Relationships between impulsivity and subjective response in an IV ethanol paradigm

Rationale

Impulsivity and individual differences in subjective response to alcohol are risk factors for alcohol problems and possibly endophenotypes for alcohol dependence. Few prior studies have addressed relationships between the two constructs.

Objectives

To predict subjective responses to ethanol, we tested self-reported impulsiveness, ethanol dose condition (high dose, low dose, or placebo), and time (seven time points) along with interactions among these variables.

Methods

The present study is a secondary analysis of data from a within-subject, placebo-controlled, dose-ranging ethanol administration study using IV infusion with a clamping technique to maintain steady-state breath alcohol concentration. The sample consisted of healthy, non-alcohol dependent social alcohol drinkers between the ages of 21 and 30 (N?=?105). Participants at varying levels of impulsivity were compared with regard to stimulant and subjective responses to three ethanol dose conditions over time.

Results

Individuals with higher impulsivity reported elavated stimulant and dampened sedative response to alcohol, particularly at the higher dose. Higher impulsivity was associated with a steeper increase in stimulant effects during the first half of clamped ethanol infusion with the higher dose.

Conclusions

These results suggest that impulsive individuals may experience enhanced reinforcing, stimulant effects, and relatively muted aversive sedative effects from alcohol. These subjective responses may relate to enhanced risk of alcohol problems among more impulsive individuals.     

The effects of age at the onset of drinking to intoxication and chronic ethanol self-administration in male rhesus macaques

Rationale

Consumption of alcohol begins during late adolescence in a majority of humans, and the greatest drinking occurs at 18–25 years then decreases with age.

Objectives

The present study measured the differences in ethanol intake in relation to age at the onset of ethanol access among nonhuman primates to control for self-selection in humans and isolate age effects on heavy drinking.

Methods

Male rhesus macaques were assigned first access to ethanol during late adolescence (n?=?8), young adulthood (n?=?8), or early middle age (n?=?11). The monkeys were induced to drink ethanol (4 %?w/v in water) in increasing doses (water then 0.5, 1.0, 1.5 g/kg ethanol) using a fixed-time (FT) 300-s schedule of food delivery, followed by 22 h/day concurrent access to ethanol and water for 12 months. Age-matched controls consumed isocaloric maltose–dextrin solution yoked to the late adolescents expected to be rapidly maturing (n?=?4).

Results

Young adult monkeys had the greatest daily ethanol intake and blood-ethanol concentration (BEC). Only late adolescents escalated their intake (ethanol, not water) during the second compared to the first 6 months of access. On average, plasma testosterone level was consistent with age differences in maturation and tended to increase throughout the experiment more for control than ethanol-drinking adolescent monkeys.

Conclusions

Young adulthood in nonhuman primates strongly disposes toward heavy drinking, which is independent of sociocultural factors present in humans. Ethanol drinking to intoxication during the critical period of late adolescence is associated with escalation to heavy drinking.     

Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats

Rationale

Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied.

Objectives

This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB).

Results

Repeated dosing (0.5 or 1.0 mg/kg/day?i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8–10 days induced tolerance to their effects on ethanol consumption.

Conclusions

This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use.     

Determining the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection

Rationale

Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the degree to which genes influence this complex behavioral phenomenon.

Objectives

The primary goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection.

Methods

Genetically heterogeneous C57BL/6J (B6) × DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. Selective breeding was conducted in two independently generated replicate sets to increase the confidence of our heritability estimates and for future correlated trait analyses.

Results

Large and significant differences in locomotor sensitization between HLS and LLS lines were evident by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h ²?=?.22). Interestingly, locomotor activity in the absence of ethanol was genetically correlated with ethanol sensitization; high activity was associated with high sensitization.

Conclusions

That changes in ethanol sensitivity following repeated exposures are genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. As alcohol use and abuse disorders develop following many repeated alcohol exposures, these data emphasize the need for future studies determining the genetic basis by which changes in response to alcohol occur.     

Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation,sensitization, and body weight loss

Rationale

Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults).

Objectives

This study compared the motor stimulating and ataxic effects of repeatedly administered morphine in adolescent, late adolescent, and adult mice.

Methods

Mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured.

Results

Acute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age.

Conclusions

Compared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents.     

Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knockout mice

Introduction

Locomotor sensitization, defined as the progressive and enduring enhancement of the motor stimulant effects elicited by repeated exposure to drugs of abuse, is the consequence of drug-induced cellular neuroadaptations that likely contribute to addictive behavior. Neuroadaptations within the dopaminergic system have been shown to be involved both in the induction phase and in the long-term expression phase of sensitization upon drug readministration after withdrawal.

Materials and methods

Mice lacking the dopamine transporter (DAT-KO) were used to test the effect of constitutive hyperdopaminergia on the durability of behavioral sensitization to both cocaine and ethanol. The effect of the DAT mutation was simultaneously tested on two inbred genetic backgrounds, C57Bl/6 and DBA/2, chosen for their contrasting addiction-related phenotypes, as well as on the hybrid F₁ offspring of a cross between C57Bl/6 and DBA/2 congenic strains.

Results and discussion

In spite of the absence of the DAT, mutant mice were able to develop long-term expression of sensitization to cocaine. Compared to their wild-type littermates, DAT-KO mice exhibited a markedly increased acute ethanol-evoked locomotor activity and developed stronger behavioral sensitization to ethanol during both induction and long-term expression phases. Interestingly, this increased ethanol-induced sensitization was potentiated by the DBA/2 genetic background.

Conclusion

These findings, showing that DAT deletion facilitates sensitization, suggest a cross-sensitization-like effect between genetic- and pharmacological-induced hyperdopaminergia.     

Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats

Rationale

Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase intake, while aversive sensations decrease it. Female sex and adolescent age are associated with lower sensitivity to intake-reducing effects and more rapid development of alcohol abuse.

Objectives

This study assessed voluntary drinking and the aversive effects of alcohol to determine whether these measures are inversely related across the sexes and development.

Methods

Voluntary drinking of 20 % ethanol in an every-other-day (EOD) availability pattern and the dose–response relationship of ethanol conditioned taste aversion (CTA) were assessed in male and female adolescent and adult rats.

Results

CTA was sex specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and individual differences but was not sex specific. Adolescents initially drank more than adults, exhibited greater day-to-day variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns.

Conclusions

These results show that the emergence of intake patterns differs between adolescents and adults. Adolescents as a group initiate drinking at high levels but decrease intake as they mature. A subset of adolescents maintained high drinking levels into adulthood. In contrast, most adults consumed at steady, low levels, but a small subset quickly established and maintained high-consumption patterns. Adolescents also showed marked deprivation-induced increases. Sex differences were not observed in EOD drinking during either adolescence or adulthood.     

Molecular and behavioral characterization of adolescent protein kinase C following high dose ethanol exposure

Rationale

Ethanol is commonly used and abused during adolescence. Although adolescents display differential behavioral responses to ethanol, the mechanisms by which this occurs are not known. The protein kinase C (PKC) pathway has been implicated in mediating many ethanol-related effects in adults, as well as gamma-aminobutyric acid (GABA_A) receptor regulation.

Objectives

The present study was designed to characterize cortical PKC isoform and GABA_A receptor subunit expression during adolescence relative to adults as well as assess PKC involvement in ethanol action.

Results

Novel PKC isoforms were elevated, while PKCγ was lower during mid-adolescence relative to adults. Whole-cell lysate and synaptosomal preparations correlated for all isoforms except PKCδ. In parallel, synaptosomal GABA_A receptor subunit expression was also developmentally regulated, with GABA_AR δ and α₄ being lower while α₁ and γ₂ were higher or similar, respectively, in adolescents compared to adults. Following acute ethanol exposure, synaptosomal novel and atypical PKC isoform expression was decreased only in adolescents. Behaviorally, inhibiting PKC with calphostin C, significantly increased ethanol-induced loss of righting reflex (LORR) in adolescents but not adults, whereas activating PKC with phorbol dibutyrate was ineffective in adolescents but decreased LORR duration in adults. Further investigation revealed that inhibiting the cytosolic phospholipase A₂/arachidonic acid (cPLA₂/AA) pathway increased LORR duration in adolescents, but was ineffective in adults.

Conclusions

These data indicate that PKC isoforms are variably regulated during adolescence and may contribute to adolescent ethanol-related behavior. Furthermore, age-related differences in the cPLA₂/AA pathway may contribute to ethanol’s age-related effects on novel and atypical PKC isoform expression and behavior.     

Modulation of ethanol consumption by genetic and pharmacological manipulation of nicotinic acetylcholine receptors in mice

Rationale

Alcohol and nicotine are commonly co-abused. Genetic correlations between responses to these drugs have been reported, providing evidence that common genes underlie the response to alcohol and nicotine. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system are important in mediating nicotine response, and several studies suggest that alcohol may also interact with these nAChRs.

Objective

The aim of this study was to examine the role of nAChRs containing α7 or β2 subunits in ethanol consumption.

Methods

A two-bottle choice paradigm was used to determine ethanol consumption in wild-type and nAChR subunit knockout mice. Challenge studies were performed using the α4β2 nAChR partial agonist varenicline.

Results

Mice lacking the β2 subunit consumed a similar amount of ethanol compared to their wild-type siblings in an ethanol-drinking paradigm. In contrast, mice lacking the α7 nAChR receptor subunit consumed significantly less ethanol than wild-type mice but consumed comparable amounts of water, saccharin, and quinine. In C57BL/6J mice, varenicline dose-dependently decreased ethanol consumption with a significant effect of 2 mg/kg, without affecting water or saccharin consumption. This effect of varenicline was not reversed in mice lacking either the α7 or β2 subunit, providing evidence that nAChRs containing one of these subunits are not required for this effect of varenicline.

Conclusions

This study provides evidence that α7 nAChRs are involved in ethanol consumption and supports the idea that pharmacological manipulation of nAChRs reduces ethanol intake. Additional nAChRs may also be involved in ethanol intake, and there may be functional redundancy in the nicotinic control of alcohol drinking.     

Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice

Rationale

Dopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals.

Objectives

Here, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms.

Methods

To test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc.

Results

There were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that down-regulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol-induced place preference.

Conclusions

We conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake.     

Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice

Rationale

Dopamine D3 receptors (D3Rs) have been implicated in behavioral sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. We used D3R knockout (D3 KO) mice to examine whether the D3R plays a permissive role in EtOH and amphetamine (AMPH) sensitization. We also investigated whether EtOH sensitization is accompanied by alterations in D3R mRNA expression or binding.

Materials and methods

After comparing EtOH sensitization in C57Bl/6 mice and DBA/2 mice, D3 KO, wild type (WT), and for comparison, D1 and D2 KOs received five biweekly injections of EtOH (2.2 g/kg, i.p.) or saline. Another group of D3 KOs and WT controls received six times AMPH (1.5 mg/kg, i.p.). D3R mRNA and binding were measured in EtOH-sensitized DBA/2 mice with in situ hybridization and [¹²⁵I]-7-OH-PIPAT autoradiography, respectively.

Results

C57Bl/6 mice expressed EtOH sensitization albeit to a lesser extent than DBA/2 mice. Compared to WT mice, D3 KOs were resistant to EtOH sensitization. The behavioral profile of D3 KOs was more similar to D1 KOs than D2 KOs, which also failed to develop EtOH sensitization. However, D3 KOs developed AMPH sensitization normally. EtOH sensitization was not accompanied by changes in either D3R mRNA or D3R binding in the islands of Calleja, nucleus accumbens, dorsal striatum, or cerebellum.

Conclusions

These results suggest a necessary role for the D3R in EtOH but not AMPH sensitization, possibly through postreceptor intracellular mechanisms. Results also suggest that different neurochemical mechanisms underlie sensitization to different drugs of abuse.     

Behavioural and neuroinflammatory effects of the combination of binge ethanol and MDMA in mice

Rationale

Binge drinking is a common pattern of alcohol consumption among young people. Binge drinkers are especially susceptible to brain damage when other substances are co-administered, in particular, 3,4-methylendioxymethamphetamine (MDMA).

Objective

To evaluate the behavioural consequences of voluntary binge ethanol consumption, alone and in combination to MDMA. Also, to elucidate the effects of the combined consumption of these two drugs on neuroinflammation.

Materials and methods

Adolescent mice received MDMA (MDMA-treated mice), ethanol (ethanol-treated mice group) or both (ethanol plus MDMA-treated mice). Drinking in the dark (DID) procedure was used as a model of binge. Body temperature, locomotor activity, motor coordination, anxiety-like and despair behaviour in adolescent mice were evaluated 48?h, 72?h, and 7?days after the treatments. Also, neuroinflammatory response to these treatments was measured in the striatum.

Results

The hyperthermia observed in MDMA-treated mice was abolished by pre-exposition to ethanol. Ethanol plus MDMA-treated mice showed lower locomotor activity. Ethanol-treated mice showed motor coordination impairment and increased despair behaviour. Anxiety-like behaviour was only seen in animals that were treated with both drugs. Contrarily, neuroinflammation was mostly seen in animals treated only with MDMA.

Conclusions

Ethanol and MDMA co-administration increases the neurobehavioural changes induced by the consumption of each one of these drugs. However, as ethanol consumption did not increase neuroinflammatory responses induced by MDMA, other mechanisms, mediated by ethanol, are likely to account for this effect and need to be evaluated.     

Opposite effects of typical and atypical anti-psychotic drugs on sensitized dopamine receptors: Sub-chronic low dose Olanzapine exposure reverses sensitization but a similar regimen of low dose haloperidol potentiates sensitization effects

Rationale

Both typical and atypical antipsychotic drugs are D2 receptor antagonists but yet appear to have markedly different effects upon the induction of dopamine sensitization.

Objective

This study aims to compare the effects of subchronic regimens of low-dose olanzapine and haloperidol administered to rats previously sensitized to apomorphine.

Methods

Initially, rats received apomorphine (2.0 mg/kg) or vehicle treatments for five consecutive days followed by a conditioning test and an apomorphine challenge test. Next, there was an antipsychotic exposure phase in which three vehicle groups and three apomorphine groups received 10 daily injections of either vehicle, haloperidol (0.03 mg/kg) or olanzapine (0.01 mg/kg). In the final phase, all groups were given a second conditioning test and apomorphine challenge test.

Results

Apomorphine induced sensitization and conditioning effects. Following haloperidol exposure, apomorphine conditioned and sensitization effects were potentiated but, in contrast, olanzapine exposure eliminated apomorphine sensitization effects. In addition, the sensitization induced by apomorphine transformed the low-dose haloperidol treatment into a potent locomotor stimulant treatment. In the vehicle groups, haloperidol and olanzapine exposure effects were equivalent and not different from vehicle treatment.

Conclusions

The profound differences observed between typical and atypical antipsychotic exposure in animals with an upregulated dopamine system are consistent with clinical evidence for lower risk of psychomotor disturbances with chronic treatment with atypical antipsychotic. Importantly, the finding that a very low dose of olanzapine reversed sensitization effects suggests that low-dose olanzapine may have clinical utility in a variety of disorders linked to sensitization of the dopamine system.     

Role for ventral pallidal GABAergic mechanisms in the regulation of ethanol self-administration

Rationale

The striatopallidal medium spiny neurons have been viewed as a final common path for drug reward, and the ventral pallidum (VP) as a convergent point for hedonic and motivational signaling. The medium spiny neurons are GABAergic, but they colocalize enkephalin.

Objective

The present study investigated the role of the GABAergic mechanisms of the VP in ethanol consumption.

Methods

The effects of bilateral microinjections of GABA_A and GABA_B receptor agonists and antagonists into the VP on voluntary ethanol consumption were monitored in alcohol-preferring Alko alcohol rats given 90 min limited access to ethanol in their home cages every other day. The influences of coadministration of GABA and opioid receptor modulators were also studied.

Results

The GABA_A receptor agonist muscimol (1–10 ng/site) decreased ethanol intake dose-dependently, while administration of the GABA_A receptor antagonist bicuculline (10–100 ng) had an opposite effect. The GABA_B receptor agonist baclofen (3–30 ng) also suppressed ethanol intake, but the GABA_B receptor antagonist saclofen (0.3–3 μg) failed to modify it. Animals coadministered with bicuculline (30 ng) and baclofen (30 ng) consumed ethanol significantly less than those treated with bicuculline alone. Coadministration of the μ-receptor agonist D-Ala2,N-Me-Phe4,Glyol5-enkephalin (DAMGO, 0.1 μg) with bicuculline counteracted, whereas the μ-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 μg) enhanced the bicuculline-induced increase of ethanol intake. When given alone, DAMGO decreased while CTOP increased ethanol intake.

Conclusions

The study provides evidence for the ventral pallidal GABAergic mechanisms participating in the regulation of ethanol consumption and supports earlier work suggesting a role for pallidal opioidergic transmission in ethanol reward.     

Role of CA2+/calmodulin on ethanol neurobehavioral effects

Rationale

The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca²⁺)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca²⁺-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol.

Objectives

In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA.

Methods

Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration.

Results

Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration.

Conclusions

These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca²⁺-dependent pathways on the central effects of ethanol.     

The role of acetaldehyde in ethanol reinforcement assessed by Pavlovian conditioning in newborn rats

Rationale

Animal studies indicate that central acetaldehyde, dependent on catalase metabolism of ethanol (EtOH), modulates ethanol reinforcement. Brain catalase activity and acetaldehyde (ACD) production are significantly higher in rat pups compare d with adults. Interestingly, infant rats show high EtOH affinity for alcohol consumption and are particularly sensitive to the drug’s reinforcing effects.

Objectives

We tested whether central ACD is necessary and sufficient to induce appetitive conditioning in newborn rats through the artificial nipple technique.

Methods

Vehicle, EtOH (100 mg%), and acetaldehyde (0.35 μmol) were administered into the cisterna magna (1 μl). Half of the animals also received a central administration of 75 μg (experiment 1) or 40 μg of d-penicillamine (experiment 2). Afterwards, pups were exposed to an olfactory cue (conditioned stimulus). One hour later, neonates were tested with an artificial nipple in the presence of the conditioned cue. Nipple attachment duration, mean grasp duration, and number of nipple disengagements served as dependent variables.

Results

Positive responses to the scented nipple occurred in neonates conditioned with EtOH or ACD (experiments 1 and 2). In experiment 1, there were indications that d-penicillamine weakened the reinforcing effects of EtOH and ACD. In experiment 2, d-penicillamine (40 μg) significantly inhibited appetitive conditioned responses dependent upon EtOH or ACD.

Conclusions

Appetitive conditioning was observed when employing either central EtOH or ACD as unconditioned stimuli. Central abduction of ACD inhibited conditioned appetitive responsiveness to the surrogate nipple. Central ACD is involved in the determination or modulation of EtOH’s motivational properties during early stages in development.     

Age-dependent effects of stress on ethanol-induced motor activity in rats

Rationale

It is important to study age-related differences that may put adolescents at risk for alcohol-related problems. Adolescents seem less sensitive to the aversive effects of ethanol than adults. Less is known of appetitive effects of ethanol and stress modulation of these effects.

Objectives

This study aims to describe the effects of acute social or restraint stress on ethanol-precipitated locomotor activity (LMA), in adolescent and adult rats. Effects of activation of the kappa system on ethanol-induced LMA were also evaluated.

Methods

Adolescent or adult rats were restrained for 90 min, exposed to social deprivation stress for 90 or 180 min or administered with the kappa agonist U62,066E before being given ethanol, and assessed for LMA.

Results

Adolescents were significantly more sensitive to the stimulating, and less sensitive to the sedative, effects of ethanol than adults. Basal locomotion was significantly increased by social deprivation stress in adult, but not in adolescent, rats. U62,066E significantly reduced basal and ethanol-induced locomotion in the adolescents. Corticosterone and progesterone levels were significantly higher in adolescents than in adults.

Conclusions

Adolescents exhibit greater sensitivity to ethanol-induced LMA and reduced sensitivity to ethanol-induced motor sedation than adult rats. Ethanol’s effects on motor activity were not affected by acute stress. Unlike adults, adolescents were insensitive to acute restraint and social deprivation stress but exhibited motor depression after activation of the endogenous kappa opioid receptor system.     

Differential alteration of the effects of MDMA (ecstasy) on locomotor activity and cocaine conditioned place preference in male adolescent rats by social and environmental enrichment

Rationale

Ecstasy (MDMA) is used predominately by adolescents and young adults. Young MDMA users are more likely than non-users to use other drugs, including cocaine. The response to stimulant drugs can be affected by environmental factors; however, little information exists about the role that housing plays in mediating effects of MDMA in adolescence.

Objectives

The present experiment examined whether social and environmental factors alter effects of MDMA on activity and cocaine reward.

Methods

Male adolescent rats were housed on PND 23. Isolated rats were housed alone (1 rat/cage) in an impoverished environment with no toys (II) or enriched with toys (IE). Social rats were housed three/cage with (SE3) or without (SI3) toys. Starting on PND 29, 5 mg/kg MDMA or saline was injected and activity was measured for 60 min once daily for five consecutive days. On PND 36–40, cocaine CPP was conducted.

Results

Saline vehicle-induced activity of II rats was higher than other groups, and all groups became sensitized to the locomotor-stimulant effects of MDMA. In II rats, maximal CPP was increased after MDMA pre-exposure compared to vehicle. Environmental enrichment blocked this; however, dose–effect curves for cocaine CPP shifted to the left in both IE and SE3 rats. In rats with just social enrichment, there were no effects of MDMA on cocaine CPP.

Conclusion

Drug prevention and treatment strategies should take into account different environments in which adolescents live. These findings show that MDMA increases cocaine reward in male adolescents, and social enrichment diminishes, while environmental enrichment enhances this.     

Alcohol craving in adolescents: bridging the laboratory and natural environment

Rationale

Initial lab studies suggest that adolescent drinkers crave alcohol when presented with alcohol cues. Whether this effect generalizes to the natural environment, however, remains unknown, and studies have not examined whether craving predicts drinking among youths.

Objectives

This study builds on existing research by pairing controlled lab-based cue reactivity assessments (CRAs) with data collected in the natural environment using ecological momentary assessment (EMA) methods. We examined whether alcohol cues evoke craving among adolescent drinkers in the lab and natural environment, and tested the clinical relevance of craving during adolescence by examining the prospective association between craving and alcohol use.

Methods

Non-treatment-seeking adolescent drinkers (N?=?42; ages 15 to 20 years) completed a lab-based CRA followed by a 1-week EMA monitoring period. During the EMA period, youth were prompted randomly throughout the day to record momentary data on craving and contextual factors (e.g., alcohol cues, peers present).

Results

Alcohol cues elicited craving in the lab, and this effect generalized to the natural environment, especially among adolescents with more alcohol problems. In addition, craving predicted subsequent drinking levels in the natural environment.

Conclusions

This study demonstrates the utility of pairing lab paradigms with EMA methods to better characterize adolescents' reactivity to alcohol cues. Results implicate craving as a clinically meaningful motivator for drinking among adolescents and highlight a potentially important target of pharmacological or behavioral intervention.     

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

Rationale

Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.

Objective

The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.

Materials and methods

Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.

Results

The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABA_A receptor ligand [³H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.

Conclusions

Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.