Pharmacology, Biochemistry and Behavior (v.86, #2)

Editorial Board (pp. ifc).

Special issue title page (pp. iii).

Adolescent cortical development: A critical period of vulnerability for addiction by Fulton Crews /; Jun He; Clyde Hodge (pp. 189-199).

Cortical growth and remodeling continues from birth through youth and adolescence to stable adult levels changing slowly into senescence. There are critical periods of cortical development when specific experiences drive major synaptic rearrangements and learning that only occur during the critical period. For example, visual cortex is characterized by a critical period of plasticity involved in establishing visual acuity. Adolescence is defined by characteristic behaviors that include high levels of risk taking, exploration, novelty and sensation seeking, social interaction and play behaviors. In addition, adolescence is the final period of development of the adult during which talents, reasoning and complex adult behaviors mature. This maturation of behaviors corresponds with periods of marked changes in neurogenesis, cortical synaptic remodeling, neurotransmitter receptors and transporters, as well as major changes in hormones. Frontal cortical development is later in adolescence and likely contributes to refinement of reasoning, goal and priority setting, impulse control and evaluating long and short term rewards. Adolescent humans have high levels of binge drinking and experimentation with other drugs. This review presents findings supporting adolescence as a critical period of cortical development important for establishing life long adult characteristics that are disrupted by alcohol and drug use.

Keywords: Alcohol; Adolescence; Cortical development; Binge drinking; Critical period

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction by Ezekiel P. Carpenter-Hyland; L. Judson Chandler (pp. 200-208).

It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears to be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, “fix” the addictive behavior in the adolescent and young adult brain.

Keywords: NMDA receptors; Dendritic spines; Experience-dependent plasticity; Adolescence; Ethanol

Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse by Cheryl A. Frye (pp. 209-219).

Progesterone (pregn-4-ene-3,20-dione; P) and its metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) are secreted by ovaries, adrenals, and glial cells. 3α,5α-THP in the midbrain ventral tegmental area mediates sexual receptivity of rodents through its actions at GABA_A, NMDA, and/or D₁ receptors. The extent to which 3α,5α-THP may influence anti-anxiety/anti-stress effects, conditioning and/or reward through these substrates and/or by altering hypothalamic pituitary adrenal axis function is discussed. Biosynthesis of 3α,5α-THP occurs in responses to mating and may underlie some of the rewarding aspects of sexual behavior. Recent findings from our laboratory which demonstrate that progestins can enhance approach to novel stimuli, conditioning, and reinforcement are reviewed. How progestins' effects on these processes may underlie response to drugs of abuse is considered and new findings which demonstrate interactions between progestins and cocaine are presented.

Keywords: Neurosteroid; Non-genomic; GABA; _A; D; ₁; receptors; NMDA rececptor; Anxiety; Affect; Learning; Cocaine; Progesterone; 3α,5α-THP

HPA function in adolescence: Role of sex hormones in its regulation and the enduring consequences of exposure to stressors by Cheryl M. McCormick; Iva Z. Mathews (pp. 220-233).

The hypothalamic–pituitary–adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.

Keywords: Adolescence; Puberty; Amphetamine; Nicotine; Stress; Cognition; Gonadal; Adrenal

Adolescence, glucocorticoids and alcohol by Mark A. Prendergast; Hilary J. Little (pp. 234-245).

This review examines the evidence that glucocorticoids are involved, during both adolescence and adulthood, in the cognitive deficits caused by long-term alcohol consumption and in the mechanism(s) of alcohol dependence. During adolescence, the hypothalamopituitary–adrenal (HPA) axis undergoes well-characterized changes in basal activity and many of these are influenced by alcohol consumption. While the former have been fairly well studied, there is little information about whether alcohol effects on the HPA in adolescents differ from those in adults. The means by which glucocorticoids may influence alcohol-related neurotoxicity are presented, and potential differences between adolescence and adults in this regard noted. The substantial evidence for involvement of glucocorticoids in alcohol-induced cognitive deficits is described, with particular reference to the consequences of alcohol withdrawal. The use of immature organotypic cultures of rodent brain in the study of alcohol neurotoxicity is considered in detail, and the information obtained from this methodology concerning the role of glucocorticoid receptors and excitable membrane proteins in this neurotoxicity. The influence of glucocorticoids on alcohol consumption and possible contributions to alcohol dependence are then considered. In conclusion, more information concerning the effects of glucocorticoids on plasticity and alcohol neurotoxicity during the adolescent period is needed.

Keywords: Alcohol; Glucocorticoids; Adolescence; Withdrawal; Neurotoxicity

How gene–stress–behavior interactions can promote adolescent alcohol use: The roles of predrinking allostatic load and childhood behavior disorders by Ulrich S. Zimmermann; Dorothea Blomeyer; Manfred Laucht; Karl F. Mann (pp. 246-262).

A variety of environmental and genetic factors modulating the risk for alcoholism have been described, which predominantly act by interacting with each other. For example, the family, peers and society determine the level of exposure to stress and alcohol, while genes modulate how sensitive an individual responds to both. The resulting behaviors feed back to the social environment, modulating and in the worst case increasing further stress exposure.We here review neurobiological evidence how such a process of mutual interaction can involve and affect drinking. In at-risk adolescents it may have been in force for many years before they have their first alcoholic drink, increasing their risk for addiction by generating allostatic load. As an example, psychiatric disorders involving attention deficit, hyperactivity, or disruptive behaviors first evolve during childhood and are influenced by all the above factors. They are also strongly associated with harmful adolescent drinking and later alcohol use disorders.One important implication of this concept is that issues such as family adversity, adolescent psychiatric disorders, or adolescent drinking might not only be associated with, but causally related to, the risk for later addiction. They are targets for preventive interventions, which should start as early as possible in subjects at-risk.

Keywords: Stress; Genes; HPA system; Alcohol; Adolescents; Addiction; Disruptive behavior; Attention deficit; Hyperactivity

Automatic and controlled processes and the development of addictive behaviors in adolescents: A review and a model by Reinout W. Wiers; Bruce D. Bartholow; Esther van den Wildenberg; Carolien Thush; Rutger C.M.E. Engels; Kenneth J. Sher; Jerry Grenard; Susan L. Ames; Alan W. Stacy (pp. 263-283).

This paper presents a review and a model of the development of addictive behaviors in (human) adolescents, with a focus on alcohol. The model proposes that addictive behaviors develop as the result of an imbalance between two systems: an appetitive, approach-oriented system that becomes sensitized with repeated alcohol use and a regulatory executive system that is not fully developed and that is compromised by exposure to alcohol. Self-regulation critically depends on two factors: ability and motivation to regulate the appetitive response tendency. The motivational aspect is often still weak in heavy drinking adolescents, who typically do not recognize their drinking as problematic. Motivation to regulate use often develops only years later, after the individual has encountered serious alcohol-related problems. Unfortunately, at that point behavioral change becomes harder due to several neurocognitive adaptations that result from heavy drinking. As we document, there is preliminary support for the central elements of the model (appetitive motivation vs. self-regulation), but there is a paucity of research directly addressing these mechanisms in human adolescents. Further, we emphasize that adolescent alcohol use primarily takes place in a social context, and that therefore studies should not solely focus on intra-individual factors predicting substance use and misuse but also on interpersonal social factors. Finally, we discuss implications of the model for interventions.

Keywords: Implicit cognition; Executive functions; Alcohol; Adolescence

Party drug use in techno nights: A field survey among French-speaking Swiss attendees by Léonie Chinet; Philippe Stéphan; Frank Zobel; Olivier Halfon (pp. 284-289).

This study was designed to investigate the lifestyle and substance use habits of dance music event attendees together with their attitudes toward prevention of substance misuse, harm reduction measures and health-care resources. A total of 302 attendees aged 16–46 years (mean=22.70, S.D.=4.65) were randomly recruited as they entered dance music events. Rates for lifetime and current use (last 30 days) were particularly high for alcohol (95.3% and 86.6%, respectively), cannabis (68.8% and 53.8%, respectively), ecstasy (40.4% and 22.7%, respectively) and cocaine (35.9% and 20.7%, respectively). Several patterns of substance use could be identified: 52% were alcohol and/or cannabis only users, 42% were occasional poly-drug users and 6% were daily poly-drug users. No significant difference was observed between substance use patterns according to gender. Pure techno and open-air events attracted heavier drug users. Psychological problems (such as depressed mood, sleeping problems and anxiety attacks), social problems, dental disorders, accidents and emergency treatment episodes were strongly related to party drug use. Party drug users appeared to be particularly receptive to harm reduction measures, such as on-site emergency staff, pill testing and the availability of cool water, and to prevention of drug use provided via counseling. The greater the involvement in party drug use, the greater the need for prevention personnel to be available for counseling. General practitioners appeared to be key professionals for accessing health-care resources.

Keywords: MDMA; Cocaine; Drug use; Dancing; Adolescents; Young adults; Problem use; Prevention; Harm reduction; Access to health care

Age of first marijuana use and the occurrence of marijuana use disorders in Southwest California Indians by Cindy L. Ehlers; Wendy S. Slutske; David A. Gilder; Philip Lau (pp. 290-296).

In several national surveys a younger age of substance usage has been associated with a higher likelihood of the development of dependence. Some studies have suggested that age at first use is primarily an environmentally driven variable, whereas others suggest that it may be partially mediated by a general vulnerability to exhibit problem behaviors. Although Native Americans, overall, have the highest prevalence of substance dependence of any US ethnic group, the relationship of age of first marijuana use on the development of dependence in Native American populations is relatively unknown. Demographic information and DSM-III-R diagnoses were obtained from 525 Southwest California Indian adults residing on contiguous reservations. Multinomial logistic regression was used to investigate the relationship between age of first use and marijuana use disorders. Early marijuana use was found to be strongly associated with abuse and dependence in this population, even in the presence of several other risk factors including externalizing diagnoses. These data suggest that effective environmental prevention efforts at reducing early marijuana use may be an important strategy to lower the prevalence of use disorders in this high risk population.

Keywords: Native Americans; Marijuana; Marijuana dependence; Cannabis use; Age of initiation

Age, sex and early environment contribute to individual differences in nicotine/acetaldehyde-induced behavioral and endocrine responses in rats by Minjung K. Park; James D. Belluzzi; Sun-Ho Han; Junran Cao; Frances M. Leslie (pp. 297-305).

Neonatal handling was used to evaluate the influence of early environment on responses to nicotine. Rats exposed as pups to daily short-term separation from the dam (H) were compared to non-handled (NH) controls. In experiment 1, prepubescent males and females, aged postnatal day (P) 30, were tested for the effect of nicotine/acetaldehyde (NicAc) on open field behavior and plasma corticosterone levels. NicAc induced increases in ambulatory activity and time spent in the center of the field in NH, but not H, males. Drug-induced increases in initial ambulatory activity, but not center time, were also seen in NH and H females. Handling, but not sex, contributed to group differences in plasma corticosterone levels. In experiment 2, NH and H rats were tested for acquisition of NicAc self-administration at three ages, P27–31, P34–38 and P90–94. Age and sex, but not handling, contributed to differences in performance of this task. Whereas males exhibited a decrease in responding with age, females did not. These findings demonstrate that neonatal handling may serve as an experimental model for individual differences in sensitivity to tobacco constituents. Furthermore, the current study indicates that stress reactivity, age and sex may play differential roles in initiating smoking behavior.

Keywords: Nicotine self-administration; Age; Sex differences; Postnatal handling; Corticosterone; Locomotion

Multiple substance use among young males by Nestor D. Kapusta; Paul L. Plener; Rainer Schmid; Kenneth Thau; Henriette Walter; Otto M. Lesch (pp. 306-311).

Neurobiological studies hypothesize a common final pathway of addictive behavior in the mesolimbic dopaminergic system. Nicotine has been shown to sensitize the reward pathway, thereby causing increased drug-seeking behavior. Since there is evidence to suggest that nicotine, alcohol and other psychoactive substances act on the same final pathway and seem to augment their effects in animal subjects, drug intake behavior of humans would likely be reflected in increased substance use of nicotine-dependent persons. We used biological markers of substance use as well as questionnaires to assess the levels of psychoactive substance use among 18-year-old males in a naturalistic cross-sectional setting. We found that increasing levels of nicotine dependence were related to higher levels of alcohol abuse and dependence. Furthermore, higher levels of nicotine dependence were associated with elevated levels of recent cannabinoid use.

Keywords: MESH-Keywords; Tobacco Dependence; Illicit Drugs; Alcohol Abuse; Alcohol Dependence; Illicit Drug Testing; Adolescents; Epidemiology; HSI

Does stress reactivity or response to amphetamine predict smoking progression in young adults? A preliminary study by Harriet de Wit; Lisa Vicini; Emma Childs; Maliha A. Sayla; Jolan Terner (pp. 312-319).

Recent studies with laboratory animals indicate that a constellation of behavioral factors predict progression to self-administer drugs. Relatively little is known about behavioral or biological factors that predict the progression in drug use from initial experimentation to regular use in human drug users. The present exploratory study examined reactivity to an acute stressor and reactivity to a single dose of a dopaminergic drug as predictors in progression to heavier smoking in young cigarette smokers over a 6-month period. Forty-four college students who were light to moderate smokers participated in three laboratory sessions, followed by a follow-up interview 6 months later to determine smoking level. On one of the laboratory sessions subjects underwent the Trier Social Stress Test, and on the others they ingested capsules containing placebo or 20 mgd-amphetamine. Outcome measures included subjective ratings of mood and measures of heart rate and salivary cortisol. We found modest positive relationships between stress reactivity and certain responses to amphetamine. Further, stress-induced increases in cortisol were positively related to increases in cigarette smoking in the 31 subjects who we were able to contact at 6 months. Although these results are highly preliminary, they resemble the relationships previously reported in laboratory animals, suggesting that some of the same factors that predict drug-self-administration in rodents predict progression in drug use among young adults.

Keywords: Acute stress; d; -Amphetamine; Smoking; Progression; Individual differences; Human; Subjective effects; Cortisol

Influence of age at drinking onset on the alcohol deprivation effect and stress-induced drinking in female rats by Marc W. Füllgrabe; Valentina Vengeliene; Rainer Spanagel (pp. 320-326).

We have recently observed increased stress responsiveness with regard to alcohol consumption in male rats that consumed alcohol since their adolescent period. Thus, early age at drinking onset can induce enhanced stress-induced alcohol drinking in male rats. However, it is not known whether female rats respond in a similar way. Therefore, we compared the drinking behavior of two female Wistar rat groups — one that acquired alcohol consumption during adolescence (adolescent group) and the other that acquired their drinking during adulthood (adult group) in a model of long-term voluntary alcohol drinking with repeated deprivation and stress phases. Furthermore, we studied the influence of age at drinking onset on the efficacy of acamprosate treatment. Thirty-nine female Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as to 5% and 20% ethanol solutions during an observation period of 29 weeks. A deprivation phase of 14 days was introduced following 8 weeks of access to alcohol in order to measure the alcohol deprivation effect (ADE). After 15 and 25 weeks of alcohol access, all animals were subjected for 3 consecutive days of forced swim and electric foot-shock stress, respectively. After 29 weeks of access to alcohol all animals underwent a second deprivation phase and the subsequent ADE was measured either under acamprosate (200 mg/kg) or vehicle treatment. Drinking before the first deprivation phase was not different between animal groups. However, the expression of the first ADE was more pronounced in adult female rats and alcohol intake stayed increased for the remainder of the experiment in the adult group. Both repeated swim stress and foot-shock stress produced a more pronounced increase in ethanol consumption in the adolescent group compared to the adult group. Acamprosate reduced relapse-like drinking in the adult female rat group. However, it had no effect on the ADE in the adolescent group. In conclusion, female rats that initiate alcohol consumption during adolescence might be more susceptible to stress-induced alcohol consumption. Adolescent alcohol drinking might also result in a reduced response to acamprosate.

Keywords: Long-term alcohol self-administration; Alcohol deprivation effect (ADE); Swim stress; Foot-shock stress; Rats; Adolescence; Acamprosate

Neurogenesis decreases during brain maturation from adolescence to adulthood by Jun He; Fulton T. Crews (pp. 327-333).

Adolescence is an important stage of brain development. Recent studies have indicated that neurogenesis in the brain occurs throughout life prompting comparisons of adolescent and adult neurogenesis. Since insulin-like growth factor 1 (IGF-1) has been implicated in promoting neurogenesis we investigated the levels of neurogenesis in adolescents (PND30) and adults (PND120) using IGF-1 over-expressing mice and IGFBP-1 (IGF binding protein-1) over-expressing mice. Proliferation and differentiation of neuroprogenitors were determined using bromodeoxyuridine (BrdU)- and doublecortin (DCX)-labeling. High levels of neurogenesis were found in both the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of the adolescents as compared with the adults. Both adolescent IGF-1 and IGFBP-1 transgenic mice as well as their wildtype controls have significantly higher expression of BrdU and DCX in the hippocampus and SVZ when compared with their adult counterparts. However, no significant differences on BrdU-labeling were found when either of transgenic mice were compared with their wildtype littermates in both age groups. These studies indicate that adolescent mice have high levels of neurogenesis compared to adults suggesting a dramatic loss of neurogenesis during the transition from adolescence to adulthood. However, the role of IGF-1 during adolescent development is still unclear.

Keywords: Neurogenesis; IGF-1; Adolescent; IGF binding protein-1

Enhancement of endocannabinoid signalling during adolescence: Modulation of impulsivity and long-term consequences on metabolic brain parameters in early maternally deprived rats by Eva María Marco; Walter Adriani; Rossella Canese; Franca Podo; Maria Paz Viveros; Giovanni Laviola (pp. 334-345).

Pharmacological modulation of the endocannabinoid system is a novel but poorly explored field for potential therapy. Early maternal deprivation represents an animal model for specific aspects of neuropsychiatric disorders. This study explored whether a pharmacological manipulation of the endocannabinoid system at adolescence may restore altered phenotypes resulting from early maternal deprivation. Wistar male rats, maternally deprived for 24 h on postnatal day (PND) 9, were administered the fatty-acid amide hydrolase (FAAH) inhibitor URB597 (0, 0.1 or 0.5 mg/kg/day) for six days during adolescence (PND 31–43), while tested in the intolerance-to-delay task. Deprived (DEP) adolescent rats showed a trend for higher impulsivity levels and an increased locomotor response to novelty when compared to non-deprived (NDEP) controls. The low dose of URB597 effectively decreased impulsive behaviour specifically in DEP subjects. Moreover, long-term metabolic brain changes, induced by drug treatment during adolescence, were detected in DEP animals using proton magnetic resonance spectroscopy (¹H MRS). Significant changes were only found within the hippocampus: N-acetyl-aspartate and total creatine were up-regulated by the low dose; glutamate and glutamate plus glutamine were conversely down-regulated by the higher dose. In summary, administration of URB597 during adolescence increased self-control behaviour and produced enduring brain biochemical modifications, in a model for neuropsychiatric disorders.

Keywords: Maternal deprivation; Adolescence; Cannabinoid drugs; Fatty-acid amide hydrolase (FAAH); Intolerance-to-delay; URB597; Rat; Magnetic resonance spectroscopy (MRS)

‘Nicotine deprivation effect' in rats with intermittent 23-hour access to intravenous nicotine self-administration by Laura E. O'Dell; George F. Koob (pp. 346-353).

Our previous work demonstrates that rats allowed extended 23-hour access to intravenous nicotine self-administration (IVSA) display voluntary, dose-related levels of nicotine intake (i.e., higher doses result in higher intake) that remain stable across 40 days. This study examined whether an escalating dose regimen with intermittent abstinence periods produces different levels of nicotine intake relative to those observed during continuous access to a fixed unit dose. Rats were trained to nose-poke for food and water in 23-hour sessions prior to and after recovery from surgical implantation of jugular catheters. Animals ( n=12) then were given access to nicotine IVSA in 4-day cycles, each separated by three intervening days of abstinence in their home cage. The unit dose available for nicotine IVSA was increased between cycles as follows: 0.015, 0.03, 0.06, 0.09 mg/kg/0.1 ml infusion/1 s, fixed ratio 1. Control rats ( n=6) were given access to saline for five 4-day IVSA periods. Nicotine dependence was assessed by examining physical signs of withdrawal following an injection of the nicotinic antagonist mecamylamine (1.5 mg/kg, i.p.). Nicotine intake dose-dependently increased between cycles. Within each cycle, nicotine intake was highest on the first day after abstinence and decreased over the next 3 days of continuous access. Mecamylamine produced a significant increase in overt signs of withdrawal in the 23-hour access animals comparable to that observed in previous studies of nicotine dependence. Our findings suggest that abstinence from nicotine may produce a “deprivation effect” in nicotine-dependent rats. In addition, intermittent access to increasing unit doses appears to produce higher levels of nicotine intake than continuous access to a constant unit nicotine dose.

Keywords: Intermittent; Intravenous self-administration; Rat; Nicotine

Some rewarding effects of androgens may be mediated by actions of its 5α-reduced metabolite 3α-androstanediol by Cheryl A. Frye (pp. 354-367).

The abuse of anabolic–androgenic steroids (AS) is a growing problem; however, the effects and mechanisms underlying their addictive effects are not well understood. Research findings regarding androgen abuse in people and hedonic effects of androgens in laboratory rats are reviewed. Androgens, like other steroids, can have traditional actions via cognate intracellular steroid receptors, as well as other substrates. Our recent results indicate that testosterone (T) metabolites may have actions in part via γ-aminobutyric acid (GABA)_A/benzodiazepine receptor complexes (GBRs) and/or dopaminergic neurons in the nucleus accumbens, to mediate T's positive hedonic states. This may provide the basis for positive reinforcing effects of androgen seeking and use behavior. Following a comprehensive review of the background literature, our findings are presented that have explored the extent to which metabolites of T mediate euphorogenic effects of androgens by acting in the nucleus accumbens. Then results regarding whether GBRs are necessary substrates for androgens' positive hedonic effects are discussed. Lastly, research that addresses if dopaminergic neurons in the nucleus accumbens are necessary for these effects of androgens are discussed. This review provides a comprehensive examination of the hedonic properties and abuse/addiction potential of androgens and the putative mechanisms underlying these effects.

Keywords: Testosterone; Reward; Reinforcement; Hedonic; Conditioning; GABA; _A; receptors; Dopamine receptors; Anxiety; Affect; Learning

A randomized clinical trial of a targeted intervention to moderate alcohol use and alcohol-related problems in at-risk adolescents by C. Thush; R.W. Wiers; N. Theunissen; J. Van den Bosch; J. Opdenacker; P. van Empelen; M. Moerbeek; F.J. M. Feron (pp. 368-376).

This study investigated the effectiveness of a targeted intervention program aimed at at-risk adolescents in a randomized clinical trial design ( N=107). This program combined intervention methods which have been proven effective in reducing drinking in young adults, such as an expectancy challenge, cognitive behavioral skill training and brief motivational feedback. Additionally, this intervention contained the new element of discussing biological, cognitive and social risk factors for developing alcohol problems. We investigated whether this seven session program was successful in changing cognitive determinants of drinking behavior and consequently in moderating alcohol use and the development of alcohol-related problems in at-risk adolescents. The intervention was effective in changing several of the targeted cognitive determinants. However, despite the changes in these cognitive determinants of drinking, the experimental group did not show a significant difference in decrease of drinking at posttest compared with the control group. The results did not yield support for any differential long term effects of the intervention. We concluded that although the present intervention successfully changed important cognitive determinants of drinking more is needed to change subsequent drinking behavior in at-risk adolescents.

Keywords: Targeted intervention; Alcohol use; Adolescents; Alcohol expectancies; Risk perception

MK-801 infusions to the ventral tegmental area and ventromedial hypothalamus produce opposite effects on lordosis of hormone-primed rats by Sandra M. Petralia; Joseph F. DeBold; Cheryl A. Frye (pp. 377-385).

Progesterone initiates female sexual behavior of rodents (lordosis) through actions at intracellular progestin receptors in the ventromedial hypothalamus. Progesterone's metabolite, 5α-pregnan-3α-ol-20-one, mediates the intensity and duration of lordosis through its actions at GABA_A receptors in the ventral tegmental area. Whether progestins can influence sexual behavior through actions that involve N-methyl-D-aspartate receptors (NMDARs) in the ventromedial hypothalamus and ventral tegmental area was investigated. The current study examines the effect of bilateral ventral tegmental area or ventromedial hypothalamus infusions of the non-competitive NMDAR antagonist (+)-MK-801 hydrogen maleate (MK-801; 0, 20, or 200 ng) on lordosis, motor activity, and NMDA R1 subtype (NMDAR1) immunoreactivity in estradiol benzoate (10 μg)+progesterone (50 μg)- and estradiol benzoate+vehicle primed rats. Compared to vehicle infusions, infusions of MK-801 to the ventral tegmental area facilitated lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)- and estradiol benzoate+vehicle primed rats. Infusions of MK-801 to the ventromedial hypothalamus inhibited lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)- and estradiol benzoate+vehicle primed rats, compared to vehicle. There was no effect of MK-801 infusions to the ventral tegmental area or the ventromedial hypothalamus on motor behavior. Immunocytochemistry for NMDAR1 revealed MK-801 (200 ng) infusions to the ventral tegmental area or ventromedial hypothalamus of estradiol benzoate (10 μg)+progesterone (50 μg)- or estradiol benzoate+vehicle primed rats significantly reduced the number of darkly stained NMDAR1-immunoreactive cells, compared to vehicle infusions. These data suggest NMDARs may be important in the mediation of hormonal actions in both the ventral tegmental area and the ventromedial hypothalamus for sexual receptivity of rodents, but in different ways.

Keywords: N; -methyl-; D; -aspartate receptors; Ventromedial hypothalamus; Ventral tegmental area; Lordosis

Ethanol sensitization in a neurodevelopmental lesion model of Schizophrenia in rats by Susan K. Conroy; Zachary Rodd; R. Andrew Chambers (pp. 386-394).

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.

Keywords: Schizophrenia; Alcohol; Sensitization; Addiction; Neonatal ventral hippocampal lesions; Dopamine; Dual diagnosis

Association between illicit drug and alcohol use and first manic episode by Ellen Frank; Elaine Boland; Danielle M. Novick; Jacopo V. Bizzarri; Paola Rucci (pp. 395-400).

In light of the established influence of substance use on the onset, course, and outcome of bipolar disorder, we performed a retrospective chart review of patients with bipolar I disorder participating in a randomized controlled trial to further investigate the relationship between alcohol and substance use and first onset of mania. A total of 59.4% ( N=101) of the 170 participants were determined to have a history of substance and/or alcohol use. Among the 101 participants with SU, use was coded in 10 (9.9%) as immediately preceding, in 50 (49.5%) as preceding mania, in 7 (6.9%) as following mania, and in 34 (33.7%) as indeterminable. Of the 10 participants with immediately preceding use, 5 experienced their first manic episode immediately after discontinuing a substance. Our findings support earlier reports detailing the high prevalence of substance use among patients with bipolar disorder. Treatments targeting alcohol and substance use among individuals with bipolar disorder are clearly needed, as are prophylactic treatments targeting adolescents and young adults who are at risk for either bipolar disorder or alcohol and substance related disorders.

Keywords: Substance use; Manic episode; Illness onset; Bipolar disorder

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients by John E. McGeary; Christianne Esposito-Smythers; Anthony Spirito; Peter M. Monti (pp. 401-406).

The VNTR polymorphism in the Dopamine D4 receptor gene ( DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship.Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene ( L≥7 [ n=25], S=<7 [ n=52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge.The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes.Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

Keywords: DRD4; Adolescents; Substance misuse

Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats by Alicia A. Walf; Cheryl A. Frye (pp. 407-414).

Estradiol (E₂) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the β isoform of estrogen receptor (ER) are important for E₂'s effects for anxiety and/or depressive behavior. Whether ERβ in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERβ in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERβ than ERα to the hippocampus, but not a control region/missed sites (i.e. the ventral tegmental area), should decrease anxiety and depressive behavior, compared to vehicle and that ERα-specific SERMs should not have the same effect. To investigate this, ovariectomized (ovx) rats were surgically-implanted with guide cannulae aimed at the hippocampus (target site) or ventral tegmental area (control site). Rats were administered vehicle, or 17β-E₂ (equal affinity for ERα and ERβ), SERMs with greater affinity for ERα vs. ERβ (17α-E₂ or propyl pyrazole triol), or SERMs with greater affinity for ERβ vs. ERα (coumestrol or diarylpropionitrile) to these sites (2 μg/μl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERβ-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17β-E₂ or ERβ SERMs entered more central squares in an open field, spent more time on the open arms of the plus maze, and spent less time immobile compared to rats administered vehicle. Administration of ERα-specific SERMs produced similar effects as vehicle administration. Thus, E₂'s anti-anxiety and anti-depressive effects may involve ERβ in the hippocampus.

Keywords: SERMs; Estradiol; Affect; Mood; Sex differences; Animal model

Self-administration of 3α-androstanediol increases locomotion and analgesia and decreases aggressive behavior of male hamsters by Cheryl A. Frye; Alicia Babson; Alicia A. Walf (pp. 415-421).

Androgens, such as testosterone (T), can have reinforcing effect, which may be due in part to actions of T's metabolite, 3α-androstanediol (3α-diol). To investigate rewarding effects of 3α-diol, gonadally intact adult male hamsters were given a two-bottle choice test to determine the amount of 3α-diol that would be self-administered over 4 days of exposure. After 2 days of habituation and 4 days of monitoring of consumption, hamsters were tested in an activity monitor and the open field (locomotion/exploration), paw lick (analgesia) and resident−intruder (aggression) tasks. Hamsters consumed significantly more 3α-diol than vehicle in the two-bottle choice test. Hamsters that were allowed to self-administer 3α-diol made significantly more beam breaks and total entries in the open field had increased latencies to pawlick, and engaged in significantly fewer attacks, than did hamsters with access to vehicle alone. Hamsters that self-administered 3α-diol had higher levels of 3α-diol in serum, hippocampus, prefrontal cortex, striatum and midbrain than did hamsters with access to vehicle alone. Together, these data suggest that 3α-diol may have rewarding effects.

Keywords: Non-genomic; Neurosteroid; Anabolic–androgenic androgens; Reward; Reinforcement

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Pharmacology, Biochemistry and Behavior (v.86, #2)

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Pharmacology, Biochemistry and Behavior (v.86, #2)