of any adolescent model requires careful consideration, and is highly dependent on the aspect of adolescence under investigation.

The present article briefly addresses neural changes and behavioral features that are highly conserved across species during adolescence. The main objective of this article is to discuss possible relationships between adolescent-typical neurobehavioral changes and ethanol use and sensitivity to ethanol effects during this developmental period.

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Adolescent-Typical Neurobehavioral Alterations

Conserved Neural Changes of Adolescence

The adolescent brain undergoes notable sculpting that is highly regional- and system-specific, and that is highly conserved across species. Many basic brain mechanisms underlying human behavior arose millions of years ago. Brain similarities conserved across mammalian species include the basics of brain structure and regionality, as well as the relative times during ontogeny when normal developmental transformations occur in the brain as well. These developmental alterations include adolescent-associated declines in cell body rich, gray matter density in some cortical and subcortical brain regions. Such declines in gray matter density may be attributable in part to increases in synaptic pruning (with estimates that up to equation M1 of the synaptic connections may be lost during adolescence in some cortical regions in primates; Bourgeois, Goldman-Rakic ​​ir Rakic, 1994 m), regionally specific apoptosis (genetically programmed cell death; Markham, Morris, & Juraska, 2007), and developmental declines in rates of neurogenesis (He & Crews, 2007), as well as developmental increases in the proportion of the brain partitioning as white matter associated with continued myelination of axons (see Crews, He, & Hodge, 2007, for review). Due undoubtedly in part to declines in the numbers of metabolically costly synaptic connections and increases in the proportion of cost-effective myelinated axons, there is a developmental decline in the amount of energy and oxygen required to carry out brain activity from early in childhood until early adolescence, with energy needs gradually declining further in adolescence to reach the low metabolic rates characteristic of the energy-efficient adult brain (Chugani, 1996 m).

Among the prominent brain regions that undergo transformation during adolescence are a number of relatively ancient brain regions that form major nodes in the neurocircuitry modulating sensitivity to and motivation for natural rewards such as social stimuli, novelty, and risks, and that may be coopted by nonnatural rewards, such as alcohol and other drugs of abuse. These include a number of forebrain areas receiving dopamine (DA) input from the ventral tegmental area and substantia nigra—regions that include portions of the prefrontal cortex, the nucleus accumbens, amygdala, and dorsal striatum. Among such alterations are substantial changes in DA and cannabinoid (CB) components of these forebrain motivational/reward systems, with a 50% or greater decline in binding capacity of certain subtypes of DA and CB receptors in some brain regions between adolescence and adulthood (e.g., Rodríguez de Fonseca, Ramos, Bonnin, & Fernández-Ruiz, 1993; Tarazi ir Baldessarini, 2000 m; Teicher, Krenzel, Thompson, & Andersen, 2003), along with marked, two to sevenfold, changes in regional levels of DA availability—often referred to as, “dopamine tone” (e.g., Andersen, 2002).

Significance of Adolescent-Typical Brain Changes

The adolescent sculpting of brain likely has a number of functional consequences for the adolescent. Certainly one function of the sculpting of the brain during adolescence is to transform the plastic, but not particularly efficient, immature brain into a more efficient, seemingly less plastic, mature brain capable of supporting adult-typical neural and behavioral function (see Spear, 2010, for discussion and references). Indeed, developmental changes in activation patterns in specific brain regions during adolescence are associated with continued cognitive and emotional development (see Rubia ir kt., 2006). Another major function of adolescent-typical brain changes, particularly in the hypothalamus and interconnected circuitry, is to trigger rises in pubertal hormones, thereby instigating the process of sexual maturation and perhaps stimulating adolescent-associated remodeling of other brain regions in sex-appropriate ways (Sisk & Zehr, 2005 m).

Of course, even during the most rapid phases of remodeling, the adolescent brain must do more, though, than serve as the substrate for the emergence of adult-typical neurobehavioral function it must support functioning of the adolescent as well. And given the developmental transformations occurring at this time in forebrain regions critical for modulating behaviors toward rewards such as social stimuli, novelty, and risks, it is not surprising that these neural changes are associated with notable age-specific increases in social interactions and peer affiliations, as well as increases in novelty-seeking and risk-taking behaviors (see Spear, 2007 for review). These age-specific behaviors are seen across adolescents of a wide variety of species and have been suggested to have, or have had, a number of adaptive benefits for the adolescent. Such potential benefits include social interaction-facilitated development of social skills, social support, and guidance of choice behavior (Harris, 1995), with novelty-seeking/risk-taking suggested to precipitate increases in peer acceptance and in the impetus to explore away from the home territory, aiding in the process of emigration, thereby avoiding inbreeding and its adverse consequences (Spear, 2000; Wilson & Daly, 1985 m).

In addition to serving as a necessary substrate for adult-appropriate neurobehavioral development while supporting cognitive and behavioral functioning throughout adolescence, the remodeling of adolescent brain may have ancillary consequences as well. For instance, among the neural systems that undergo ontogenetic change during adolescence are many that are affected by ethanol and other drugs of abuse, which may alter sensitivity and adaptations to these substances during adolescence, and potentially influence propensity for their use.

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Ethanol Use and Sensitivity During Adolescence

Alcohol drinking typically begins during adolescence, with some use of alcohol being normative by about 14 years of age in the United States, well before the legal drinking age. Per episode use of alcohol among 12- to 20-year-olds is about twofold higher than that of legal drinkers (Cheminės medžiagos piktnaudžiavimas ir psichikos sveikatos paslaugų administravimas, 2006). Elevated drinking of alcohol during adolescence is not only seen in human adolescents, but often in adolescents of other species as well. For instance, under a number of circumstances, adolescent rats drink two to threefold more than their adult counterparts (e.g., Doremus, Brunell, Rajendran, & Spear, 2005).

Attenuated Sensitivity to the Aversive Effects of Ethanol among Adolescents

Animal studies have shown that adolescents not only voluntarily drink substantially more alcohol than adults under many circumstances, but they also differ in their sensitivity to various alcohol effects. For instance, adolescent rats have been shown to be considerably less sensitive than their adult counterparts to many of the presumably undesired effects of alcohol that may normally serve as cues to moderate intake. These effects include ethanol-induced social inhibition („Varlinskaya & Spear“, 2002 m), sedation (Draski, Bice, & Deitrich, 2001; Moy, Duncan, Knapp, & Breese, 1998; Silveri & Spear, 1998), motor impairment (White ir kt., 2002), and even hangover effects (Doremus, Brunell, Varlinskaya, & Spear, 2003; „Varlinskaya & Spear“, 2004 m). Dysphoric effects as assessed via alcohol-related conditioned taste aversions (CTA) have also been found to be less pronounced in adolescents than adults, with adolescents requiring higher doses and more pairings of a novel taste and ethanol to develop an aversion to that taste (Anderson, Varlinskaya, & Spear, 2008). By-in-large it is not possible to test whether similar ethanol insensitivities are seen in human adolescents, given ethical constraints against giving alcohol to youth. Yet, there is an early study by Behar et al. (1983) that gave a dose of ethanol that produced blood alcohol levels (BALs) in the moderate consumption range to a group of 8- to 15-year-old boys and gave them a number of tests of intoxication. Much to the apparent surprise of these investigators, the boys showed little sign of intoxication when indexed subjectively, clinically or on objective physical tests of intoxication. They noted that they “were impressed by how little gross behavioral change occurred in the children … after a dose of alcohol which had been intoxicating in an adult population (Behar et al., 1983, p 407). Thus, while little investigated, the limited evidence to date suggests that attenuated sensitivity to the impairing and intoxicating effects of ethanol in simple animal models of adolescence in the rat may also be characteristic of human adolescents as well. An adolescent insensitivity to ethanol effects that normally serve to moderate drinking is consistent with the well-known increase in frequency of so-called “binge” drinking among human adolescents (Johnston, O'Malley, Bachmanas ir Schulenbergas, 2007 m), and with data discussed earlier that adolescents drink on average twice as many drinks per occasion as do adults.

Studies in adolescent rats suggest that the relative insensitivity of adolescents to these intoxicating and impairing effects of ethanol may be attenuated even further by prior stress or a history of prior ethanol use. For instance, higher alcohol exposure levels are necessary to suppress social behavior in adolescents than adults; this insensitivity to the social suppressing effects of ethanol is attenuated among adolescents even further following 5 days of repeated restraint stress (Doremus-Fitzwater, Varlinskaya, & Spear, 2007). Likewise, chronic exposure to ethanol has been reported to induce tolerance to aversive and sedative effects of ethanol among adolescents (Diaz-Granados & Graham, 2007; Swartzwelder, Richardson, Markwiese-Foerch, Wilson, & Little, 1998), thus further attenuating the sensitivity of adolescents to these ethanol effects. However, while it is clear that under some circumstances, repeated ethanol exposure induces chronic tolerance among adolescents, further attenuating their ethanol insensitivities, chronic tolerance often emerges in adults as well, and the data are mixed as whether expression of chronic tolerance is more (e.g., Diaz-Granados & Graham, 2007) or less (e.g., Ristuccia & Spear, 2005) pronounced, or even equivalently expressed (e.g., „Varlinskaya & Spear“, 2007 m), among adolescents relative to mature animals.

Accentuated Adolescent Sensitivity to Appetitive/Rewarding Effects of Ethanol during Adolescence

In contrast to the attenuated sensitivity that adolescents show to many of the aversive, impairing, inhibitory, and sedating effects of ethanol when compared with adults, adolescents are more sensitive to a few selected effects of ethanol. On the one hand, adolescent rats have been shown by the Swartzwelder group to be more sensitive than adults to ethanol-induced disruptions in brain plasticity (indexed electrophysiologically in terms of long-term potentiation) and memory performance in a spatial (Morris) water maze (see White & Swartzwelder, 2005, for review). Similar enhanced sensitivity to ethanol-related memory performance was also seen in young people just after they had reached legal drinking age (21 – 25 years) when they were compared with an older group of young adults (25–29 years) in terms of performance on both verbal and nonverbal learning and memory tasks following a moderate (0.6 g/kg) dose of ethanol (Acheson, Stein, & Swartzwelder, 1998). Such enhanced sensitivity of adolescents to ethanol-induced disruptions in memory performance is particularly unfortunate given the attenuated sensitivity of adolescents to aversive and intoxicating effects of ethanol that may serve as cues to terminate intake. That is, because of their unique patterns of sensitivity to ethanol, adolescents may be able to drink more, although their brains may be more sensitive to the memory disrupting effects of the drug.

Elevated intake of ethanol may also be promoted during adolescence by increases in sensitivity to several appealing effects of ethanol: ethanol-induced social facilitation, ethanol’s rewarding effects, and potentially even “self-medicating,” restorative effects of ethanol. By far the best characterized of these effects is the accentuated sensitivity of adolescents to ethanol-induced facilitation of social behavior. That is, adolescent rats have been shown in numerous studies to show increases in social interactions following challenge with low doses of ethanol when placed with a novel, same-sex peer in a familiar, nonthreatening situation, whereas adults do not show social facilitation under these test circumstances (reviewed in Spear & Varlinskaya, 2005). Human adolescents as well cite social facilitation as being one of the, if not the most important, consequences of alcohol drinking (e.g., Beck, Thombs, & Summons, 1993).

A couple of recent animal studies suggest that adolescents may likewise be unusually sensitive to ethanol’s rewarding effects when compared with adults. Assessing age differences in the rewarding effects of ethanol in rats has proved challenging in a number of respects. Studies of conditioned place preferences have frequently been used to demonstrate the rewarding consequences of a variety of drugs in rodents (as discussed later) but are less consistently effective in revealing rewarding effects of ethanol in rats. And simple Pavlovian conditioning likewise may not yield clear signs of ethanol’s rewarding properties in rats, perhaps in part because of conditioned behaviors induced by the conditioned stimulus (CS) that may compete with expression of preferences at the time of test (see Pautassi, Myers, Spear, Molina, & Spear, 2008). Yet, using other approaches, age differences in ethanol’s rewarding properties are beginning to be examined in rats. One strategy has been to examine heart rate (HR) responses to alcohol, given evidence in human studies that the magnitude of alcohol-induced tachycardia is positively correlated with subjective measures of ethanol’s rewarding effects (Holdstock, King, & de Wit, 2000; Ray, McGeary, Marshall, & Hutchison, 2006). Using this approach, when adolescent and adult rats were given 2 hr limited access to saccharin-sweetened ethanol or the sweetener alone, only the adolescents self-administered enough ethanol to show IIR increases that exceeded their response to the sweetened control solution alone (Ristuccia & Spear, 2008). Thus, adolescents were more likely than adults to voluntarily consume sufficient amounts of ethanol to gain its rewarding benefits. Using a second-order conditioning task—where ethanol was paired with an oral CS (CS1) in phase 1 of conditioning, the oral CS1 was paired with a visually/tactilely distinct place (CS2) in phase 2, and then animals were tested for their preference for the CS2 during testing—adolescents showed stronger evidence of appetitive conditioning to ethanol than did adults (Pautassi ir kt., 2008 m). Thus, using two diverse strategies, two recent studies have shown adolescent rats to demonstrate stronger positively rewarding effects of ethanol than adults.

Adolescent rats may also become unusually sensitive to the anxiolytic properties of ethanol under circumstances when their baseline anxiety levels are elevated due to prior exposure to stressors or a history of alcohol exposure. Repeated restraint stress or chronic ethanol not only decreases sensitivity to ethanol’s impairing effects (as mentioned earlier) but also increases anxiety as indexed by notable suppression of baseline levels of social behavior, with ethanol sensitively restoring levels of social behavior, particularly among adolescents. More specifically, chronic ethanol exposure was found to elevate basal levels of anxiety among adolescents, but not adults, with these anxiogenic effects reversed by ethanol („Varlinskaya & Spear“, 2007 m). Acute and repeated exposure to restraint stress likewise was found to increase basal anxiety levels, with these anxiogenic effects sensitively reversed by ethanol among adolescents, but only following chronic stress in adults (Doremus-Fitzwater ir kt., 2007; „Varlinskaya & Spear“, 2006 m). Consequently, ethanol may serve to counter anxiety induced by prior stress or ethanol exposure, with these anxiolytic, “self-medicative” effects particularly pronounced in adolescents.

Relationship between Ethanol Sensitivities and Ethanol Use/Abuse

The apparent attenuation in sensitivity to aversive and intoxicating effects of ethanol seen normally during adolescence may interact with other risk factors that further decrease ethanol sensitivity, increasing propensity for problems with alcohol at this time. Indeed, a decreased sensitivity to alcohol intoxication has long been known as a risk factor for problematic alcohol involvement. As stated by Schuckit (1994) “a lower sensitivity to moderate doses of alcohol is associated with an increase in the risk of future alcoholism, perhaps through increasing the chances that a person will drink more heavily.” One major factor contributing to attenuated alcohol responses is genetic background, with an insensitivity to aversive and intoxicating ethanol effects seen not only in offspring with a family history of alcoholism (e.g., in sons of male alcoholics—Newlin & Thomson, 1990) but also in numerous lines of rodents selectively bred for high levels of voluntary ethanol consumption (McBride & Li, 1998). And as discussed earlier, a history of prior ethanol use and prior stressors may further attenuate the sensitivity of adolescents to ethanol’s impairing and sedating effects. Thus, a genetic-based insensitivity to alcohol’s aversive and intoxicating effects when combined with early initiation of alcohol use during adolescence, prior environmental stress, and the ontogenetic insensitivity normally seen during adolescence could potentially act as triple or quadruple “whammies” to precipitate high levels of alcohol use when genetically at risk youth undergo stressful circumstances and begin to drink early in adolescence, a pattern of elevated intake that could place them on a trajectory for later problematic alcohol use.

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Adolescent-Typical Patterns of Ethanol Sensitivity: Generalizability to Other Drugs and Natural Rewards

There is emerging evidence that the adolescent-typical pattern of attenuated aversive versus accentuated appetitive properties may be seen not only to ethanol but to other drugs as well. One of the ways that the rewarding properties of drugs and other appetitive stimuli have been assessed is via conditioned place preferences (CPP). Using this procedure, animals are exposed to a particular place in the presence of the potential reward, whereas they, are given equivalence exposure to an alternative place in the absence of that potentially rewarding stimulus; after a number of such exposures, when animals are tested by being allowed to freely access both places, to the extent that they find the stimulus reinforcing, they should spend more time in the chamber previously paired with that stimulus than control animals who had not been exposed to the stimulus in either chamber. Using CPP, a number of studies have shown adolescents to demonstrate stronger nicotine-induced CPP than adults (Shram, Funk, Li, & Lê, 2006; Torres, Tejeda, Natividad, & O’Dell, 2008; Vastola, Douglas, Varlinskaya, & Spear, 2002). There are also reports of enhanced CPP to cocaine and other psychomotor stimulants among adolescent rats relative to adults (Badanich, Adler, & Kirstein, 2006; „Brenhouse & Andersen“, 2008 m; Zakharova, Leoni, Kichko, & Izenwasser, 2009; Zakharova, Wade, & Izenwasser, 2009), although these findings are not ubiquitous, with some studies failing to observe age-related differences (Aberg, Wade, Wall, & Izenwasser, 2007; Campbell, Wood, & Spear, 2000).

In contrast to the enhanced sensitivity often demonstrated by adolescents to the appetitive properties of alcohol and other drugs, they conversely appear to be less sensitive to aversive effects of these substances. For instance, studies even within the same experimental series have reported that, relative to adults, adolescent exhibit both greater sensitivity to nicotine-induced CPP, but attenuated sensitivity to nicotine’s aversive properties that emerge at higher doses when indexed either via CTA (Shram ir kt., 2006) or conditioned place aversions (Torres ir kt., 2008). Likewise, adolescent rats also have been shown to exhibit attenuated CTA for amphetamine relative to adults (Infurna & Spear, 1979).

Intriguingly, these characteristic adolescent patterns of attenuated aversive/accentuated appetitive properties of drugs may even extend to some extent to certain natural rewards as well. For instance, adolescent rats show CPP for a social peer even when socially housed, whereas social CPP was evident only in isolate housed (i.e., socially deprived) adult rats (Douglas, Varlinskaya, & Spear, 2004). Similar results were seen in male (but not female) rats in a study assessing CPP induced by exposure to novel stimuli (Douglas, Varlinskaya, & Spear, 2003). When assessing positive hedonic responses to sucrose using a taste reactivity paradigm, adolescents were found to exhibit greater positive responding than adults to certain concentrations of sucrose, while consistently showing less negative taste responses to the aversive substance quinine („Wilmouth & Spear“, 2009 m).

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Summary and Potential Implications for Prevention Science in Human Adolescents

It is a long way from research with simple models of adolescence in the rat to the development of strategies for prevention of adolescent risk behaviors in humans. Yet, a number of promising findings have emerged that may ultimately have implications for prevention science. With full acknowledgement of the fragility of such translational efforts at this early stage in the study of the basic science of adolescence, a few tentative, but potentially promising areas for further consideration, are presented here:

  1. Certain adolescent-typical behaviors may be biological driven by relatively ancient reward/motivational systems in brain. To the extent that there are strong biological underpinnings for adolescent risk-taking, prevention research may be more usefully directed toward development of contexts promoting “safer” risk-taking, than focused on the goal of eliminating risk-taking behaviors per se. Through promoting “safer” contexts for risk-taking, the goal would be to permit young people to experience novel and exciting stimuli in appealing, drug-free contexts that minimize chances for harm.
  2. Stressors may further exacerbate adolescent-typical sensitivities to alcohol, making them even less sensitive to aversive effects used as cues to reduce drinking, but more sensitive to ethanol’s rewarding effects. Acute and chronic stressors also increase anxiety, with that anxiety particularly likely to be reversed by alcohol in adolescence. To the extent that similar stressor/alcohol effects are seen in humans, stressful economic, neighborhood, family, or other life contexts may serve to encourage even greater alcohol consumption levels among adolescents. These findings highlight the importance of working to reduce stress levels within the typical contexts of adolescence, and to help adolescents increase their capacity to cope with stressors.
  3. An attenuated sensitivity to ethanol during adolescence may permit relatively high levels of alcohol intake in adolescence, with this normal developmental insensitivity perhaps combining with genetic background and a history of stress and prior alcohol use to further exacerbate ethanol insensitivities—a known risk factor for development of alcohol abuse problems. There appears to be little awareness among adolescents that insensitivity to the intoxicating/aversive effects of ethanol is a sign of pažeidžiamumas to the development of alcohol problems, rather than an index of resiliency. Educating adolescents (and those that interact with them) as to how vulnerability for problematic alcohol use is expressed may help those who are resistant to alcohol recognize their vulnerability and moderate their intake accordingly. A culture change is needed from viewing more rapidly inebriated individuals as highly vulnerable to alcohol to recognizing that the greatest vulnerability for later abuse often resides within those who are relatively resistant to the intoxicating effects of alcohol.
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Padėka

The research presented in this article was supported by NIH grants R37 AA012525, R01 AA016887, R01 AA018026, and R01 AA012453.

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Nuorodos

  • Aberg M, Wade D, Wall E, Izenwasser S. MDMA (ekstazio) poveikis aktyvumui ir kokainą sąlygojančiai vietovei suaugusiems ir paaugliams žiurkėms. Neurotoksikologija ir teratologija. 2007;29(1): 37-46. [PMC nemokamas straipsnis] [PubMed]
  • Acheson SK, Stein RM, Swartzwelder HS. Semantinės ir figūrinės atminties sutrikimas ūminiu etanoliu: nuo amžiaus priklausantys efektai. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 1998;22(7): 1437-1442.
  • Andersenas SL. Antrojo pasiuntinio ciklinio AMP pokyčiai vystymosi metu gali būti dėmesio trūkumo / hiperaktyvumo sutrikimo (ADHD) motorinių simptomų pagrindas. Elgesio smegenų tyrimas. 2002;130(1-2): 197-201. [PubMed]
  • Anderson RI, Varlinskaya EI, Spear LP. Isolation stress and ethanol-induced conditioned taste aversion in adolescent and adult male rats. Poster Presented at the Annual Meeting of the International Society for Developmental Psychobiology; Washington, DC. 2008.
  • Badanich KA, Adler KJ, Kirstein CL. Paaugliai skiriasi nuo suaugusiųjų kokainą sąlygojančios vietovės pasirinkimo ir kokaino sukeltas dopamino kiekis branduolyje accumbens septi. Europos farmakologijos žurnalas. 2006;550(1-3): 95-106. [PubMed]
  • Beck KH, Thombs DL, Summons TG. The social context of drinking scales: Construct validation and relationship to indicants of abuse in an adolescent population. Priklausomybę sukeliantis elgesys. 1993;18(2): 159-169. [PubMed]
  • Behar D, Berg CJ, Rapoport JL, Nelson W, Linnoila M, Cohen M, et al. Behavioral and physiological effects of ethanol in high-risk and control children: A pilot study. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 1983;7(4): 404-410.
  • Bourgeois JP, Goldman-Rakic ​​PS, Rakic ​​P. Synaptogenesis reeso beždžionių prefrontalinėje žievėje. Cerebral Cortex (New York, NY, 1991) 1994;4(1): 78-96.
  • Brenhouse HC, Andersen SL. Vėlavęs išnykimas ir stipresnis kokainą sąlygojamos vietos pirmenybės atkūrimas paaugliams žiurkėms, palyginti su suaugusiais. Elgesio neurologija. 2008;122(2): 460-465. [PubMed]
  • Campbell JO, Wood RD, Spear LP. Kokaino ir morfino sukeltos vietos gydymas paaugliams ir suaugusiesiems. Fiziologija ir elgesys. 2000;68(4): 487-493. [PubMed]
  • Chugani HT. Neuroimaging of developmental non-linearity and developmental pathologies. In: Thatcher RW, Lyon GR, Rumsey J, Krasnegor N, editors. Developmental neuroimaging: Mapping the development of brain and behavior. San Diego, CA: Academic Press; 1996. pp. 187–195.
  • Įgulos F, He J, Hodge C. paauglių žievės vystymasis: kritinis priklausomybės pažeidžiamumas. Farmakologija, biochemija ir elgesys. 2007;86(2): 189-199.
  • Diaz-Granados JL, Graham DL. The effects of continuous and intermittent ethanol exposure in adolescence on the aversive properties of ethanol during adulthood. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2007;31(12): 2020-2027.
  • Doremus TL, Brunell SC, Rajendran P, Spear LP. Veiksniai, turintys įtakos padidėjusiam etanolio vartojimui paaugliams, palyginti su suaugusiais žiurkėmis. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2005;29(10): 1796-1808.
  • Doremus TL, Brunell SC, Varlinskaya EI, Spear LP. Anxiogeninis poveikis nutraukus ūminį etanolį paaugliams ir suaugusiems žiurkėms. Farmakologija, biochemija ir elgesys. 2003;75(2): 411-418.
  • Doremus-Fitzwater TL, Varlinskaya EI, Spear LP. Impact of repeated stress on responsivity to ethanol-induced changes in social behavior in adolescent and adult rats. Poster Presented at the Annual Meeting of the Society for Neuroscience; San Diego, CA. 2007.
  • Douglas LA, Varlinskaya EI, Spear LP. Novel-object place conditioning in adolescent and adult male and female rats: Effects of social isolation. Fiziologija ir elgesys. 2003;80(2-3): 317-325. [PubMed]
  • Douglas LA, Varlinskaya EI, Spear LP. Rewarding properties of social interactions in adolescent and adult male and female rats: Impact of social versus isolate housing of subjects and partners. Plėtros psichobiologija. 2004;45(3): 153-162. [PubMed]
  • Draski LJ, Bice PJ, Deitrich RA. Developmental alterations of ethanol sensitivity in selectively bred high and low alcohol sensitive rats. Farmakologija, biochemija ir elgesys. 2001;70(2-3): 387-396.
  • Harris JR. Where is the child’s environment? A group socialization theory of development. Psichologinė apžvalga. 1995;102: 458-489.
  • Jis J, Crews FT. Neurogenezė mažėja smegenų brendimo metu nuo paauglystės iki pilnametystės. Farmakologija, biochemija ir elgesys. 2007;86(2): 327-333.
  • Holdstock L, King AC, de Wit H. Subjektyvūs ir objektyvūs atsakai į etanolį vidutiniškai/sunkiai ir mažai socialiai geriantiems. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2000;24(6): 789-794.
  • Infurna RN, Spear LP. Amfetamino sukelto skonio slopinimo vystymosi pokyčiai. Farmakologija, biochemija ir elgesys. 1979;11(1): 31-35.
  • Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE. Monitoring the future national survey results on drug use, 1975–2006: Volume 1, Secondary school students (NIH Publication No 07-6205) Bethesda, MD: National Institute on Drug Abuse; 2007.
  • Markham JA, Morris JR, Juraska JM. Neuron number decreases in the rat ventral, but not dorsal, medial prefrontal cortex between adolescence and adulthood. Neurologija. 2007;144(3): 961-968. [PubMed]
  • McBride WJ, Li TK. Animal models of alcoholism: Neurobiology of high alcohol-drinking behavior in rodents. Critical Reviews in Neurobiology. 1998;12(4): 339-369. [PubMed]
  • Moy SS, Duncan GE, Knapp DJ, Breese GR. Sensitivity to ethanol across development in rats: Comparison to [3H]zolpidem binding. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 1998;22(7): 1485-1492.
  • Newlin DB, Thomson JB. Alcohol challenge with sons of alcoholics: A critical review and analysis. Psichologinis biuletenis. 1990;108(3): 383-402. [PubMed]
  • Pautassi RM, Myers M, Spear LP, Molina JC, Spear NE. Paauglėms, bet ne suaugusioms žiurkėms būdingas etanolio sukeltas apetitinis antrosios eilės kondicionavimas. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2008;32(11): 2016-2027.
  • Ray LA, McGeary J, Marshall E, Hutchison KE. Risk factors for alcohol misuse: Examining heart rate reactivity to alcohol, alcohol sensitivity, and personality constructs. Priklausomybę sukeliantis elgesys. 2006;31(11): 1959-1973. [PubMed]
  • Ristuccia RC, Spear LP. Jautrumas ir toleravimas etanolio autonominiam poveikiui paaugliams ir suaugusiems žiurkėms pakartotinai įkvepiant garus. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2005;29(10): 1809-1820.
  • Ristuccia RC, Spear LP. Autonomic responses to ethanol in adolescent and adult rats: A dose–response analysis. Alcohol (Fayetteville, NY) 2008;42(8): 623-629.
  • Rodríguez de Fonseca F, Ramos JA, Bonnin A, Fernández-Ruiz JJ. Presence of cannabinoid binding sites in the brain from early postnatal ages. NeuroReport. 1993;4(2): 135-138. [PubMed]
  • Rubia K, Smith AB, Woolley J, Nosarti C, Heyman I, Taylor E, et al. Progresyvus priekinės galvos smegenų aktyvacijos didėjimas nuo vaikystės iki pilnametystės įvykių metu vykstančių kognityvinės kontrolės užduočių metu. Žmogaus smegenų atvaizdavimas. 2006;27: 973-993. [PubMed]
  • Schuckit MA. Low level of response to alcohol as a predictor of future alcoholism. „American Journal of Psychiatry“. 1994;151(2): 184-189. [PubMed]
  • Shram MJ, Funk D, Li Z, Lê AD. Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine. Psichofarmakologija. 2006;186(2): 201-208. [PubMed]
  • Silveri MM, Spear LP. Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 1998;22(3): 670-676.
  • Sisk CL, Zehr JL. Brendimo hormonai organizuoja paauglių smegenis ir elgesį. Neuroendokrinologijos sienos. 2005;26(3-4): 163-174. [PubMed]
  • Spear LP. Paauglių smegenų ir su amžiumi susijusios elgesio apraiškos. Neurologijos ir biologinės elgsenos apžvalgos. 2000;24(4): 417-463. [PubMed]
  • Spear LP. Besivystančios smegenys ir paaugliams būdingi elgesio modeliai: evoliucinis požiūris. In: Walker E, Romer D, redaktoriai. Paauglių psichopatologija ir besivystančios smegenys: smegenų ir prevencijos mokslo integravimas. Niujorkas: „Oxford University Press“; 2007. 9 – 30.
  • Spear LP. Paauglystės elgesio neurologija. Niujorkas: Nortonas; 2010 m.
  • Spear LP, Varlinskaya EI. Adolescence: Alcohol sensitivity, tolerance, and intake. Recent Developments in Alcoholism: An Official Publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism. 2005;17: 143-159.
  • Cheminių medžiagų piktnaudžiavimo ir psichikos sveikatos paslaugų administracija National Survey on Drug Use and Health, Series H-30, DHHS Publication SMA 06-4194. Rockville, MD: 2006. 2005 m. Nacionalinio narkotikų vartojimo ir sveikatos tyrimo rezultatai: nacionalinės išvados.
  • Swartzwelder HS, Richardson RC, Markwiese-Foerch B, Wilson WA, Little PJ. Plėtros skirtumai dėl etanolio tolerancijos. Alcohol (Fayetteville, NY) 1998;15(4): 311-314.
  • Tarazi FI, Baldessarini RJ. Dopamino D(1), D(2) ir D(4) receptorių lyginamoji raida žiurkės priekinėse smegenyse. International Journal of Developmental Neuroscience: The Official Journal of the International Society For Developmental Neuroscience. 2000;18(1): 29-37. [PubMed]
  • Teicher MH, Krenzel E, Thompson AP, Andersen SL. Dopamino receptorių genėjimas peripubertaciniu laikotarpiu nėra susilpnintas dėl NMDA receptorių antagonizmo žiurkėms. Neurologijos laiškai. 2003;339(2): 169-171. [PubMed]
  • „Torres OV“, „Tejeda HA“, „Natividad LA“, „O'Dell LE“. Padidėjęs pažeidžiamumas dėl teigiamo nikotino poveikio paauglystės vystymosi laikotarpiu. Farmakologija, biochemija ir elgesys. 2008;90(4): 658-663.
  • Varlinskaya EI, Spear LP. Ūmus etanolio poveikis paauglių ir suaugusių žiurkių socialiniam elgesiui: bandymo situacijos pažinimo vaidmuo. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2002;26(10): 1502-1511.
  • Varlinskaya EI, Spear LP. Ūminis etanolio pašalinimas (pagirios) ir socialinis elgesys paauglių ir suaugusių patinų ir patelių Sprague-Dawley žiurkėms. Alkoholizmas, klinikiniai ir eksperimentiniai tyrimai. 2004;28(1): 40-50.
  • Varlinskaya EI, Spear LP. Acute restraint stress increases sensitivity to social consequences of ethanol in adolescent rats. Poster Presented at the Annual Meeting of the International Society for Developmental Psychobiology; Atlanta, GA. 2006.
  • Varlinskaya EI, Spear LP. Lėtinė tolerancija socialinėms etanolio pasekmėms paauglėms ir suaugusioms Sprague-Dawley žiurkėms. Neurotoksikologija ir teratologija. 2007;29(1): 23-30. [PMC nemokamas straipsnis] [PubMed]
  • Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP. Nikotino sukeltos sąlyginės vietos pirmenybė paaugliams ir suaugusiems žiurkėms. Fiziologija ir elgesys. 2002;77(1): 107-114. [PubMed]
  • Balta AM, Swartzwelder HS. Su amžiumi susijęs alkoholio poveikis atminties ir su smegenų funkcijomis susijusioms paaugliams ir suaugusiesiems. Recent Developments in Alcoholism: An Official Publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism. 2005;17: 161-176.
  • White AM, Truesdale MC, Bae JG, Ahmad S, Wilson WA, Best PJ, et al. Differential effects of ethanol on motor coordination in adolescent and adult rats. Farmakologija, biochemija ir elgesys. 2002;73(3): 673-677.
  • Wilmouth CE, Spear LP. Hedonic sensitivity in adolescent and adult rats: Taste reactivity and voluntary sucrose consumption. Farmakologija, biochemija ir elgesys. 2009;92(4): 566-573.
  • Wilson M, Daly M. Competitiveness, risk taking, and violence: The young male syndrome. Ethology and Sociobiology. 1985;6: 59-73.
  • Zakharova E, Leoni G, Kichko I, Izenwasser S. Diferencinis metamfetamino ir kokaino poveikis suaugusiems ir paaugliams žiurkių patekimo į vietą sąlygomis ir lokomotoriniu aktyvumu. Elgesio smegenų tyrimas. 2009;198(1): 45-50. [PMC nemokamas straipsnis] [PubMed]
  • Zakharova E, Wade D, Izenwasser S. Jautrumas kokainą sąlygojančiam atlygiui priklauso nuo lyties ir amžiaus. Farmakologija, biochemija ir elgesys. 2009;92(1): 131-134.