Effects of the alpha 2-antagonist idazoxan on monoaminergic parameters measured in the cerebrospinal fluid of rabbits

The alpha 2-antagonist idazoxan was administered intravenously to rabbits. The increase in central noradrenergic, dopaminergic and serotonergic activity was followed as a function of time by determining neuronal parameters in the cerebrospinal fluid (CSF) and was compared with changes previously determined after yohimbine. These parameters include the enzyme dopamine-beta-hydroxylase (D beta H), the noradrenergic metabolites 3-methoxy-4-hydroxyphenylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the dopaminergic metabolite 3-methoxy-4-hydroxyphenylacetic acid (HVA) and the serotonergic metabolite 5-hydroxyindole acetic acid (5-HIAA). Control experiments with physiological saline were also performed. D beta H activity increased to 211% in control experiments, and to 570 and 530%, respectively after yohimbine and idazoxan. Compared to the control experiments yohimbine was able to elevate VMA, MHPG and HVA concentrations, but 5-HIAA levels were reduced. Idazoxan caused increased MHPG concentrations, slight increases in VMA, little effect on HVA and no effect on 5-HIAA levels. We conclude that idazoxan was as potent as yohimbine as an alpha 2-antagonist in our in vivo experiments and that idazoxan shows a much greater selectivity with regard to the noradrenergic system.     

Effects of yohimbine in obsessive compulsive disorder

The ₂-adrenergic receptor antagonist yohimbine was administered to 12 drug-free patients with obsessive compulsive disorder (OCD) and to 12 healthy subjects. Changes in behavior, cardiovascular symptoms, and in plasma levels of cortisol and the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed. Yohimbine had no significant effect on OCD symptoms. The OCD patients did not differ from healthy controls in their behavioral and MHPG response to yohimbine. In contrast to healthy subjects, OCD patients, like previous reports of depressed and panic disorders patients, had an increased cortisol response to yohimbine. These data suggest it is unlikely that abnormal noradrenergic function plays a primary role in the pathogenesis of OCD.     

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.     

Effects of noradrenergic alpha-2 receptor antagonism or noradrenergic lesions in the ventral bed nucleus of the stria terminalis and medial preoptic area on maternal care in female rats

Rationale

Maternal behavior in laboratory rats requires a network of brain structures including the ventral bed nucleus of the stria terminalis (BSTv) and medial preoptic area (mPOA). Neurotransmitter systems in the BSTv and mPOA influencing maternal behaviors are not well understood, although norepinephrine is an excellent candidate because the BSTv contains the densest noradrenergic fiber plexus in the forebrain and norepinephrine in the mPOA is known to influence other female reproductive functions.

Objectives

We hypothesized that downregulated noradrenergic activity in the BSTv and mPOA is necessary for mothering.

Methods

Postpartum mother?Clitter interactions were observed after BSTv infusion of yohimbine (an ??2 autoreceptor antagonist that increases norepinephrine release), and after BSTv or mPOA infusion of the more selective ??2 autoreceptor antagonist idazoxan. Lastly, noradrenergic input to the BSTv/mPOA was selectively lesioned in nulliparous rats with anti-DBH-saporin to determine if this would facilitate mothering.

Results

BSTv yohimbine almost abolished retrieval of pups but did not significantly affect dams?? ability to initiate contact, lick, or nurse them. BSTv idazoxan disrupted retrieval somewhat less than yohimbine, but significantly reduced nursing. mPOA idazoxan impaired retrieval more severely than that found after BSTv infusion. Anti-DBH-saporin almost eliminated noradrenergic terminals in the BSTv and reduced them by over 60?% in the mPOA, but did not promote maternal responding. It also did not affect females?? anxiety-related behavior.

Conclusions

Downregulated noradrenergic activity in the BSTv and mPOA is necessary for postpartum maternal behavior in rats, but eliminating this system alone is insufficient to promote maternal behaviors in nulliparous females.     

Evaluation of parameters for central neuronal activity in cerebrospinal fluid of rabbits following yohimbine

Rabbits were treated intravenously with yohimbine at a dose of 5 mg/kg. The concomitant increase in noradrenergic activity was followed in function of time by measuring dopamine-beta-hydroxylase activity and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) levels in cerebrospinal fluid. In addition, the effect of yohimbine on the dopaminergic, serotonergic and enkephalinergic neurotransmission was also determined. For this purpose, the dopamine metabolite, 3-methoxy-4-hydroxyphenylacetic acid (HVA), the serotonin metabolite, 5-hydroxy-indole acetic acid (5-HIAA) and methionine-enkephalin (Met-Enk) were quantified. The D beta H activity in control experiments, in which physiological saline was administered, increased up to 200% whereas in the yohimbine experiments a rise to 500-600% was observed. VMA and MHPG levels increased to 290%, and 209% respectively. HVA levels reached a value of 233% versus the concentration before drug injection, whereas 5-HIAA concentrations initially slightly increased and thereafter decreased. In the corresponding control experiments metabolite concentrations were virtually stable. Following yohimbine injection, methionine-enkephalin concentrations did not show significant variations compared with the control experiments. We conclude that noradrenergic and dopaminergic neurotransmission are increased following administration of the alpha 2-antagonist yohimbine whereas serotonergic neurotransmission is slightly decreased and enkephalinergic neurotransmission is unaltered. The value of the different parameters for measuring neuronal activity in cerebrospinal fluid is discussed.     

Trait differences in response to chronic nicotine and nicotine withdrawal in rats

Introduction

Understanding an individual’s vulnerability to drug addiction has important implications for the development of effective personal treatment plans. Although theories acknowledge impulsive behaviour as a key component of drug addiction, little is known about the influence of trait impulsivity on an individual’s susceptibility to the effects of psychostimulants on impulsivity at critical phases of the addiction cycle.

Methods

This study investigated the short and longer-term effects of chronic nicotine administration on impulsive choice in rats selected for high (HI) and low impulsivity (LI) on a delay discounting task. Rats prepared with subcutaneously osmotic mini-pumps received either nicotine (3.16 mg/kg/day [freebase]) or saline for 7 days. Performance was assessed during chronic treatment, early and late withdrawal, and in response to acute nicotine challenges following prolonged abstinence.

Results

Chronic nicotine increased impulsive choice in LI but not HI animals. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by opposing effects on impulsive choice in HI and LI animals. A transient decrease in impulsivity was observed in HI animals whilst the LI group remained more impulsive for up to 1 week following drug termination. Following normalisation of behaviour, acute nicotine challenges (0.125, 0.25, 0.5 mg/kg, SC) markedly increased impulsive choice regardless of trait impulsivity and drug history.

Conclusion

The results indicate that only LI individuals are vulnerable to chronic drug- and withdrawal-induced impairments in self-control which may increase the likelihood of the transition to, and maintenance of, nicotine dependence.     

Effect of yohimbine stress on reacquisition of oxycodone seeking in rats

Rationale

Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse.

Objective

To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking.

Methods

One hundred thirty-two male Sprague?CDawley rats underwent place conditioning with oxycodone (2?mg/kg, SC; ×6?days), extinction (vehicle?×?6?days), and reconditioning with 0, 0.25, 2, or 5?mg/kg oxycodone (2?days). Yohimbine (0, 2.5, or 5?mg/kg, IP) was administered 30?min prior to reconditioning.

Results

Pretreatment with 2.5?mg/kg yohimbine increased, while 5?mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n?=?30) further indicated that the effect of yohimbine was specific to reacquisition.

Conclusion

The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse.     

The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats

Rationale

Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-d-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice.

Objectives

Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice.

Methods

Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755.

Results

Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition.

Conclusions

NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.     

Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine

Rationale

Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized.

Objective

To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a β antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist).

Methods

Sprague–Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays).

Results

Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice.

Conclusions

The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior.     

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

Rationale

Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.

Objective

The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).

Methods

We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ??HI?? and low impulsive ??LI??, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.

Results

Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.

Conclusions

These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.     

Impaired cliff avoidance reaction in dopamine transporter knockout mice

Rationale

Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.

Objectives

Impulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating.

Results

DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice.

Conclusion

These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.     

The association between the catechol-O-methyltransferase Val108/158Met polymorphism and hyperactive–impulsive and inattentive symptoms in youth

Rationale

Hyperactivity, impulsivity, and inattention are major symptoms occurring in attention-deficit/hyperactivity disorder. This disorder is highly heritable, multifactorial, polygenic, and associated primarily with dysfunctions of dopaminergic, noradrenergic, and serotonergic systems.

Objectives

The present study tested the possible association of the catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) polymorphism with hyperactive–impulsive and inattentive symptoms in male youth.

Method

Polymorphism COMT Val108/158Met was analyzed in 807 male unrelated Caucasian young subjects: 231 healthy controls, 195 subjects with moderate hyperactive symptoms and 254 subjects with moderate inattentive symptoms, 111 subjects with severe hyperactive symptoms and 90 subjects with severe inattentive symptoms, all evaluated using Swanson, Nolan, and Pelham Questionnaire IV criteria.

Results

The frequency of the COMT genotypes, alleles, and the homozygous Met/Met genotype versus Val carriers (χ ² test with standardized residuals) differed significantly between subjects without and subjects with hyperactive–impulsive and inattentive symptoms. In addition, significantly higher hyperactive–impulsive and inattentive scores were found in subjects with the Met/Met genotype compared to carriers of other COMT genotypes. These significant results were due to the more frequent occurrence of Met/Met genotype or the Met allele in subjects with moderate and severe hyperactive–impulsive and inattentive symptoms compared to matched controls.

Conclusion

These results suggest that the Met/Met genotype or the Met allele of the COMT Val108/158Met, contributing to higher dopaminergic activity, are significantly overrepresented in subjects with moderate or severe hyperactive–impulsive and inattentive symptoms, and that this polymorphism is significantly associated with hyperactive–impulsive and inattentive symptoms in young boys and adolescents.     

Yohimbine administration and cue-reactivity in cocaine-dependent individuals

Rationale

Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.

Objectives

The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.

Methods

In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n?=?32), cocaine-dependent women (n?=?30), control men (n?=?32), and control women (n?=?25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.

Results

Yohimbine increased ratings of anxiety both before (p?p?=?0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p?=?0.001). Yohimbine also significantly increased craving, compared with placebo (p?p?=?0.006). Yohimbine also increased salivary cortisol (p?p?=?0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p?Conclusions Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.     

Amphetamine challenge decreases yohimbine binding to α2 adrenoceptors in Landrace pig brain

Rationale

The noradrenaline (NA) system is implicated in neurodegenerative and psychiatric disorders; however, our understanding is impaired by the lack of well-validated radioligands to assess NA function and release. Yohimbine, an ??2 adrenoceptor antagonist, has recently been developed as a carbon-11 [11C]-labeled radioligand for positron emission tomography (PET) imaging studies.

Objectives

Here we explore the hypothesis that yohimbine can be used as an in vivo tracer of NA receptor binding and release during amphetamine challenges in Landrace pigs.

Methods

Pigs underwent baseline PET scans with [11C]yohimbine and were then challenged with 10?mg/kg?d-amphetamine 20?min prior to a second [11C]yohimbine scan. Using the Logan analysis model, volumes of distribution were calculated from fits of the kinetic data 25?C90?min post-yohimbine injection.

Results

Amphetamine decreased [11C]yohimbine volume of distribution in the brain regions under investigation, including the thalamus, caudate nucleus, and cortical regions.

Conclusion

These data suggest that the binding of [11C]yohimbine to ??2 adrenoceptors may be displaceable by increases in synaptic concentrations of the endogenous ligand, NA, and possibly dopamine, suggesting the possibility that [11C]yohimbine may be used as a surrogate marker of NA release in vivo.     

Behavioral,biochemical, and blood pressure responses to alprazolam in healthy subjects: Interactions with Yohimbine

The effect of single doses of alprazolam (1.5 mg) and yohimbine (30 mg) and alprazolam and yohimbine given together on plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), cortisol, blood pressure, and subjective behavioral ratings was studied in eight healthy subjects. In comparison to placebo, alprazolam significantly reduced plasma MHPG and cortisol, systolic and diastolic blood pressure, and increased subjective ratings of drowsiness and mellow. Yohimbine and the alprazolam-yohimbine combination significantly increased plasma free MHPG. Concomitant yohimbine administration antagonized the effects of alprazolam on blood pressure and attenuated alprazolam-induced changes in cortisol and subjective ratings. The ability of alprazolam to decrease plasma MHPG and blood pressure contrasts with previously reported effects of diazepam. The implications of the findings of the present investigation to the postulated role of brain noradrenergic function in the etiology of panic anxiety and the therapeutic mechanism of action of antipanic treatment are discussed.     

Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task

Rationale

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

Objectives

To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward.

Materials and methods

Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays.

Results

Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine.

Conclusions

The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.     

Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals

Rationale

In laboratory animals, the biological stressor yohimbine (α₂-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking.

Objectives

This clinical study tested whether yohimbine increases opioid-seeking behavior.

Methods

Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone [12 and 24 mg IM in counterbalanced order, labeled drug A (session 1) and drug B (session 2)]. During each of six later sessions (within-subject, double-blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (drug A or B) vs money ($2) following different oral yohimbine pretreatment doses (0, 16.2, and 32.4 mg).

Results

Behavioral economic demand intensity and peak responding (O _max) were significantly higher for hydromorphone 2 than 1 mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (P _max?=?909, 3,647, and 3,225 for placebo, 16.2, and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (P _max?=?2,656, 3,193, and 3,615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic?≈?15 and diastolic?≈?10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood.

Conclusions

These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose.     

Differential effects of dopamine transporter inhibitors in the rodent Iowa gambling task

Rationale

The Iowa Gambling Task (IGT) can be used to quantify impulsive and risky choice behaviors in psychiatric patients, e.g., bipolar disorder (BD) sufferers. Although developing treatments for these behaviors is important, few predictive animal models exist. Inhibition of the dopamine transporter (DAT) can model profiles of altered motor activity and exploration seen in patients with BD. The effect of DAT inhibition on impulsive choices related to BD has received limited study however. We used a rodent IGT to elucidate the effects of similarly acting drugs on risky choice behavior.

Objectives

We hypothesized that (1) C57BL/6 mice could adopt the “safe” choice options in the IGT and (2) DAT inhibition would alter risk preference.

Methods

Mice were trained in the IGT to a stable risk-preference and then administered the norepinephrine/DAT inhibitor amphetamine, or the more selective DAT inhibitors modafinil or GBR12909.

Results

Mice developed a preference for the “safe” option, which was potentiated by amphetamine administration. GBR12909 or modafinil administration increased motor impulsivity, motivation significantly, and risk preference subtly.

Conclusions

The rodent IGT can measure different impulse-related behaviors and differentiate similarly acting BD-related drugs. The contrasting effects of amphetamine and modafinil in mice are similar to effects in rats and humans in corresponding IGT tasks, supporting the translational validity of the task. GBR12909 and modafinil elicited similar behaviors in the IGT, likely through a shared mechanism. Future studies using a within-session IGT are warranted to confirm the suitability of DAT inhibitors to model risk-preference in BD.     

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.     

A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

Introduction

The prefrontal cortex (PFC) receives serotonergic input from the dorsal raphe nucleus of the brainstem, as well as noradrenergic input from another brainstem nucleus, the locus coeruleus. A large number of studies have shown that these two neurotransmitter systems, and drugs that affect them, modulate the functional properties of the PFC in both humans and animal models.

Results

Here I examine the hypothesis that serotonin (5-HT) plays a general role in activating the PFC, whereas norepinephrine (NE) plays a general role in deactivating this brain region. In this manner, the two neurotransmitter systems may have opposing effects on PFC-influenced behavior. To assess this hypothesis, three primary lines of evidence are examined comprising the effects of 5-HT and NE on impulsivity, cognitive flexibility, and working memory.

Discussion

While all of the existing data do not unequivocally support the activation/deactivation hypothesis, there is a large body of support for it.