Atypical Dopamine Research Articles

Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors.

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication.

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction.

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine-associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.

Behavioral economic analysis of the effects of AHN 1‐055 and JHW 007, atypical dopamine uptake inhibitors, on cocaine self administration

Benztropine analogs and other atypical dopamine uptake inhibitors selectively decrease cocaine self‐administration in rats at doses that do not affect responding maintained by other reinforcers. In the current study a behavioral economic approach was employed to further characterize the behavioral mechanisms of effects of benztropine analogs (AHN 1‐055, JHW 007) on responding maintained by cocaine injection in rats. Behavioral economic analyses represent a translational approach that take into account the price of the reinforcer as an important determinant of consumption. Two groups of rats were trained to respond for food (45 mg pellet) or cocaine (0.32 mg/kg/inj) under a fixed‐ratio (FR) 5 schedule in experimental sessions comprising five 20‐min components. In selected sessions the FR value was increased (5, 10, 20, 40, 80) during successive components to determine demand curves, which plot consumption (reinforcers obtained) against price (FR value). An exponential function was fitted to the data to derive the consumption at zero price (Q0) and the rate of decrease in consumption (essential value). AHN 1‐055 (1.78–10 mg/kg, IP), JHW 007 (3.2–10 mg/kg, IP) or vehicle was administered immediately before each demand curve determination. Consumption of cocaine or food decreased as the price (FR requirement) increased. At low doses AHN 1‐055 shifted downward and to the right the cocaine and the food demand curves. A larger dose shifted the curves leftward and downward. Analysis of the demand curve parameters indicated that AHN 1‐055 had equivalent effects on the essential value of cocaine or food but was more effective in decreasing Q0 for cocaine (%Δ= −83%) compared to food (%Δ=−27%). The effects of JHW 007 were less than those of AHN 1‐055, with only trends for decreases in Q0 for cocaine, and no significant difference in essential value for cocaine or food. Therefore, AHN 1‐055, but not JHW 007, selectively decreased consumption at zero price. The current findings obtained using an approach that takes in account the price of the reinforcer, indicate that AHN 1‐055 might be more effective than JHW 007 in reducing selectively consumption of cocaine.Support or Funding InformationThis work was supported by NIDA Intramural Research Program

DAT Conformation Does Not Predict the Ability of Atypical Dopamine Uptake Inhibitors to Substitute for Cocaine.

The reuptake inhibition of dopamine (DA) through the DA transporter (DAT) is thought to be the primary mechanism underlying the reinforcing effects of cocaine [1,2]. However, there are several DA reuptake inhibitors that do not produce appreciable cocaine-like effects in vivo [2-4]. Previously, there were several relatively viable hypotheses related to the mechanisms underlying the atypical effects of such agents, but new studies have decreased this number [3,5]. The new findings may contribute to the development of a better understanding of what constitutes cocaine-like behavioral effects.

Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation.

Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS).

Molecular determinants of biased agonism at the dopamine D₂ receptor.

The development of biased (functionally selective) ligands provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial β-arrestin recruitment.

Modulation of methamphetamine׳s locomotor stimulation and self-administration by JHW 007, an atypical dopamine reuptake blocker

JHW 007 [N-(n-butil)-3α-[bis(4′-fluorophenil)methoxi]-tropane] belongs to the family of N-substituted benztropine (BZT) analogs, atypical dopamine transporter (DAT) blockers that are able to strongly modulate cocaine- and amphetamine-related behavior. In the present study, we tested in rats the ability of JHW 007 to alter the stimulant and reinforcing properties of methamphetamine (METH) using locomotor activity, fixed ratio and progressive ratio (PR) self-administration tests. The results showed that JHW 007 attenuated METH-induced locomotor stimulation in a dose-dependent manner and had no stimulant effects when administered alone. The BZT analog, given as a pre-treatment, attenuated METH self-administration without affecting responding for sucrose. In the PR tests JHW 007 produced an increase of the breaking point achieved for both METH- and sucrose self-administration, suggesting that the ability of the BZT analog to reduce self-administration may be linked to its ability to enhance the reinforcing properties of METH. Taken together, these data suggest that DAT inhibition with a high affinity blocker such as JHW 007 can exert differential effects on METH-associated behaviors, reducing METH-induced motor stimulation but augmenting METH׳s reinforcing effects.

Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.

Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats.

Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 µg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((-)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate), d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.

SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity

SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine) is an atypical dopamine receptor-1 (D1 receptor) agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo. Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [(3)H]-serotonin, [(3)H]-norepinephrine or [(3)H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 (2-8 mg/kg) were intraperitoneally injected 30 min before the tests. SKF83959 was a competitive inhibitor of SERT (K(i)=1.43±0.45 μmol/L), but a noncompetitive inhibitor of NET (K(i)=0.60±0.07 μmol/L) and DAT (K(i)=9.01±0.80 μmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (K(i)=0.89±0.24 μmol/L) and DAT (K(i)=1.47±0.31 μmol/L) and a noncompetitive inhibitor of NET (K(i)=0.18±0.04 μmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner. SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.

The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens

Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been postulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psychomotor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimulant abuse. The results indicated that JHW007 did not produce sensitized locomotor activity when given alone but prevented the sensitized motor behavior induced by chronic AMPH administration. Morphological analysis of medium spiny neurons of the nucleus accumbens revealed that JHW 007 prevented the neuroadaptations induced by chronic AMPH exposure, including increments in dendritic arborization, lengthening of dendritic processes and increases in spine density. Furthermore, data revealed that AMPH produced an increase in the density of asymmetric, possibly glutamatergic synapses in the nucleus accumbens, an effect that was also blocked by JHW007 pretreatment. The present observations demonstrate that JHW007 is able to prevent not only AMPH-induced behavioral sensitization but also the long-term structural changes induced by chronic AMPH in the nucleus accumbens. Such findings support the development and evaluation of BZT derivatives as possible leads for treatment in stimulant addiction.

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D(1) receptor) agonist, has shown many D(1) receptor-independent effects, such as neuroprotection, blockade of Na(+) channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF83959 dramatically promoted the binding of (3)H(+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on (3)H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on (3)H-1,3-di(2-tolyl)-guanidine ((3)H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D(1) receptor-independent effect of the drug.

Identification and Characterization of a Novel Class of Atypical Dopamine Receptor Agonists

The D3 dopamine receptor exhibits tolerance and slow response termination (SRT) properties that are not exhibited by the closely-related D2 dopamine receptor. We previously demonstrated that the induction of tolerance elicits a unique conformational change in the D3 receptor. Here we tested the hypothesis that the tolerance and SRT properties of the D3 receptor are ligand-dependent. We used pharmacophore modeling and in silico screening approaches coupled with electrophysiological and biochemical methods to identify and functionally characterize the novel dopamine receptor agonists. We identified cis-8-OH-PBZI (PBZI), FAUC73 and an additional novel compound, ES609, which although they are full D3 receptor agonists, do not induce the tolerance and SRT properties of the D3 receptor. In addition, PBZI has full intrinsic activity at D2L, is a partial agonist at D2S and exhibits functional selectivity at D4.2 dopamine receptors. ES609 is a partial agonist at D2S, D2L and D4.2 receptors, and exhibits functional selectivity at D2L and D4.2 dopamine receptors. We have discovered a novel class of atypical dopamine receptor agonists that include three structurally dissimilar compounds. These new agonists will help determine the physiological and pathophysiological relevance of D3 receptor tolerance and SRT properties.

R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse

(±)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated. (±)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure. (±)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.

Can the Stereotypy‐Inducing Effects of Atypical Dopamine Uptake Inhibitors Account for Their Blockade of Cocaine Self Administration?

Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the stereotypy‐induction produced by Coc. The BZT analogs, however, were inactive alone and did not significantly change the effects of Coc. Thus it appears that the induction of stereotypy does not account for the decreases in Coc SA produced by BZT analogs. The present study further supports the development of N‐substituted BZT analogs as medications to treat Coc abuse. Supported by NIDA IRP.

Drug hoarding: A case of atypical dopamine dysregulation syndrome in a RLS patient

Drug hoarding: A case of atypical dopamine dysregulation syndrome in a RLS patient

Discovery of Drugs to Treat Cocaine Dependence: Behavioral and Neurochemical Effects of Atypical Dopamine Transport Inhibitors

Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure-activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.

Altered Dopamine Signaling in Naturally Occurring Maternal Neglect

BackgroundChild neglect is the most common form of child maltreatment, yet the biological basis of maternal neglect is poorly understood and a rodent model is lacking.Methodology/Principal FindingsThe current study characterizes a population of mice (MaD1) which naturally exhibit maternal neglect (little or no care of offspring) at an average rate of 17% per generation. We identified a set of risk factors that can predict future neglect of offspring, including decreased self-grooming and elevated activity. At the time of neglect, neglectful mothers swam significantly more in a forced swim test relative to nurturing mothers. Cross-fostered offspring raised by neglectful mothers in turn exhibit increased expression of risk factors for maternal neglect and decreased maternal care as adults, suggestive of possible epigenetic contributions to neglect. Unexpectedly, offspring from neglectful mothers elicited maternal neglect from cross-fostered nurturing mothers, suggesting that factors regulating neglect are not solely within the mother. To identify a neurological pathway underlying maternal neglect, we examined brain activity in neglectful and nurturing mice. c-Fos expression was significantly elevated in neglectful relative to nurturing mothers in the CNS, particularly within dopamine associated areas, such as the zona incerta (ZI), ventral tegmental area (VTA), and nucleus accumbens. Phosphorylated tyrosine hydroxylase (a marker for dopamine production) was significantly elevated in ZI and higher in VTA (although not significantly) in neglectful mice. Tyrosine hydroxylase levels were unaltered, suggesting a dysregulation of dopamine activity rather than cell number. Phosphorylation of DARPP-32, a marker for dopamine D1-like receptor activation, was elevated within nucleus accumbens and caudate-putamen in neglectful versus nurturing dams.Conclusions/SignificanceThese findings suggest that atypical dopamine activity within the maternal brain, especially within regions involved in reward, is involved in naturally occurring neglect and that MaD1 mice are a useful model for understanding the basis of naturally occurring neglect.

Olanzapine therapy in anorexia nervosa: psychobiological effects

Dopamine impairments occur in anorexia nervosa. The aim of this study was to see whether treatment with the atypical dopamine antagonist antipsychotic olanzapine improves the disorder. Thirty anorexics, 18 restricted and 12 bingeing-purging, underwent a 3-month course of cognitive behavioral therapy, plus at random and double-blinded oral olanzapine (2.5 mg for 1 month, 5 mg for 2 months) in half and oral placebo in the other half of them. BMI, psychopathological aspects (eating disorder inventory, Hamilton Rating Scale, Buss-Durkee Rating Scale, Yale Brown Cornell for Eating Disorders Rating Scale, temperament-character inventory), and homovanillic acid blood concentrations for dopamine secretion, were monitored at baseline and then monthly during the trial. At the end of the trial BMI, total eating disorder inventory, total Yale Brown Cornell for Eating Disorders Rating Scale, Buss-Durkee Rating Scale, Hamilton Rating Scale scores and in olanzapine-treated patients the subitems of eating disorder inventory ineffectiveness and maturity fear, of Buss-Durkee Rating Scale direct aggressiveness, of temperament-characteristic inventory persistence had improved significantly. When stratified for anorexia nervosa subtype, BMI changes were significant among anorexia nervosa bingeing-purging patient, 'depression' (Hamilton Rating Scale) and 'direct aggressiveness' (Buss-Durkee Rating Scale) among anorexia nervosa bingeing-purging patients, 'persistence' (temprerament-characteristic inventory), among anorexics restricted patients, with a trend toward significance for obsessivity-compulsivity (Yale Brown Cornell for Eating Disorders Rating Scale). homovanilic acid blood levels increased significantly in the cognitive behavioral therapy+olanzapine group. No correlations were observed between homovanilic acid concentrations and psychopathological parameters. The pharmacological treatment can significantly improve specific aspects of anorexia nervosa.

Blockade of Cue‐induced Brain Activation of Abstinent Alcoholics by a Single Administration of Amisulpride as Measured With fMRI

Once alcohol dependence is established, alcohol-associated cues may induce dopamine release in the reward system, which is accompanied by alcohol craving and may lead to relapse. In cocaine addicts, dopamine release in the thalamus was positively correlated with cocaine craving. We tested the effects of the atypical dopamine D(2/3) blocker amisulpride on cue-induced brain activation in a functional magnetic resonance imaging (fMRI) paradigm. Alcohol-associated and neutral pictures were presented in a block design to 10 male abstinent alcoholics (1-3 weeks after detoxification) and 10 healthy men during fMRI. The fMRI scans were acquired before and 2 hours after the oral application of 400 mg amisulpride. Before and after each scan, alcohol craving was measured with visual analogue scales. Before the application of amisulpride, alcohol versus control cues elicited a higher blood oxygen level-dependent (BOLD) signal in the left frontal and orbitofrontal lobe, left cingulate gyrus, bilateral parietal lobe, and bilateral hippocampus in alcoholics compared with healthy controls. After amisulpride, alcoholics showed a reduced activation in the right thalamus compared with the first scan. Alcoholics no longer showed significant differences in their cue-elicited BOLD response after amisulpride medication compared with medication-free controls. Self-reported craving was not affected by amisulpride medication. Amisulpride medication was associated with reduced cue-induced activation of the thalamus, a brain region closely connected with frontostriatal circuits that regulate behavior and may influence relapse risk.