Differential effects of amphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine.

Evidence suggests that some amphetamine-like stimulants may enhance accumbens dialysate dopamine to the greater extent than caudate dopamine. To test our hypothesis that the difference in transmitter response may derive, in part, from the degree to which released dopamine in the two regions is metabolized to 3-methoxytyramine, we compared the effects of amphetamine with the uptake blockers, nomifensine and cocaine, on caudate and accumbens dialysate concentrations of dopamine, its acid metabolites and 3-methoxytyramine. The percentage increases in accumbens dopamine were significantly greater than in caudate only after the uptake blockers. All three drugs promoted dose-dependent increases in dialysate 3-methoxytyramine which, although temporally delayed, generally paralleled the increases in dopamine. However, after the administration of uptake blockers, the ratio of dialysate 3-methoxytyramine to dopamine was greater in caudate than in accumbens. In addition, the acid metabolite patterns were the same in the two regions after amphetamine, but were qualitatively different after the uptake blockers. These results indicate that the relative degree of metabolism of released dopamine to 3-methoxytyramine in caudate and accumbens may contribute to the regional differences in dopamine response to uptake blockers.     

Differential effects of cocaine on firing rate and pattern of dopamine neurons: role of alpha1 receptors and comparison with L-dopa and apomorphine

Psychostimulants, including cocaine, have two opposing effects on dopamine (DA) neurons: a DA-mediated inhibition and a non-DA-mediated excitation. The latter, expressed as an increase in both firing rate and a slow oscillation (SO) in firing pattern, has been shown to require forebrain inputs to DA neurons and activation of adrenergic alpha(1) receptors. However, since the effect was observed when the DA-mediated inhibition was blocked by a D2 antagonist, it is uncertain whether the underlying mechanism also plays a role in cocaine's effects in normal animals where D2-like receptors are not blocked. This study showed that under such conditions, cocaine decreased firing rate and bursting without significantly inhibiting the SO in DA neurons recorded in the ventral tegmental area. Different from cocaine, l-dopa and apomorphine, two nonpsychostimulant DA agonists known to lack the alpha(1)-mediated excitatory effect, consistently inhibited all three measures of DA cell activity. Blockade of alpha(1) receptors by prazosin did not enhance cocaine's ability to inhibit firing rate and bursting, but it did enable cocaine to inhibit the SO. These results suggest that in control rats where D2-like receptors are not blocked, alpha(1) receptors play an important role in cocaine's effect on the SO but not in its effect on firing rate and bursting of DA neurons. The maintained SO after cocaine injection may reflect continued modulation of DA neurons by forebrain inputs, regulate the pattern of DA release, and provide a temporal structure for selection of synaptic inputs to DA neurons.     

The reinforcing efficacy of the dopamine reuptake inhibitor 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) as measured by a progressive-ratio schedule and a choice procedure in rhesus monkeys

The present series of experiments was undertaken to investigate the variables that influence the reinforcing efficacy of psychostimulants. The time of onset for dopamine transporter (DAT) occupancy of the long-acting, high-affinity DAT blocker 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) was measured using an ex vivo binding assay in rodents and was determined to be significantly longer than for cocaine (30 min versus 2 min). To assess the reinforcing efficacy of PTT relative to cocaine, a discrete-trials drug-drug choice procedure (n = 3) and a progressive-ratio (PR) schedule (n = 4) were used in rhesus monkeys. Cocaine (0.003-0.56 mg/kg/injection) and PTT (0.003-0.03 mg/kg/injection) maintained responding greater than saline under the PR schedule. Maximal breaking points were significantly higher for cocaine compared with PTT. A separate group of monkeys prepared with double-lumen catheters was allowed to choose between cocaine (saline and 0.03-0.3 mg/kg/injection) and PTT (saline, and 0.01 and 0.03 mg/kg/injection). Under these conditions, PTT was not preferred over saline. When saline or 0.01 mg/kg/injection PTT was available as alternatives to cocaine, the highest dose of cocaine maintained greater than 80% choice. When 0.03 mg/kg/injection PTT was the alternative to cocaine, cocaine choice declined to approximately 50%, and total cocaine intake was decreased by ~70% at the highest cocaine dose. These results suggest that the reinforcing efficacy of PTT is less than cocaine in nonhuman primates. Data from studies with PTT indicate that slow-onset, long-acting DAT inhibitors can decrease cocaine self-administration while not functioning robustly as reinforcers, and support the further investigation of these drugs as treatment for cocaine addiction.     

Effects of RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide], an orally active, selective dopamine D(3) receptor partial agonist in animal models of cocaine abuse

Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.7 nM) and rat (K(i) = 1.6 nM) D(3) receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D(2) receptor. The molecule bound with moderate (100-250 nM) affinity to 5-hydroxytryptamine 1A (5-HT(1A)) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D(3) partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.     

Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo

The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation differed markedly between the two drugs, with much shorter onset and duration of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarly, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-lived increase in DA in the NAc, whereas i.p. 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (>/=2 h) elevation in accumbens DA. In contrast to i.p. administration, local infusion of 4-Cl-BZT (1-100 microM) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent than did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of action than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavioral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo.     

Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.

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.     

Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: focus on dopamine, norepinephrine and glutamate

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.     

Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate,a piperidine-based analog of cocaine

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.     

Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and benztropine analogs

Analogs of benztropine (BZT) bind to the dopamine (DA) transporter and inhibit DA uptake but often have behavioral effects that differ from those of cocaine and other DA-uptake inhibitors. To better understand these differences, we examined the relationship between locomotor-stimulant effects of cocaine, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)-piperazine (GBR 12909), and BZT analogs [(3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (AHN 1-055) and (N-allyl-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (AHN 2-005)] and their in vivo displacement of the DA transporter ligand [125I]3beta-(4-iodophenyl)-tropan-2beta-carboxylic acid isopropyl ester hydrochloride (RTI-121) in striatum. Cocaine, GBR 12909, and BZT analogs each displaced [125I]RTI-121 and stimulated locomotor activity in a dose- and time-dependent manner. The time course revealed a slower onset of both effects for AHN 1-055 and AHN 2-005 compared with cocaine and GBR 12909. The BZT analogs were less effective than cocaine and GBR 12909 in stimulating locomotor activity. Locomotor stimulant effects of cocaine were generally greater than predicted by the regression of displacement of [125I]RTI-121 and effect at short times after injection and less than predicted at longer times after injection. This result suggests that the apparent rate of occupancy of the DA transporter, in addition to percentage of sites occupied, contributes to the behavioral effects of cocaine. The present results suggest that among drugs that act at the DA transporter, the slower apparent rates of occupancy with the DA transporter by the BZT analogs may contribute in an important way to differences in their effectiveness.     

Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys

Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3beta-(4-chlorophenyl)tropane-2beta-[3-(4'-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED(50)) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED(50) dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED(50) dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.     

Effects of L-DOPA on nigral dopamine neurons and local field potential: comparison with apomorphine and muscimol

The purpose of this study was to evaluate the involvement of endothelin (ET)(B) receptor-mediated action in the sex differences in balloon injury-induced neointimal formation using the spotting-lethal rat, which carries a naturally occurring deletion in its ET(B) receptor gene. Male and female ET(B)-deficient and wild-type rats underwent balloon injury of the carotid artery. In the wild-type rats, the neointima/media ratio was significantly lower in females than in males, but this sex difference was attenuated by ovariectomy and restored by treatment with 17β-estradiol (20 μg/kg/day). In the ET(B)-deficient rats, the neointima/media ratio of the male and female rats was markedly increased to the same level, and this increase was not affected by ovariectomy or 17β-estradiol treatment. Treatment with (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (J-104132) (10 mg/kg/day), an ET(A)/ET(B) dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ET(B)-deficient rats, but not the female wild-type rats. In addition, 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621) (30 mg/kg/day), a selective ET(B) receptor antagonist, abolished the sex difference of balloon injury-induced neointimal formation. 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (10 mg/kg/day), a selective ET(A) receptor antagonist, and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent in males but not intact females. These results indicate that the sex difference in balloon injury-induced neointimal formation was abolished by genetic ET(B) receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ET(A) receptor-mediated action seem to be responsible for the abolition of sex differences in the ET(B) receptor-inhibited condition.     

Effects of alpha adrenoceptor and dopamine receptor agonists and antagonists on ganglionic transmission

Effects of alpha adrenoceptor and dopamine (DA) receptor agonists and antagonists on ganglionic transmission were studied in pentobarbital-anesthetized, open-chest dogs. Changes in tachycardia produced by preganglionic cardiac nerve stimulation were monitored as a measure of ganglionic transmission. Several agonists, injected i.a. into the blood supply of the stellate ganglion, inhibited ganglion transmission. This effect was localized to the ganglion as none of the agonists, in the highest doses studied, inhibited tachycardia produced by postganglionic cardiac nerve stimulation. The potency order of the agonists was UK 14,304 (alpha-2 adrenoceptor agonist) greater than norepinephrine (NE) greater than dipropyl DA (DA2 dopamine receptor agonist) greater than DA greater than or equal to phenylephrine (alpha-1 adrenoceptor agonist) greater than fenoldopam (DA1 dopamine receptor agonist). UK 14,304 was over 200 times more potent than fenoldopam, being active in nanomole doses, whereas NE was more potent than DA. Rauwolscine, an alpha-2 adrenoceptor antagonist, antagonized the inhibitory effects of NE and DA and was the only antagonist, given i.a. or i.v., that facilitated ganglionic transmission; frequency-response curves of tachycardia induced by preganglionic nerve stimulation were dose-dependently augmented. SCH 23390, in double the full DA1 antagonist dose, had no effect on frequency-response curves or on NE- or DA-induced ganglionic inhibition. Domperidone antagonized the effect of DA but had no effect on ganglionic inhibition produced by NE or on frequency-response curves of tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency.

Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, have been examined for their stimulatory effects on locomotor activity and for their ability to displace [3H]WIN 35,428 binding in vivo in mice. These compounds, like WIN 35,428, lack an ester link between the phenyl group and the tropane ring and have para-substitutions on the phenyl ring. They were much more potent than (-)-cocaine in producing increases in locomotor activity. In addition, they were more potent than (-)-cocaine in inhibiting [3H]WIN 35,428 binding in vivo in mouse striatum. Thus, these compounds demonstrate similar high potency in behavioral tests and in receptor binding assays, both in vivo and in vitro. Results support the hypothesis of a relationship between binding at the dopamine transporter and the behavioral effects of cocaine-like drugs. Further, assuming that maximal occupancy occurs with total displacement of [3H]WIN 35,428 binding in vivo, the data suggest that maximal locomotor effects occur with near total occupancy of transporter binding sites.     

Characterization of the effects of cocaine and GBR 12909, a dopamine uptake inhibitor, on behavior in the squirrel monkey.

The behavioral effects of cocaine and GBR 12909, a highly selective dopamine uptake inhibitor, were compared in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination and a second-order schedule of drug self-administration. Both drugs exhibited similar pharmacological profiles; intermediate doses increased response rates markedly and higher doses decreased response rates below control values. The magnitude of the rate-increasing effect was similar for cocaine and GBR 12909, although cocaine was approximately 3 times more potent. In contrast, the direct-acting dopamine agonists, SKF 38393 and quinpirole, produced only decreases in response rates. When cocaine and GBR 12909 were studied in combination with dopamine antagonists, the effects of either on fixed-interval performance were attenuated in a similar manner by a D1-selective antagonist (SCH 23390) and a D2-selective antagonist (spiperone), indicating the involvement of both D1 and D2 receptor subtypes. In contrast, an alpha 1-selective antagonist (prazosin) did not alter the dose-effect curve for cocaine or GBR 12909 in a manner that indicated a pharmacological antagonism. When doses of cocaine were administered in combination with GBR 12909, the effects on behavior were additive. However, the combined effects of cocaine and SKF 38393 or cocaine and quinpirole were more complex and did not appear to be additive. When the cocaine or GBR 12909 was self-administered under a second-order, fixed-interval schedule of drug injection, schedule-appropriate responding was maintained and the potency difference between the two drugs was comparable to that observed under the stimulus-termination schedule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the administration of amphetamine, either alone or in combination with reserpine or cocaine, on regional brain beta-phenylethylamine and dopamine release.

The effect of amphetamine sulfate (AMPH) on beta-phenylethylamine (PEA) and 3-methoxytyramine (3MT) levels in the rat frontal and cingulate cortices, the nucleus accumbens, and the striatum were evaluated after the administration of either cocaine or reserpine alone and in combination with AMPH. The purpose of this study was to evaluate the neuromodulator properties of PEA on dopamine (DA) release as reflected by 3MT steady-state concentrations. The highest concentration of PEA was found in the nucleus accumbens, followed by the cingulate and frontal cortices, and then the striatum. Time-course effects of the intraperitoneal administration of 5 mg/kg AMPH on PEA and 3MT concentrations were similar but not identical. AMPH at a dosage of 1 mg/kg significantly increased PEA concentration only in the striatum. A dosage of 2.5 mg/kg reserpine, which markedly depressed 3MT levels in all brain regions studied except the striatum, significantly reduced PEA concentrations only in the nucleus accumbens. This dosage of reserpine reduced DA concentrations by more than 80% in all regions examined, but its effects on norepinephrine were less marked. Pretreatment with cocaine (10 mg/kg) or reserpine (2.5 mg/kg) potentiated the effects of 1 mg/kg AMPH on PEA and 3MT levels in the frontal cortex and of 3MT in the striatum. Pretreatment with either 1 mg/kg reserpine (specifically used to partially mobilize DA storage) or cocaine (10 mg/kg) produced quantitative changes in the effects of 5 mg/kg AMPH on PEA and 3MT levels that were region-specific. For example, in contrast to the cortical regions and the nucleus accumbens, the AMPH-induced increase in 3MT was potentiated in the striatum. On the other hand, the increase in brain PEA produced by AMPH (5 mg/kg) was not influenced by either increased cytoplasmic DA (as deduced from the effects of 1 mg/kg reserpine pretreatment) or DA uptake inhibition (as deduced from the effect of cocaine pretreatment) in the frontal cortex or the nucleus accumbens. Furthermore, the increase in PEA produced by AMPH (5 mg/kg) in the cingulate cortex and the striatum were abolished and potentiated, respectively, by these drug pretreatments. Our results suggest that although DA release and PEA formation are stimulated by AMPH, these effects appear to involve mechanisms that are not directly related and hence suggest a dissociation between 3MT and PEA formation in the brain. Our work also suggests that PEA is most likely not to be co-released with DA following the administration of AMPH. Therefore, it is concluded that whatever physiological role PEA may play in central synaptic transmission, its effects do not appear to be dependent on DA release.     

A comparative study of the structures,thermal stabilities and energetic performances of two energetic regioisomers: 3(4)-(4-aminofurazan-3-yl)-4(3)-(4-nitrofurazan-3-yl)furoxan

Although energetic regioisomers have attracted intensive attention due to their interesting structure–property correlation, their effective synthesis and accurate identification has remained very difficult. In this paper, we synthesized two energetic regioisomers, namely 3-(4-aminofurazan-3-yl)-4-(4-nitrofurazan-3-yl)furoxan (ANFF-34) and 4-(4-aminofurazan-3-yl)-3-(4-nitrofurazan-3-yl)furoxan (ANFF-43), via a controllable strategy with improved yields of 32% and 38%, respectively. The structures of ANFF-34 and ANFF-43 were unambiguously identified using comparative studies of ¹⁵N NMR and single-crystal X-ray diffraction. Moreover, their thermal behaviours, and non-isothermal thermodynamic parameters were systematically investigated. Both ANFF-34 (T_m: 116.2 °C, T_d: 255.4 °C) and ANFF-43 (T_m: 106.2 °C, T_d: 255.6 °C) have similar thermal decomposition processes to that of DNTF. The superior performances of ANFF-34 (ρ: 1.8 g cm⁻³, D: 8214 m s⁻¹, P: 30.5 GPa, IS > 40 J) and ANFF-43 (ρ: 1.7 g cm⁻³, D: 7868 m s⁻¹, P: 27.0 GPa, IS > 40 J) indicate their great potential to be used as melt-cast carrier explosives. This study provides a solid foundation for the design and synthesis of new energetic compounds through isomer effects.

Two energetic regioisomers ANFF-34 and ANFF-43 with satisfactory thermal behaviors and low mechanical sensitivities were comparatively studied.     

Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys

The present study examined the effects of two novel dopamine D3 receptor compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide], an antagonist, and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole-induced yawning when administered i.m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i.m. injections of saline (0.5 ml) and cocaine (0.3 mg/kg). Neither D3 compound (0.03-3.0 mg/kg; n=3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group of monkeys, responding was maintained under a second-order schedule of either food (1.0-g pellets; n=3) or cocaine (0.1 mg/kg/injection; n=4) presentation. When responding was stable, a dose of NGB 2904 (1.0-5.6 mg/kg i.v.) or CJB 090 (0.3-3.0 mg/kg i.v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food-maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine-like effects. The present findings support the continued examination of D3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel therapeutic agents.