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The abuse of synthetic cathinones ("bath salts") with psychomotor stimulant and/or entactogenic properties emerged as a public health concern when they were introduced as "legal" alternatives to drugs of abuse such as cocaine or MDMA. In this study, experiments were conducted in nonhuman primates to examine how differences in transporter selectivity might impact the reinforcing effects of synthetic cathinones. Rhesus monkeys (N = 5) were trained to respond for intravenous injections under a fixed-ratio (FR) 30, timeout 60-s schedule of reinforcement. The reinforcing effects of selected cathinones (e.g., MDPV, αPVP, MCAT, and methylone) with a range of pharmacological effects at dopamine and serotonin transporters were compared to cocaine and MDMA using dose-response analysis under a simple FR schedule and behavioral economic procedures that generated demand curves for two doses of each drug. Results show that one or more doses of all drugs were readily self-administered in each subject and, excepting MDMA (21 injections/session), peak levels of self-administration were similar across drugs (between 30 and 40 injections/session). Demand elasticity for the peak and the peak + 1/2-log dose of each drug did not significantly differ, and when data for the two doses were averaged for each drug, the following rank-order of reinforcing strength emerged: cocaine > MCAT = MDPV = methylone > αPVP = MDMA. These results indicate that the reinforcing strength of synthetic cathinones are not related to their selectivity in binding dopamine or serotonin transporter sites., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen-two brain regions involved in cognitive function and motoric behavior-identified in a whole brain analysis. Six adult male squirrel monkeys self-administered cocaine (0.32 mg/kg/inj) over 140 sessions. Six additional monkeys that had not received any drug treatment for ~1.5 years served as drug-free controls. Resting-state fMRI imaging sessions at 9.4 Tesla were conducted under isoflurane anesthesia. Functional connectivity maps were derived using seed regions placed in the left dACC or putamen. Results show that cocaine maintained robust self-administration with an average total intake of 367 mg/kg (range: 299-424 mg/kg). In the cocaine group, functional connectivity between the dACC seed and regions primarily involved in motoric behavior was weaker, whereas connectivity between the dACC seed and areas implicated in reward and cognitive processing was stronger. In the putamen seed, weaker widespread connectivity was found between the putamen and other motor regions as well as with prefrontal areas that regulate higher-order executive function; stronger connectivity was found with reward-related regions. dACC connectivity was associated with total cocaine intake. These data indicate that functional connectivity between regions involved in motor, reward, and cognitive processing differed between subjects with recent histories of cocaine self-administration and controls; in dACC, connectivity appears to be related to cumulative cocaine dosage during chronic exposure.

Rationale: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior., Objectives: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior., Methods: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement., Results: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups., Conclusions: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR-/- mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR-/- mice, cocaine-induced increases in DA and glutamate release were blunted. γ-Amino-butyric acid efflux was unaffected in the SR-/- mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction., (© 2017 Society for the Study of Addiction.)

Rationale: The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability., Objectives: The present study examined the effects of several novel "norepinephrine (NE)-preferring" monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169)., Methods: Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine., Results: Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the "NE-preferring" releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects., Conclusions: These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other "NE-preferring" monoamine releasers should provide insight into their potential for the management of cocaine addiction.

Rationale: Monoamine releasers with prominent dopaminergic actions, e.g., D-methamphetamine (D-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, D-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder., Objectives: The L-isomer of methamphetamine (L-MA), unlike D-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether L-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration., Methods: Separate groups (N = 4-5) of rhesus monkeys were studied to determine whether L-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement., Results: L-MA, like D-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10-day treatments with continuously infused L-MA (0.032-0.32 mg/kg/h, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding., Conclusions: These results indicate that L-MA both shares discriminative stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. L-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (∼98 and ∼29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose-effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction., Competing Interests: Statement of Interest None.

Cocaine abuse and dependence is a major public health problem that continues to challenge medication-based treatment. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on both serotonin and dopamine systems. In recent preclinical studies, acute buspirone treatment reduced cocaine self-administration at doses that did not also decrease food-reinforced behavior in rhesus monkeys (Bergman et al, 2012). The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of cocaine and food. Five adult rhesus monkeys (Macaca mulatta) were trained to self-administer cocaine and food during four 1-h daily sessions under a second-order schedule of reinforcement (FR2 [VR 16:S]). Buspirone (0.32 and 0.56 mg/kg/h) was administered intravenously through one lumen of a double-lumen catheter every 20 min for 23 h each day for 7-10 consecutive days. Each buspirone treatment period was followed by saline control treatment until drug- and food-maintained responding returned to baseline levels. Buspirone significantly reduced responding maintained by cocaine, and shifted the dose-effect curve downwards. Buspirone had minimal effects on food-maintained responding. In cocaine discrimination studies, buspirone (0.1-0.32 mg/kg, IM) did not antagonize the discriminative stimulus and rate-altering effects of cocaine in four of six monkeys. These findings indicate that buspirone selectively attenuates the reinforcing effects of cocaine in a nonhuman primate model of cocaine self-administration, and has variable effects on cocaine discrimination.

Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 µg/kg/injection) for over 24 hours. Pre-treatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative-stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((+/-)-1-[2,3- (Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments.

Rationale: The relative reinforcing strength of cocaine can be characterized by the distribution of operant behavior during the availability of other reinforcing stimuli., Objective: To develop a procedure to rapidly evaluate the relative reinforcing strength of cocaine in monkeys., Methods: Monkeys were trained to respond on two levers under concurrent fixed-ratio 30 (FR30) schedules of reinforcement. Responding on one lever resulted in food delivery, responding on the alternative lever resulted in delivery of IV saline or cocaine (0.032 or 0.1 mg/kg per injection). Daily sessions consisted of three 30-min components separated by 10-min timeout periods. The availability of saline, 0.032, or 0.1 mg/kg per injection cocaine varied across components, and only in an ascending order. The relative reinforcing strength of 0.0032-0.32 mg/kg per injection cocaine was examined by substituting different unit doses for the training doses of cocaine. Effects of cocaine pretreatment on response distribution were determined by giving IM injections of 0.1-1.8 mg/kg cocaine 10 min prior to sessions of saline availability., Results: Increasing unit doses of cocaine monotonically increased the distribution of responding on the injection-lever and monotonically deceased response rates. Responding occurred predominantly on the food-lever during availability of saline or 0.0032 mg/kg per injection cocaine, whereas availability of 0.032-0.32 mg/kg per injection produced >90% of responding on the injection-lever. Availability of 0.01 mg/kg per injection cocaine resulted in approximately equal levels of responding on the food- and injection-levers. Presession IM cocaine injections dose-dependently increased responding on the injection-lever., Conclusions: Stable behavior can be maintained under concurrent FR schedules of food and cocaine presentation in monkeys, and the distribution of behavior on food- and injection-levers is dependent on the available dose of cocaine.

Rationale: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration., Objective: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys., Methods: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages., Results: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance., Conclusions: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.

Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

The aim of this study was to compare two PET ligands, 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and (18)F-labeled CFT, 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT), in detecting presynaptic dopaminergic hypofunction in early Parkinson's disease (PD). These ligands reflect different aspects of presynaptic dopaminergic function, since [(18)F]FDOPA mainly reflects 6-[(18)F]fluorodopamine (fluorodopamine) synthesis and storage whereas [(18)F]CFT uptake is related to dopamine transporter function. Eight de novo patients with PD who had never been on antiparkinsonian medication were investigated with [(18)F]FDOPA and [(18)F]CFT PET. Five healthy volunteers were studied as controls. In PD patients, both [(18)F]FDOPA and [(18)F]CFT uptakes were significantly reduced both in the contralateral and ipsilateral anterior and posterior putamen. The reduction was greatest in the contralateral posterior putamen (to 28% of control mean for [(18)F]FDOPA, P < 0.0001 and to 16% for [(18)F]CFT, P < 0.0001). Individually, all patients' [(18)F]FDOPA and [(18)F]CFT uptake values in the contralateral anterior and posterior putamen were below 3 SD of the control mean. In the caudate nucleus, the mean uptake of both tracers was significantly reduced both ipsilaterally and contralaterally, but less severely than in the putamen (to 69% of the control mean for [(18)F]FDOPA, P = 0.003 and to 60% for [(18)F]CFT, P = 0.001 contralaterally). Our results show that both [(18)F]FDOPA as well as [(18)F]CFT sensitively detect presynaptic dopaminergic hypofunction in early PD. They demonstrate a considerable reduction of tracer uptake that is greatest in the posterior putamen, followed by the anterior putamen and the caudate nucleus., (Copyright 2001 Wiley-Liss, Inc.)

The objective of this article was to study the reproducibility and effect of levodopa on dopamine transporter function measurements using 2beta-carbomethoxy-3beta-(4-[18F]fluorophenyl)tropane ([18F]CFT) positron emission tomography (PET). Seven de novo patients with Parkinson's disease (PD) were studied twice, before and after three months of levodopa medication. Eight healthy volunteer subjects participated in the reproducibility study. The [18F]CFT PET scan was done twice with an interval of approximately 2.5 months. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. The [18F]CFT uptake was calculated as the region-cerebellum:cerebellum ratio at 180 to 210 minutes. Three-month levodopa treatment in PD patients had no significant effect on [18F]CFT uptake in any striatal subregion between the two PET scans. In PD patients, the percent change from baseline was 4.1% in the anterior putamen, 1.9% in the posterior putamen, and 4.0% in the caudate nucleus. No significant differences in [18F]CFT uptake between the first and second PET scan in any striatal subregion occurred in healthy controls. The intraclass correlation, indicating the reproducibility of the PET scan within subjects, was 0.94 for the anterior putamen, 0.86 for the posterior putamen, and 0.91 for the caudate nucleus. The percent change from baseline was 4.0% in the anterior putamen, 1.1% in the posterior putamen, and 2.8% in the caudate nucleus. Long-term levodopa treatment in PD patients had no effect on the [18F]CFT uptake in the striatum and the test-retest reproducibility was very high. These findings confirm [18F]CFT as a suitable ligand to monitor progression of PD.

Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.

We studied the rate of progression of striatal dopamine transporter function in Parkinson's disease (PD). Eight patients with early PD without antiparkinsonian medication and 7 healthy volunteers were investigated with [18F]CFT positron emission tomography (PET). The PET scan was carried out twice at an approximate 2-year interval. The uptake of [18F]CFT was calculated as a region-cerebellum:cerebellum ratio at 180 to 210 minutes after injection. At the first PET scan, the [18F]CFT uptake in PD patients in the putamen was 1.45 +/- 0.45 (mean +/- SD) (42% of the control mean) and 2.43 +/- 0.59 in the caudate nucleus (76% of the control mean). The ratios declined by the time of the second PET scan, and the rate of annual decline of the baseline mean in PD patients was 13.1% in the putamen and 12.5% in the caudate nucleus. In controls, the corresponding figures were 2.1% for the putamen and 2.9% for the caudate nucleus. The decline in [18F]CFT uptake was significantly higher in PD patients than in controls. Thus, dopamine transporter ligands such as [18F]CFT seem to be sensitive markers for the rate of progression in PD.

The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.

[18F] beta-CFT is a novel PET ligand for dopamine reuptake sites. In this study, [18F]beta-CFT uptake was studied in nine patients with early Parkinson's disease (PD) without antiparkinsonian medication and in six age-matched controls. The uptake of [18F]beta-CFT was calculated as a (region-cerebellum)/cerebellum ratio at 150-210 min after injection. The mean uptake in the putamen contralateral to the predominant symptoms (1.04+/-0.40, mean +/- SD; P<0.001) was reduced to 31% of the mean control value. In the "ipsilateral" putamen, the ratio in PD patients (1.50+/-0.50, P<0.001) was reduced to 45% of the control mean (3.33+/-0.61). Individually, all PD patients had [18F]beta-CFT uptake values below 2 SD from the control mean in the contralateral putamen. The decline in [18F]beta-CFT uptake in the caudate nucleus was milder than that seen in the putamen. The uptake was reduced contralaterally (2.19+/-0.47, P<0.01) to 67% and ipsilaterally (2.49+/-0.54, P<0.05) to 77% of the control mean (3.17+/-0.61). In the medial frontal cortex or dorsolateral prefrontal cortex, no significant difference in [18F]beta-CFT uptake between patients and controls was seen. In conclusion, [18F]beta-CFT is a powerful ligand to demonstrate presynaptic dopaminergic defect in PD and shows a clear separation of patient and control values.

We have characterized the usage of [18F]CFT (also known as [18F]WIN 35,428) as a radioligand for in vivo studies of human dopamine transporter by PET. CFT was labeled with 18F to a high specific activity, and dynamic PET scans were conducted in healthy volunteers at various time points up to 5 h from [18F]CFT injection. The regional distribution of [18F]CFT uptake correlated well with the known distribution of dopaminergic nerve terminals in the human brain and also with that of other dopamine transporter radioligands. Striatal binding peaked at 225 min after injection and declined thereafter, demonstrating the reversible nature of the binding to the dopamine transporter. Therefore, due to the relatively long half-life of 18F (109.8 min), PET scans with [18F]CFT could easily be conducted during the binding equilibrium, allowing estimation of Bmax/Kd values (i.e., binding potential). Binding potentials for putamen and caudate measured at equilibrium were 4.79+/-0.11 and 4.50+/-0.23, respectively. We were able to also visualize midbrain dopaminergic neurons (substantia nigra) with [18F]CFT in some subjects. In conclusion, the labeling of CFT with 18F allows PET scans to be conducted at binding equilibrium, and therefore a high signal-to-noise ratio and reliable quantification of binding potential can be achieved. With a high resolution 3D PET scanner, the quantification of extrastriatal dopamine transporters should become possible.

Dopamine D1 agonists differing in efficacy with respect to stimulation of adenylate cyclase activity and other in vitro and in vivo criteria were evaluated for their capacity to modulate the behavioral effects of cocaine in squirrel monkeys. Monkeys were trained either to respond on a fixed-ratio schedule in which lever pressing terminated a stimulus associated with electric shock or to discriminate cocaine from vehicle using a two-lever drug-discrimination procedure. When administered in combination with cocaine, D1 agonists displaying relatively low efficacy (SKF 38393, SKF 75670) attenuated both the rate-altering effects of cocaine on fixed-ratio responding and the discriminative-stimulus effects of cocaine, resulting in overall rightward shifts of the cocaine dose-response functions. Maximal attenuation of the behavioral effects of cocaine by the D1 partial agonists was comparable to that produced by the D1 antagonist SCH 39166. In contrast, D1 agonists displaying relatively high efficacy (SKF 81297, SKF 82958, SKF 83189) either had little effect on or accentuated the rate-altering and discriminative-stimulus effects of cocaine. The results show that D1 partial agonists can act as functional cocaine antagonists and may be viable candidate medications for the management of cocaine addiction.

We describe the 18F-radiolabelling synthesis (18F; T(1/2) = 109.8 min) of 2-beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (also known as CFT or WIN 35,428) and the biodistribution of this compound in rats. 18F-labelled CFT has high chemical and radiochemical purity and relatively high specific radioactivity [specific radioactivity up to 14.8 GBq/mumol (400 mCi/mumol) at end of synthesis]. Striatum to cerebellum radioactivity uptake ratios were calculated from digitised images of rat brain slices recorded with a phosphoimaging device, the maximum ratio of about 10 was obtained at 2 h postinjection. Pretreatment of the rats with a specific dopamine transport inhibitor, GBR 12909, showed that CFT binding is specific in striatum. The highest accumulation of 18F-radioactivity was found in the liver, urine, striatum, and kidney of the rat. Clearance from blood was rapid. The uptake in bone was low, indicating that [18F]CFT is not defluorinated. The relatively long half-life of 18F makes it possible to study the uptake of [18F]CFT in the brain, as equilibrium between specific and non-specific binding is reached. This will improve the signal to noise ratio as compared to positron emission tomography (PET) studies with [11C]CFT (11C; T(1/2) = 20.4 min). CFT labelled with 18F is clearly a promising radioligand for PET studies of the dopamine transporter system in humans.

The effects of cocaine alone and after pretreatment with selective mu and kappa opioids were determined in squirrel monkeys trained to discriminate i.m. injections of cocaine from vehicle in a two-lever discrimination procedure. Lever pressing was maintained under a fixed ratio schedule of food presentation. When administered alone, cocaine engendered dose-related increases in the proportion of cocaine-appropriate responding with an average ED50 of 0.19 mg/kg. Pretreatment with the mu agonists morphine (0.3 and 1.0 mg/kg), levorphanol (0.03 and 0.1 mg/kg) and methadone (0.1 and 0.3 mg/kg), as well as the mu partial agonist buprenorphine (3.0 and 5.6 micrograms/kg), potentiated the discriminative stimulus effects of cocaine such that the cocaine dose-effect functions were shifted to the left and the average ED50 for cocaine was reduced maximally by about one order of magnitude. None of the mu agonists consistently substituted for cocaine when administered alone, indicating that the observed interactions were not simply the result of additive discriminative stimulus effects. A similar potentiation by mu agonists was observed for the effects of cocaine on fixed ratio response rate. In contrast to the mu agonists, pretreatment with the kappa agonists N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yll-4- benzofuranacetamide (CI 977; 3.0 and 5.6 micrograms/kg) and benzeneacetamide methane sulfonate (U 50,488; 0.3 and 1.0 mg/kg) attenuated the discriminative stimulus effects of cocaine in most monkeys, resulting in a modest (2- to 3-fold) increase in the average ED50 for cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

The involvement of dopamine (DA) receptor subtypes in the discriminative stimulus effects of cocaine was investigated in squirrel monkeys trained to discriminate cocaine from vehicle using a two-lever choice procedure. Lever pressing was maintained under a 10-response fixed-ratio schedule of food presentation. In substitution tests, (-)-cocaine and its high-affinity analogs 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (CCT) engendered dose-related increases in the proportion of cocaine-appropriate responses. Full (97-100%) substitution for the training dose of cocaine was observed with all three drugs, the rank order of potency being: CCT greater than CFT greater than cocaine. DA agonists differing in selectivity for D1 and D2 receptor subtypes [6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297), 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958), (+)-4-propyl-9-hydroxynapthoxazine [(+)-PHNO], quinpirole, quinelorane, (-)-4,6,6a,7,8,-12b-hexahydro-7-methyl-indolo[4,3-ab]phen ant hridine (CY 208-243) and (-)-apomorphine] also engendered dose-related increases in cocaine-appropriate responses. However, maximally effective doses of these drugs occasioned an average of only 54 to 77% responses on the cocaine-associated lever and markedly reduced response rates. Combinations of the D1 agonist SKF 81297 and the D2 agonist (+)-PHNO did not engender a consistently higher proportion of cocaine-appropriate responses than did either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Self-administration of the high-affinity cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and cocaine were compared in squirrel monkeys responding under a second-order schedule of IV drug injection. Both CFT and cocaine maintained self-administration in all subjects. As the dose of either drug was increased, the rate of responding first increased and then decreased. Although the two drugs had qualitatively similar effects, CFT was approximately six times more potent than cocaine. This potency relation corresponds closely with the potency relations reported for CFT and cocaine in studies of dopamine uptake inhibition and binding at cocaine recognition sites. The results are consistent with the view that the reinforcing effects of cocaine-like drugs are mediated at cocaine recognition sites associated with the dopamine uptake system, and suggest that radioligand probes based on CFT may be suitable markers for these sites.

The behavioral effects of cocaine were compared with those of several cocaine derivatives and structurally distinct drugs that inhibit monoamine uptake. Squirrel monkeys were trained to respond under a fixed-interval schedule of stimulus-shock termination, and dose-effect curves were determined by administering cumulative doses i.v. Among the cocaine congeners, (-)-cocaine, (+)-pseudococaine and 1 alpha H, 3 alpha, 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate produced dose-related increases in response rate, whereas (-)-pseudococaine, (-)-benzoylecgonine and (-)-benzoylnorecgonine did not increase responding consistently over a 100-fold or greater range of doses. 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine, which selectively inhibits uptake of dopamine, and mazindol, methylphenidate, nomifensine and bupropion, which inhibit uptake of dopamine as well as other monoamines, had behavioral effects similar to those of cocaine. In contrast, desipramine and citalopram, which selectively inhibit uptake of norepinephrine and serotonin, respectively, produced only dose-related decreases in response rate. The results combined with previous studies demonstrate a close correspondence between the potencies of 15 different drugs for producing cocaine-like behavioral effects and for displacing specifically bound [3H]cocaine in caudate-putamen. These findings are consistent with the view that the behavioral effects of cocaine and related drugs are linked to their actions at specific cocaine recognition sites associated with the dopamine uptake system.

The self-administration of cocaine was compared with that of bupropion, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, mazindol, methylphenidate and nomifensine, drugs that displace [3H]cocaine from its binding sites and have monoamine uptake inhibiting effects in common with those of cocaine. Squirrel monkeys responded under a second-order fixed-interval schedule of consequent i.v. drug injection, and dose-effect curves were established by determining stable rates of responding maintained by saline and a range of doses of each drug. Cocaine (0.01-0.56 mg/kg/injection), bupropion (0.1-3.0 mg/kg/injection), 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3- phenylpropyl)piperazine-(0.03-1.0 mg/kg/injection), methylphenidate (0.01-0.3 mg/kg/injection) and nomifensine (0.01-0.3 mg/kg) maintained comparable rates and patterns of responding in all subjects, whereas mazindol (0.03-0.3 mg/kg) maintained self-administration behavior in only half the monkeys studied. The present results in conjunction with those of previous studies in squirrel monkeys reveal a close correspondence between the relative potencies of cocaine and related drugs for maintaining i.v. self-administration and for increasing rates of schedule-controlled responding, suggesting that the reinforcing and psychomotor-stimulant effects of the drugs are mediated similarly. The potency relations observed in the present study also agree generally with those observed for displacement of specifically bound [3H]cocaine in monkey caudate-putamen suggesting that the reinforcing effects of cocaine involve its actions at specific recognition sites in brain.

Specific binding sites for [3H]cocaine were identified in caudate-putamen membranes prepared from nonhuman primate brains (Macaca fascicularis and Saimiri sciureus). Saturation of the sites was determined in competition studies using a fixed concentration of [3H]cocaine (2.7 nM) and increasing concentrations of unlabeled cocaine (1 pM-100 microM). Computer resolution of the shallow displacement curve (nH, 0.58) revealed that a two-component binding model [Kd1, 19.2 nM, maximum binding1 (Bmax1), 28.3 pmol/g of tissue; Kd2, 1120 nM, Bmax2, 431 pmol/g of tissue] was statistically preferred over a one-component model (K.50, 283 nM, Bmax, 471 pmol/g of tissue). Binding of [3H]cocaine was NaCl-dependent, with specific binding reduced by 72% when NaCl (100 mM) was omitted from the incubation medium. [3H]Cocaine was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of cocaine and its phenyltropane analog. Cocaine congeners displaced specifically bound [3H]cocaine with IC50 values ranging from 17 nM to over 100 microM in the following rank order of potency: WIN 35,428 greater than WIN 35,065-2 greater than (-)-cocaine greater than WIN 35,981 greater than (-)-norcocaine greater than WIN 35,140 greater than (+)-cocaine, (+)-pseudococaine greater than 3 alpha-tropanyl-1H-indole-carboxylic acid ester greater than 1 alpha H-3 alpha-5 alpha H-tropan-3-yl-3,5-dichlorobenzoate greater than benzoylecgonine, benzoylnorecgonine and (-)-pseudococaine. Several monoamine uptake inhibitors structurally unrelated to cocaine also displaced [3H]cocaine with IC50 values ranging from 1.6 nM to 50 microM. The rank order of potency was: ( +/- )-trans-3-(3',4'-dichlorophenyl)-N-methyl-1-indanamine greater than mazindol greater than nomifensine greater than methylphenidate 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]- 4-(3-phenylpropyl)piperazine, N-[1-(2- benzo(b)thiophenyl)cyclohexyl]piperidine greater than (-)-cocaine greater than 1-amino-4-phenylbicyclo-[2,2,2]-octane greater than bupropion, nisoxetine greater than desipramine, talsupram greater than citalopram. Other drugs, including the dopamine releasing agent (+)-amphetamine and the dopamine receptor agonists (-)-apomorphine, (+)-4-propyl-9-hydroxy-naphthoxazine, quinpirole and SKF 38393 were weak displacers of [3H]cocaine. Monoamine neurotransmitters also were relatively weak, but dopamine was considerably more potent than either norepinephrine or serotonin.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of food deprivation on the self-administration of cocaine were assessed in three rhesus monkeys under different schedules of reinforcement. In one subject, decreasing body weight to 80% of free-feeding weight (ffw) resulted in increase response rates and number of cocaine infusions taken. The same effects were observed in a second subject when restricted food intake resulted in 88% ffw. When schedule contingencies limited the number of infusions available, reduction to 90% ffw in the third subject resulted in increased response rates. These data suggest that food deprivation can be a potent variable in responding maintained by cocaine self-administration.

Under baseline conditions, responding was maintained by intravenous cocaine delivery (100 micrograms/kg/infusion) under a fixed ratio 10 schedule in three rhesus monkeys. During test sessions, the onset of each cocaine infusion was accompanied by a delivery of electric shock of pre-determined duration and intensity. At intermediate intensity levels, the electric shock delivery initially reduced cocaine maintained responding. Although test sessions were separated by at least three baseline sessions, adaptation to the punishing effect of shock occurred within five test sessions in each monkey. Adaptation did not occur at higher intensity levels which completely eliminated cocaine-maintained responding, even when this intensity was tested prior to intermediate intensity levels.

The present studies were conducted to examine the relationship between discriminative stimulus effects of MA and its ability to increase extracellular levels of DA in the n. accumbens (nACC) shell. Fist, the behavioral effects of cumulatively administered MA, cocaine (COC), and related stimulants were determined in rats trained to discriminate IP injections of MA (0.3 or 1.0 mg/kg) from saline. In other studies, in vivo microdialysis was used to determine the effects of cumulatively administered MA and COC on extracellular DA levels in the nACC shell, d-Amphetamine, COC, GBR 12909, methylphenidate and AM 2547 produced dose-related and full substitution for 0.3 mg/kg MA. In contrast, comparable doses of COC, GBR 12909, methylphenidate and AM 2547 did not fully mimic the effects of 1.0 mg/kg MA. In microdialysis studies, MA (0.3 - 3 mg/kg) and COC (3 - 30 mg/kg) produced a dose-dependent increase in DA efflux in the nACC shell to approximate maxima of, respectively, 1700% and 550% of control values. In 1.0 mg/kg MA-trained rats, the ED50 dose of MA (0.34 mg/kg) and cocaine (3.98 mg/kg) produced approximately 340% and 210% increases in DA, respectively. In 0.3 mg/kg MA-trained rats, the ED50 dose of MA (0.11 mg/kg) and cocaine (3.03 mg/kg) produced approximately 220% and 200% increases DA levels, respectively. Taken together, these results support a prominent role for dopamine in MA-like discriminative-stimulus effects. [ABSTRACT FROM AUTHOR]

Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine. The prevalence of symptoms reported on withdrawal in different studies also covers a wide range from 11% or less to 100%. It is suggested that the evidence leads to the conclusion that non pharmacological factors related to knowledge and expectation are the prime determinants of symptoms and their reported prevalence on withdrawal of caffeine after regular consumption. [Copyright &y& Elsevier]