Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy.

Gene therapy in its current design is an irreversible process. It cannot be stopped in case of unwanted side effects, nor can expression levels of therapeutics be adjusted to individual patient's needs. Thus, the Gene-Switch (GS) system for pharmacologically regulable neurotrophic factor expression was established for treatment of parkinsonian patients. Mifepristone, the synthetic steroid used to control transgene expression of the GS vector, is an approved clinical drug. However, pharmacokinetics and -dynamics of mifepristone vary considerably between different experimental animal species and depend on age and gender. In humans, but not in any other species, mifepristone binds to a high-affinity plasma carrier protein. We now demonstrate that the formulation of mifepristone can have robust impact on its ability to activate the GS system. Furthermore, we show that a pharmacological booster, ritonavir (Rtv), robustly enhances the pharmacological effect of mifepristone, and allows it to overcome gender- and species-specific pharmacokinetic and -dynamic issues. Most importantly, we demonstrate that the GS vector can be efficiently controlled by mifepristone in the presence of its human plasma carrier protein, α1-acid glycoprotein, in a "humanized" rat model. Thus, we have substantially improved the applicability of the GS vector toward therapeutic use in patients.

Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine.

Acute central nervous system exposure to dextroamphetamine (d-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semimechanistic pharmacokinetic and pharmacodynamic (PK/PD) model with consideration of these multiple effects as a basis was developed. Integrated pharmacokinetics of d-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid were characterized using a population approach. This PK model was then linked to an indirect-response pharmacodynamic model using as a basis the measurement of extracellular striatal dopamine, also via microdialysis. In both rats and nonhuman primates (NHPs), d-amphetamine stimulation of dopamine outflow (reverse transport) through DAT was primarily responsible for the dose-linear increase in dopamine. As well, in both species a moderator function was needed to account for loss of the dopamine response in the presence of a relatively sustained d-amphetamine ECF exposure, presumptive of an acute tolerance response. PK/PD model structure was consistent between species; however, there was a 10-fold faster return to baseline dopamine in NHPs in response to an acute d-amphetamine challenge. These results suggest preservation from rodents to NHPs regarding the mechanism by which amphetamine increases extracellular dopamine, but a faster system response in NHPs to tolerate this increase. This microdialysis-based PK/PD model suggests greater value in directing preclinical discovery of novel approaches that modify reverse transport stimulation to treat amphetamine abuse. General value regarding insertion of an NHP model in paradigm rodent-to-human translational research is also suggested.

Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response.

BACKGROUND: Challenges specific to the discovery and development of candidate CNS drugs have led to implementation of various in silico, in vitro and in vivo approaches to improve the odds for commercialization of novel treatments. NEW METHOD: Advances in analytical methodology and microdialysis probe design have enabled development of a non-human primate model capable of measuring concentrations of drugs or endogenous chemicals in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Linking these to population modeling reduces animal numbers to support predictive translational sciences in primates. Application to measure D-amphetamine exposure and dopamine response in ECF and CSF demonstrate the approach. RESULTS: Following a 0.1 mg/kg intravenous bolus dose of D-amphetamine, a population approach was used to build a plasma compartmental-based and brain physiologic-based pharmacokinetic (PK) model linking drug concentrations in plasma to brain ECF and CSF concentrations. Dopamine was also measured in brain ECF. The PK model was used to simulate the relationship between D-amphetamine exposure and dopamine response in ECF over a wide dose range. COMPARISONS WITH EXISTING METHODS: Ability to co-sample and measure drug and endogenous substances in blood, brain ECF and/or CSF, coupled with population modeling, provides an in vivo approach to evaluate CNS drug penetration and effect in non-human primates. CONCLUSIONS: A method to measure drug and endogenous neurochemicals in non-human primate brain fluids is demonstrated. Its basis in non-human primates merits improved confidence regarding predictions of drug exposure and target engagement in human CNS.

Novel, potent, selective and brain penetrant vasopressin 1b receptor antagonists.

Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3 mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.

Environmental and Pharmacological Modulation of Amphetamine- Induced 50-kHz Ultrasonic Vocalizations in Rats.

Rats emit high-frequency 50-kHz ultrasonic vocalizations (USV) in appetitive situations like social interactions. Drugs of abuse are probably the most potent non-social elicitors of 50-kHz USV, possibly reflecting their euphorigenic properties. Psychostimulants induce the strongest elevation in 50-kHz USV emission, particularly amphetamine (AMPH), either when applied systemically or locally into the nucleus accumbens (Nacc). Emission of AMPH-induced 50-kHz USV depends on test context, such as the presence of conspecifics, and can be manipulated pharmacologically by targeting major neurotransmitter systems, including dopamine (DA), noradrenaline (NA), and serotonin (5-HT), but also protein kinase C (PKC) signaling. Several D1 and D2 receptor antagonists, as well as typical and atypical antipsychotics block the AMPH-induced elevation in 50-kHz USV. Inhibiting D1 and D2 receptors in the Nacc abolishes AMPH-induced 50-kHz USV, indicating a key role for this brain area. NA neurotransmission also regulates AMPH-induced 50-kHz USV emission given that α 1 receptor antagonists and α 2 receptor agonists exert attenuating effects. Supporting the involvement of the 5-HT system, AMPH-induced 50-kHz USV are attenuated by 5-HT2C receptor activation, whereas 5-HT2C receptor antagonism leads to the opposite effect. Finally, treatment with lithium, tamoxifen, and myricitrin was all found to result in a complete abolishment of the AMPH-induced increase in 50-kHz USV, suggesting the involvement of PKC signaling. Neurotransmitter systems involved in AMPH-induced 50-kHz USV emission only partially overlap with other AMPH-induced behaviors like hyperlocomotion. The validity of AMPHinduced 50-kHz USV as a preclinical model for neuropsychiatric disorders is discussed, particularly with relevance to altered drive and mood seen in bipolar disorder.

Affective communication in rodents: serotonin and its modulating role in ultrasonic vocalizations.

Serotonin (5-hydroxytryptamine, 5-HT) is an important modulatory neurotransmitter and functions as a key neurodevelopmental signal in the mammalian brain. 5-HT plays a prominent role in regulating various types of psychological processes and functions, including mood and emotion, particularly anxiety, but also in regulating social behavior. Consequently, the 5-HT system is implicated in various neuropsychiatric disorders, such as anxiety disorders and depression or autism spectrum disorders (ASD), with selective 5-HT reuptake inhibitors being the frontline medication. Mice and rats perceive and emit ultrasonic vocalizations (USV). It is widely believed that the various distinct USV types reflect the animal's affective state, such as anxiety or pleasure. Furthermore, they serve communicative functions, for instance, as alarm calls or social contact calls. Manipulations targeting the 5-HT system alter affective ultrasonic communication in rodents throughout life, probably because of its important role in regulating anxiety and social behavior. Ample evidence indicates the involvement of the 5-HT system in modulating isolation-induced USV in pups. Later in life, the 5-HT system plays a strong modulatory role in the emission of aversive 22-kHz USV in rats. So far, little is known about the role of 5-HT in the production of interaction-induced USV in mice and appetitive 50-kHz USV in rats, although recent findings also suggest a modulatory effect of the 5-HT system. Assessment of rodent USV is a valuable method to investigate mood and emotion, and to enhance our understanding of, and develop novel pharmacological therapies for neuropsychiatric disorders, such as anxiety disorders and depression or ASD.

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory.

Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory.

Critical involvement of 5-HT2C receptor function in amphetamine-induced 50-kHz ultrasonic vocalizations in rats.

RATIONALE: Rats emit various distinct types of ultrasonic vocalizations (USV), with high-frequency 50-kHz USV typically occurring in appetitive situations being elicited by administering drugs of abuse, most notably amphetamine (AMPH), possibly reflecting drug wanting/craving and/or liking. OBJECTIVES: Because 50-kHz USV emission is, at least in part, dopamine (DA) dependent and 5-HT2C agonists inhibit DA neurotransmission, we hypothesized that AMPH-induced 50-kHz USV can be attenuated by pretreatment with a 5-HT2C agonist. METHODS: In experiments I and II, a dose-response curve for AMPH-induced 50-kHz USV was established, and the partial dependency of AMPH-induced 50-kHz USV on DA neurotransmission was validated by pretreatment with the D2-antagonist eticlopride. In experiment III, rats were pretreated with the 5-HT2C agonist CP 809,101 (0.0, 0.3, 1.0, 3.0, and 10 mg/kg), while in experiment IV, CP 809,101 (3.0 mg/kg), the 5-HT2C antagonist SB 242084 (1.0 mg/kg), or the combination of the two, was applied before AMPH administration (2.0 mg/kg). Finally, in experiment V, rats were treated with SB 242084 (0.0, 0.1, 0.3, and 1.0 mg/kg) only, i.e., in absence of AMPH. RESULTS: The 5-HT2C agonist CP 809,101 dose-dependently blocked AMPH-induced 50-kHz USV, most notably trills, a call subtype that is considered to exclusively reflect a positive affective state, while the 5-HT2C antagonist SB 242084 induced opposite effects. Moreover, SB 242084 induced 50-kHz USV by its own. CONCLUSIONS: 5-HT2C receptors are critically involved in AMPH-induced 50-kHz USV, with 5-HT2C antagonism resulting in a stimulant-like effect. Attenuation of drug wanting/craving and/or liking by coadministration of a 5-HT2C agonist could be a translational pharmacodynamic biomarker.

NOGO-66 receptor deficient mice show slow acquisition of spatial memory task performance.

The Nogo-66 receptor (NgR1) is part of a co-receptor complex on neurons that transmits a signal for inhibition of neurite outgrowth. In addition, NgR1 function has also been related to other disorders such as schizophrenia and Alzheimer's disease. Here, we studied the effect of life-long deletion of NgR1 (ngr(-/-)) in tests for cognition and positive symptoms of schizophrenia. In the water maze, ngr(-/-) mice learned to locate the hidden platform as well as wild type mice, although with slower acquisition. Deletion of NgR1 did not affect amphetamine- or phencyclidine (PCP)-induced hyperactivity, two models of positive symptoms of schizophrenia. Taken together, ngr(-/-) animals show slower acquisition of a spatial learning and memory task.

On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists.

RATIONALE: The clinical efficacy of the monoamine and noradrenaline transporter inhibitors methylphenidate and atomoxetine in attention deficit/hyperactivity disorder implicates noradrenergic neurotransmission in modulating inhibitory response control processes. Nonetheless, it is unclear which adrenoceptor subtypes are involved in these effects. OBJECTIVES: The present study aimed at investigating the effects of adrenoceptor agonists on inhibitory response control as assessed in the rodent 5-choice serial reaction time task, a widely used translational model to measure this executive cognitive function. RESULTS: Consistent with the previous reported effects of atomoxetine, the noradrenaline transporter inhibitor desipramine improved inhibitory response control, albeit the effect size was smaller compared to that of atomoxetine. Methylphenidate exerted a bimodal effect on inhibitory response control. Interestingly, the preferential ß2-adrenoceptor agonist clenbuterol improved inhibitory response control. Moreover, clenbuterol improved visuospatial attention in the task, an effect that was also observed with the preferential ß1-adrenoceptor agonist dobutamine. By contrast, although the preferential α1-adrenoceptor and α2-adrenoceptor agonists (phenylephrine and clonidine, respectively) and the non-selective ß-adrenoceptor agonist (isoprenaline) were found to alter inhibitory response control, this was probably secondary to the simultaneous increments in response latencies and omissions observed at effective doses. CONCLUSIONS: Taken together, these findings further strengthen the notion of noradrenergic modulation of inhibitory response control and attentional processes and particularly reveal the involvement of ß2-adrenoceptors therein.

Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties.

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.

Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease.

One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.

5-HT6 antagonism attenuates cue-induced relapse to cocaine seeking without affecting cocaine reinforcement.

Re-exposure to drug-related cues elicits drug-seeking behaviour and relapse in humans even after months of abstinence. Similarly, in laboratory rats, drug-associated stimuli reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study mechanisms underlying cocaine relapse. 5-HT6 receptors (5-HT6Rs) are abundantly expressed in brain areas such as the nucleus accumbens and prefrontal cortex, which are critically involved in cocaine reinforcement and relapse. Nevertheless, the role of 5-HT6Rs in relapse mechanisms has not been investigated. We report here that the 5-HT6R antagonists SB-271046 and Ro-04-6790 significantly attenuate cue-induced cocaine seeking. However, effective doses of both 5-HT6R antagonists did not affect cocaine self-administration. This indicates that 5-HT6Rs are specifically involved in the secondary reinforcing properties of cocaine, leaving primary reinforcement and ability to perform an operant response unaffected. As such, 5-HT6Rs may represent a novel target for the prevention of relapse to cocaine seeking.

Antidepressant treatment in anxiety disorders.

Antidepressant drug treatment is the clinical standard of care for all types of anxiety disorders. Broad efficacy of selective serotonin reuptake inhibitors suggests the importance of enhanced serotonergic function of the anxiolytic properties of current antidepressants. However, analysis of the preclinical evidence indicates that most conventional "anxiolytic" drug tests are not sensitive to antidepressants. Such dissociation is not surprising because of the traditional approach to validation of preclinical tests that is to a large extent based on establishing face validity as well as sensitivity to benzodiazepine anxiolytics. The present review argues for extending the cognitive model of antidepressant drug action to cover their anxiolytic properties as well. Such an approach is based on ambiguity or uncertainty in a broad sense as the hallmark of human stress that has different expressions ready for experimental modeling. These possibilities include schedule-induced behaviors that are directly based on intermittent reinforcement, conditioning to ambiguous stimuli, social stress where agonistic confrontations are possible but not predictable or controlled by the subject, and an even larger class of behaviors that are critically dependent on the inhibition of the prepotent responses in exchange for the ambiguous possibility of a later gain in reinforcement. Interestingly, in all these cases, antidepressant drug treatment is clearly effective in preclinical laboratory settings. One of the cognitive functions that appears to be affected by antidepressant drugs is inhibitory control. Inhibition of prepotent responding has beneficial effects in the "uncertainty" stress situations discussed above and therefore it is this cognitive function that may be critical for anxiolytic effects of antidepressants and novel anxiolytic drug development.

Dopamine receptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats.

A neuropsychological hallmark of attention deficit/hyperactivity disorder (ADHD) is the reduced ability to tolerate delay of reinforcement, leading to impulsive choice. Genetic association studies have implicated several genes involved in dopaminergic neurotransmission in ADHD. In this study, we investigated whether differences in the expression level of these dopamine-related genes of rats predict the individual level of impulsive choice. Among all frontostriatal brain regions tested, only in the medial prefrontal cortex (mPFC), we observed significant positive correlations between impulsive choice and transcript levels of the dopamine receptor D(1), the dopamine receptor D(5) and calcyon. Local mPFC infusions of the D(1)/D(5) receptor antagonist SCH 23390 and agonist SKF 38393 resulted in increased impulsive choice, in agreement with the idea that endogenous receptor D(1)/D(5) stimulation in the mPFC promotes the choice of large delayed rewards. Together, these data indicate that this class of dopamine receptors in the mPFC plays a pivotal role in impulsive choice, and aberrancies thereof might contribute to ADHD symptomatology.

Amphetamine decreases behavioral inhibition by stimulation of dopamine D2, but not D3, receptors.

Behavioral disinhibition is a manifestation of impulsive behavior that is prominent in the psychopathology of various psychiatric disorders such as addiction, attention-deficit hyperactivity disorder, mania, and personality disorders. Impulsivity may be studied by measuring anticipatory responses made before the presentation of a food-predictive, brief light stimulus in a two-choice serial reaction time task. In such serial reaction time tasks, amphetamine has been shown to produce dose-dependent increases in premature responding in a manner dependent on dopamine D(2)-like receptor stimulation. So far, it is unknown whether it is the D(2) or D(3) receptor that is involved in this form of impulsivity. In this study, rats were trained in a two-choice serial reaction time task until baseline performance was stable. Next, effects of the dopamine D(2) preferring antagonist L-741,626 and selective D(3) antagonist SB-277011 were assessed alone and in the presence of amphetamine. Neither L-741,626 nor SB-277011 affected behavioral inhibition, although the latter significantly increased reaction time at 10 mg/kg. Amphetamine dose-dependently increased impulsivity. The effect of amphetamine was attenuated by L-741,626 (3 mg/kg), whereas SB-277011 (3 mg/kg) had no effect. Therefore, amphetamine-induced behavioral disinhibition depends on D(2), but not D(3), receptor stimulation.

Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression.

There is a growing body of evidence indicating that stimulation of metabotropic glutamate type II receptors (mGlu2/3) reduces anxiety in laboratory animals and humans. Surprisingly, it was reported that mGlu2/3 receptor antagonists have antidepressant- and anxiolytic-like activities in laboratory animal studies as well. The present study aimed to resolve this controversy by characterizing behavioral effects of a selective mGlu2/3 receptor antagonist, LY-341495, in a variety of animal models sensitive to clinically used anxiolytic and antidepressant agents. In agreement with previous reports, LY-341495 (0.3-3 mg/kg, i.p.) reduced immobility in the mouse forced swim test. LY-341495 was also effective in the marble burying test in mice, although similar effects were observed after administration of various drugs including methamphetamine. Further, LY-341495 had no effects in the elevated plus maze and stress-induced hyperthermia tests in mice, as well as on punished drinking (Geller-Seifter's test) and differential reinforcement of low rates of responding (DRL) in rats. It is concluded that behavioral profile of mGlu2/3 receptor antagonists as represented by LY-341495 is different from that of conventional anxiolytic and antidepressant drugs.

Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control.

RATIONALE: Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D(1) and D(2) receptors and the nucleus accumbens (Acb) in this respect. OBJECTIVE: The present experiments were designed to study the role of dopamine D(1) and D(2) receptors in the Acb in inhibitory response control. METHODS: Rats were trained in a five-choice serial reaction time task and received bilateral infusions into the Acb core or shell of either SCH 23390 or eticlopride (representing selective dopamine D(1) and D(2) receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined. RESULTS: Eticlopride into either the Acb core or shell did not affect premature responding, a measure for inhibitory response control, but increased reaction time and errors of omission. In contrast, SCH 23390 into both regions reduced premature responding, slightly improved attentional performance in the core and increased errors of omission in the shell. Amphetamine robustly increased premature responding which was dose-dependently blocked by eticlopride in the Acb core and attenuated by eticlopride in the shell. In addition, amphetamine slightly decreased accuracy and reaction time, and these effects were inhibited by eticlopride in both regions. SCH 23390 infusion into the Acb core or shell did not alter amphetamine's effects. CONCLUSION: Our data provide evidence for the involvement of dopamine D(1) and D(2) receptors in the Acb core and shell in inhibitory response control and attentional performance.

Behavioral disinhibition requires dopamine receptor activation.

RATIONALE: Behavioral disinhibition is a manifestation of impulsive behavior that is prominent in the psychopathology of various psychiatric disorders, but the underlying neural mechanisms are unclear. Behavioral disinhibition can be investigated by measuring premature responding in the 5-choice serial reaction time task (5-CSRTT) in which attentional parameters can be measured as well. OBJECTIVE: The objective of the study was to investigate the involvement of dopamine neurotransmission in behavioral disinhibition using the 5-CSRTT in rats. METHODS: The effects of amphetamine, cocaine, nicotine, the dopamine reuptake inhibitor GBR 12909, the noradrenaline reuptake inhibitor desipramine, the dopamine D1 receptor antagonist SCH 23390, and the dopamine D2 receptor antagonist eticlopride were studied in rats that were well-trained in the 5-CSRTT. Subsequently, the effects of amphetamine, cocaine, and nicotine were tested after pretreatment with SCH 23390 or eticlopride. RESULTS: What amphetamine, cocaine, and nicotine had in common is that they increased premature responding. However, these drugs had distinct effects on attentional parameters. GBR 12909 also enhanced premature responding, whereas desipramine reduced it. Eticlopride by itself had no effect on premature responding but it attenuated the increases in this parameter evoked by amphetamine, cocaine, or nicotine. SCH 23390 reduced premature responding on its own and also reduced its drug-induced enhancement. CONCLUSIONS: The present data show that behavioral disinhibition, i.e., the inability to withhold a premature response, is a common effect of drugs of abuse and that this effect is the result of enhanced dopaminergic neurotransmission. In addition, dopamine D1 and D2 receptors play important, but perhaps distinct roles, in inhibitory control of behavior.

Critical involvement of dopaminergic neurotransmission in impulsive decision making.

BACKGROUND: Impulsive decision making, apparent as intolerance for reinforcement delay, is prominent in attention-deficit/hyperactivity disorder. Commonly prescribed for this condition, amphetamine (Adderall), reduces impulsive decision making; however, the neuropharmacologic mechanism of this effect of amphetamine is unclear. METHODS: We investigated the involvement of dopaminergic and noradrenergic neurotransmission in impulsive decision making in rats, using a delayed reward task. RESULTS: Amphetamine and methylphenidate decreased impulsive decision making, which was mimicked by the selective dopamine reuptake inhibitor GBR 12909 but not by the noradrenaline reuptake inhibitor desipramine. Impulsive choice was increased by the dopamine D1 receptor antagonist SCH-23390 but not the dopamine D2 receptor antagonist eticlopride. The effect of amphetamine on impulsive choice was attenuated by pretreatment with eticlopride, whereas amphetamine retained its effect on impulsivity in the presence of SCH-23390. The alpha2 adrenoceptor agonist clonidine increased impulsivity, but the alpha1 adrenoceptor agonist phenylephrine did not affect impulsive decision making. CONCLUSIONS: These data demonstrate an important role for dopaminergic neurotransmission in impulsive decision making, whereby tolerance to delay of reinforcement depends on dopamine D1 receptor activation. Activation of dopamine D2 receptors appears to mediate the beneficial effects of amphetamine on impulsive behavior. Noradrenergic neurotransmission may play a minor role in impulsive choice.