Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects.

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3).

Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials.

Central Nervous System (CNS)-related safety concerns are major contributors to delays and failure during the development of new candidate drugs (CDs). CNS-related safety data on 141 small molecule CDs from five pharmaceutical companies were analyzed to identify the concordance between rodent multi-parameter neurofunctional assessments (Functional Observational Battery: FOB, or Irwin test: IT) and the five most common adverse events (AEs) in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence and pain. In the context of this analysis, the FOB/IT did not predict the occurrence of these particular AEs in man.

Appropriate experimental approaches for predicting abuse potential and addictive qualities in preclinical drug discovery.

Introduction: Drug abuse is an increasing social and public health issue, putting the onus on drug developers and regulatory agencies to ensure that the abuse potential of novel drugs is adequately assessed prior to product launch.

Areas Covered: This review summarizes the core preclinical data that frequently contribute to building an understanding of abuse potential for a new molecular entity, in addition to highlighting models that can provide increased resolution regarding the level of risk. Second, an important distinction between abuse potential and addiction potential is drawn, with comments on how preclinical models can inform on each.

A translational pharmacology approach to understanding the predictive value of abuse potential assessments.

Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk.

The predictive validity of the rat self-administration model for abuse liability.

The self-administration model is the primary non-clinical approach for assessing the reinforcing properties of novel compounds. Given the now frequent use of rats in self-administration studies, it is important to understand the predictive validity of the rat self-administration model for use in abuse liability assessments. This review of 71 drugs identifies high concordance between findings from rat self-administration studies and two clinical indicators of abuse liability, namely reports of positive subjective-effects and the DEA drug scheduling status.

Tramadol acts as a weak reinforcer in the rat self-administration model, consistent with its low abuse liability in humans.

Rodent models of abuse potential are considered to represent a false positive with respect to the low risk of abuse liability associated with the atypical opioid analgesic tramadol. This may reflect either the predictive limitations of the models used to formulate this proposition (drug discrimination and conditioned place preference) or the predictive ability of the rodent per se. To address this concern, we used the rat self-administration model to examine the reinforcing properties of tramadol (0.

The mGluR5 antagonist MTEP dissociates the acquisition of predictive and incentive motivational properties of reward-paired stimuli in mice.

An environmental stimulus paired with reward (a conditioned stimulus; CS) can acquire predictive properties that signal reward availability and may also acquire incentive motivational properties that enable the CS to influence appetitive behaviors. The neural mechanisms involved in the acquisition and expression of these CS properties are not fully understood. The metabotropic glutamate receptor, mGluR5, contributes to synaptic plasticity underlying learning and memory processes.

The alpha4beta2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats.

Introduction: The alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline has greater efficacy than other pharmacotherapeutic aids for smoking cessation. This presents an opportunity to evaluate the predictive validity of rat models of nicotine taking and relapse. The aim of this study was to evaluate the ability of varenicline to attenuate nicotine self-administration and relapse, as modelled by the reinstatement model of nicotine relapse in rats.

AMPA-receptor GluR1 subunits are involved in the control over behavior by cocaine-paired cues.

The learning processes underlying the formation of drug-cue associations involve changes in synaptic transmission mediated by AMPA receptors. Here, we examine the consequences of targeted deletion of the gene encoding GluR1 subunits of AMPA receptors (gria1 knockouts (KO)) on cocaine self-administration and on the ability of cocaine-paired cues to affect cocaine-seeking in mice. Cocaine self-administration was unaffected by gria1 deletion, as was the ability of a cocaine-paired cue to reinstate responding following extinction, following either a 3 or a 66 day delay.

Effects of deletion of gria1 or gria2 genes encoding glutamatergic AMPA-receptor subunits on place preference conditioning in mice.

Rationale: The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effects of a number of stimuli. Critically, this classical conditioning procedure requires the formation of associations between a rewarding stimulus and environmental cues, and the ability of these cues to direct subsequent behaviour.

Objectives: The purpose of the current experiments was to examine the role of glutamatergic transmission via subunit-specific populations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the formation of stimulus--reward associations involving contextual stimuli.

Involvement of AMPA receptor GluR2 subunits in stimulus-reward learning: evidence from glutamate receptor gria2 knock-out mice.

Presence of the glutamate receptor 2 (GluR2) subunit prevents calcium influx through AMPA-receptor complexes; deletion of this subunit results in enhanced hippocampal long-term potentiation. We investigated whether mice lacking the GluR2 subunit [gria2 knock-out (KO) mice] displayed impairments in learning stimulus-reward associations, and the subsequent ability of reward-paired cues to control motivated behavior. Both gria2 KO and wild-type (WT) mice learned to associate a light/tone stimulus with food delivery, as evidenced by approach toward the food magazine after the presentation of the cues (pavlovian conditioning).

Sensitization of psychomotor stimulation and conditioned reward in mice: differential modulation by contextual learning.

Incentive motivation theory ascribes a critical role to reward-associated stimuli in the generation and maintenance of goal-directed behavior. Repeated psychomotor stimulant treatment, in addition to producing sensitization to the psychomotor-activating effects, can enhance the incentive salience of reward-associated cues and increase their ability to influence behavior. In the present study, we sought to investigate this incentive sensitization effect further by developing a model of conditioned reinforcement (CR) in the mouse and investigating the effects of a sensitizing treatment regimen of amphetamine on CR.

Selective disruption of stimulus-reward learning in glutamate receptor gria1 knock-out mice.

Glutamatergic neurotransmission via AMPA receptors has been an important focus of studies investigating neuronal plasticity. AMPA receptor glutamate receptor 1 (GluR1) subunits play a critical role in long-term potentiation (LTP). Because LTP is thought to be the cellular substrate for learning, we investigated whether mice lacking the GluR1 subunit [gria1 knock-outs (KO)] were capable of learning a simple cue-reward association, and whether such cues were able to influence motivated behavior.

Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice.

Brain serotonin [5-hydroxytryptamine (5-HT)] systems substantially influence the effects of cocaine; however, the contributions of individual 5-HT receptor subtypes to the regulation of cocaine responses are unclear. A line of mutant mice devoid of 5-HT2C receptors was used to examine the contribution of this receptor subtype to the serotonergic modulation of cocaine responses. Mutants display enhanced exploration of a novel environment and increased sensitivity to the locomotor stimulant effects of cocaine.

Increased vulnerability to self-administer cocaine in mice prenatally exposed to cocaine.

Rationale: At least 40,000 infants born each year in the U.S. are estimated to have been exposed to crack cocaine and, therefore, may be at risk for increased vulnerability to cocaine addiction.

Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice.

Previously, it was reported that both norepinephrine transporter (NET) and dopamine transporter (DAT) knockout (KO) mice were sensitive to the reinforcing effects of cocaine. However, assessing the locomotor-stimulant effects of cocaine in these subjects has proven difficult due to significant differences in their baseline activity compared to wild-type controls. The present studies were designed to clarify the role of NET and DAT in the stimulant effects of acute and repeated cocaine utilizing these knockout mice, and thereby assess the role of these substrates in the locomotor stimulant effects of cocaine.

Reinstatement of cocaine seeking in 129X1/SvJ mice: effects of cocaine priming, cocaine cues and food deprivation.

Rationale And Objectives: The mechanisms underlying relapse to cocaine seeking induced by exposure to priming cocaine injections, cues associated with cocaine self-administration and environmental stressors have been studied in rats. Here we describe a reinstatement method for studying relapse to cocaine seeking in mice, a suitable species for studying the effect of genetic manipulations such as gene knockout or gene over-expression on compulsive drug use.

Methods: Male mice of the 129X1/SvJ strain were trained for 14-16 days to self-administer cocaine (0.

Intravenous cocaine-induced activity in A/J and C57BL/6J mice: behavioral sensitization and conditioned activity.

The stimulant properties of cocaine have been extensively investigated in the mouse using either intraperitoneal (i.p.) or subcutaneous (s.