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The dopamine D 3 receptor (D 3 R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson's disease, and substance use disorders. However, studies investigating the D 3 R's precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most D 3 R-targeted compounds often also interact with D 2 receptors (D 2 R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D 2 R or D 3 R antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects. Pretreatment with the selective D 2 R antagonist L-741,626 attenuated, while pretreatment with the selective D 3 R antagonist PG01037 enhanced, the locomotor-activating effects of both acute cocaine administration as well as sensitization following repeated cocaine dosing. While both antagonists potentiated cocaine-induced increases in presynaptic dopamine release, we report for the first time that D 3 R blockade uniquely facilitated dopamine-mediated excitation of D 1 -expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D 3 R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D 2 R antagonism or nonselective D 2 -like receptor antagonists, and is likely mediated by facilitating D 1 -mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D 3 R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.

The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.

Objectives: Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration., Methods: In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions., Results: Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine., Conclusions: Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H₁ receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Rationale: Glutamatergic projection neurons in the medial prefrontal cortex (mPFC) are hyperexcitable in cocaine-sensitized animals, resulting in increased excitatory output to addiction-associated regions such as the ventral tegmental area (VTA) and nucleus accumbens. Evidence suggests that Group I metabotropic glutamate receptor 5 (mGluR5) is necessary for cocaine sensitization, and stimulation of this receptor in the mPFC potentially alters cell excitability directly through glutamate release or indirectly through downstream signaling cascades., Objectives and Methods: Experiments in this report examined the role of mPFC mGluR5 in behavioral sensitization to cocaine. Group I mGluR agonist dihydroxyphenylglycine (DHPG) (15 nmol/side), mGluR5 antagonist 3((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (15 nmol/side), mGluR1 antagonist YM298198 (15 nmol/side), AMPA receptor antagonist CNQX (1 nmol/side), and/or saline were administered through cannulae implanted 1 mm above the mPFC and/or VTA in male rats. Cocaine (15 mg/kg, i.p.) was systemically administered for four consecutive days to induce sensitization and/or once on test day immediately preceding locomotor monitoring., Results: Intra-mPFC DHPG induced an mGluR5-mediated cross-sensitization to cocaine preventable through the prior administration of an AMPA receptor antagonist in the VTA. Furthermore, mGluR5 blockade in the mPFC failed to prevent the initiation of sensitization. However, intra-mPFC injections of the mGluR5 antagonist MTEP prevented the expression of cocaine sensitization at 21, but not 7, days following daily cocaine injections suggesting a possible role for mPFC mGluR5 in the persistence of the cocaine-sensitized state., Conclusions: These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response.

Progesterone decreases cocaine self-administration in women and in female rats. In a previous study using rats selectively bred for high (HiS) or low (LoS) saccharin intake, HiS rats escalated their cocaine intake compared with LoS rats. Our goal was to examine the effects of progesterone on the escalation of cocaine self-administration in HiS and LoS rats. Four groups of female rats were compared: HiS P (progesterone treated), LoS P, HiS VEH (vehicle treated), and LoS VEH. Rats were trained to self-administer 0.8 mg/kg cocaine intravenously under a fixed-ratio 1 schedule during daily short-access (ShA) 2-h sessions. Rats then self-administered three randomly-presented doses of cocaine (0.2, 0.4, and 1.6 mg/kg), and then had daily 6-h long-access (LgA) sessions with 0.4 mg/kg of cocaine for 21 days. Cocaine intake was then reassessed with the four doses under the ShA condition. Throughout the experiment, rats were treated with daily subcutaneous injections of progesterone (0.5 mg/kg) or an equal volume of vehicle 30 min before each session. During the initial ShA condition, HiS rats earned more cocaine infusions than LoS rats at all doses, and during the subsequent LgA condition, HiS rats escalated cocaine intake, whereas the LoS rats maintained a steady rate. Progesterone treatment potentiated escalation of cocaine intake in the HiS rats but had an opposite effect on LoS rats, attenuating their cocaine self-administration. Results from the post-LgA dose-response ShA condition indicated that both LoS and HiS vehicle-treated and progesterone-treated rats earned more infusions than pre-LgA, but mainly at low doses. These results suggest that genetic differences in drug abuse vulnerability contribute differentially to treatment outcomes during escalation, a critical phase of the drug abuse process.

Methylenedioxymethamphetamine (MDMA; "Ecstasy") is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0 mg/kg) and cocaine (10 or 20 mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic-dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01-0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.

Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity., (2009 Elsevier Ltd. All rights reserved.)

The pattern of activation of dopamine (DA) neurotransmission in the nucleus accumbens (NAc) of rats produced by H(1) histamine antagonists which have behavioral effects like those of psychostimulant drugs was examined. Diphenhydramine and (+)-chlorpheniramine were compared with triprolidine, a potent and selective H(1) antagonist and (-)-chlorpheniramine which is less active than its enantiomer at H(1) receptors. Affinities of the drugs to DA, serotonin, and norepinephrine transporters at H(1) receptors and potencies for DA uptake inhibition in striatal synaptosomes were determined to assess mechanisms by which the compounds increased DA levels. Intravenous diphenhydramine (1.0-3.0 mg/kg) (+)- and (-)-chlorpheniramine (1.0-5.6 mg/kg) but not triprolidine (1.0-3.0 mg/kg) elicited a cocaine-like pattern of stimulation of DA transmission with larger effects in the NAc shell than core. The absence of stereospecific effects with chlorpheniramine enantiomers along with the lack of an effect with triprolidine suggest that the effects on DA transmission were not related to H(1) receptor antagonism. Although in vivo potencies were not directly related to DA transporter affinities, it is hypothesized that actions at that site modulated by other actions, possibly those at the serotonin transporter, are primarily responsible for the neurochemical actions of the drugs on DA neurotransmission and might underlie the occasional misuse of these medications.

Nucleus accumbens glutamate transmission plays a critical role in cocaine priming-induced reinstatement of drug seeking. Previous studies have demonstrated that systemic or intra-accumbens shell administration of an NMDA receptor antagonist reinstates cocaine-seeking behavior. However, it is unclear if antagonizing NMDA receptors in the nucleus accumbens core or shell subregions will differentially affect cocaine reinstatement. To investigate this possibility, we microinjected the competitive NMDA receptor antagonist AP-5 (0, 3 or 30 microg) into either the nucleus accumbens core or shell and assessed the reinstatement of cocaine-seeking behavior. When microinjected into the shell, both doses of AP-5 produced reinstatement of cocaine seeking. In contrast, when administered into the core, only the highest dose of AP-5 reinstated cocaine-seeking behavior; moreover, the magnitude of this effect was substantially less than when AP-5 was administered into the shell. This study provides evidence that pharmacological antagonism of NMDA receptors in the nucleus accumbens core or shell promotes the reinstatement of cocaine seeking.

Concurrent abuse of cocaine and heroin is a common problem. Methadone is effective for opioid dependence. The question arises as to whether combining agonist-like or antagonist-like medication for cocaine with methadone for opioid dependence might be efficacious. Two parallel studies were conducted. One examined sustained release d-amphetamine and the other risperidone for cocaine dependence, each in combination with methadone. In total, 240 subjects (120/study) were recruited, who were both cocaine and heroin dependent and not currently receiving medication. All provided consent. Both studies were carried out for 26 weeks, randomized, double-blind and placebo controlled. Study I compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended clinic twice/week, provided urine samples, obtained medication take-home doses for intervening days, and completed self-report measures. Each had one behavioral therapy session/week. In Study I, reduction in cocaine use was significant for the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in all groups with a trend toward greater reduction in the 30/60 mg d-amphetamine group. In Study II, methadone reduced illicit opioid use but cocaine use did not change in the risperidone or placebo groups. There were no adverse medication interactions in either study. The results provide support for the agonist-like (d-amphetamine) model in cocaine dependence treatment but not for antagonist-like (risperidone) treatment. They coincide with our previous reports of amphetamine or risperidone administered singly in cocaine-dependent individuals.

The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence.

This panel explores the "state of the art" in conceptualization and research pertinent to program quality in substance user treatment. First, seven critical questions for program quality are identified and discussed. Second, a recent national evaluation of treatment examines the implications of long-term patient outcomes for treatment quality. Third, a large number of clinical trials of behavioral and pharmacological treatments for cocaine dependence were conducted during the 1990s; this research is synthesized and interpreted. Fourth, progress is reported in improving the quality of treatment through standardized criteria for patient placement matching.

Myocardial ischaemia and left ventricular dysfunction have been described in cocaine users. Whether nitric oxide (NO) inhibition may potentiate the effects of cocaine on coronary circulation and ventricular function is still unknown. In order to test this hypothesis, 38 pentobarbital-anaesthetized pigs were instrumented for systolic blood pressure, coronary blood flow, left ventricular dp/dt, cardiac output, left ventricular end-diastolic and end-systolic lengths and shortening fraction. The pigs were randomized into three groups: control group: i.v. saline (n = 5); group 1: i.v. cocaine, 10 mg kg-1 over 20 min (n = 17); group 2: the same doses of cocaine 30 min after i.c. L-NAME 20 microg/kg min-1 infusion (n = 16). In order to know whether the observed effects were specific of NO inhibition, in five pigs i.c. L-arginine was simultaneously infused with L-NAME, in five pigs i.c. NTG, an endothelial-independent vasodilator, was simultaneously infused with L-NAME before cocaine was administered, and in nine additional pigs the proximal left anterior descending (LAD) flow was reduced to around 20% of the basal value by means of a mechanical occluder before cocaine was administered. Cocaine i.v did not change the coronary blood flow, while it induced a significant reduction in cardiac output, left ventricular dp/dt and shortening fraction (15 +/- 4-8 +/- 4%, P < 0.05). When cocaine was administered after L-NAME infused i.c. during 30 min, a significantly more severe reduction of the shortening fraction (12 +/- 3-4 +/- 2%, P < 0.0001) was induced; this effect was abolished by simultaneous perfusion of L-arginine i.c. NTG. The results when cocaine was administered after the 20% LAD flow reduction by mechanical occluder did not differ from those of cocaine alone. NO inhibition intensifies the cocaine-induced left ventricular dysfunction.