Preclinical studies have documented that serotonin (5-HT) can modulate the behavioral effects of cocaine. The present study examined the ability of 5-HT to attenuate the reinforcing and neurochemical effects of cocaine in nonhuman primates. In squirrel monkeys trained to self-administer cocaine (0.1 and 0.3 mg/injection) under a second-order schedule of i.v. drug delivery, the 5-HT uptake inhibitor alaproclate (3.0 and 10.0 mg/kg) and the 5-HT direct agonist quipazine (0.3-1.0 mg/kg) decreased response rates at doses that had no significant effect on behavior maintained by an identical schedule of stimulus termination. The neurochemical bases of the observed drug interactions on behavior were investigated further using in vivo microdialysis techniques in a separate group of awake monkeys to monitor drug-induced changes in extracellular dopamine (DA). Cocaine (1.0 mg/kg) elevated the concentration of DA in the caudate nucleus to approximately 300% of basal levels. Pretreatment with alaproclate or quipazine attenuated cocaine-induced increases in extracellular DA at the same pretreatment doses that decreased cocaine self-administration. The results obtained suggest that increasing brain 5-HT activity can attenuate the reinforcing effects of cocaine, ostensibly by decreasing the ability of cocaine to elevate extracellular DA in brain areas that mediate the behavioral effects. These findings extend those reported previously for the behavioral-stimulant effects of cocaine and identify a potential neurochemical mechanism underlying drug interactions on behavior.Abuse of stimulant drugs such as cocaine persists as a major health problem in the United States (Chilcoat and Johanson, 1998). Clearly, there is a great need for pharmacological treatments to combat abuse of these drugs; however, no pharmacotherapy has demonstrated sufficient efficacy for widespread clinical use (Carroll et al., 1999). A better understanding of the effects of cocaine on central nervous system neurochemistry will help identify effective approaches in developing medications for treating cocaine dependence.The behavioral-stimulant and reinforcing effects of cocaine have been linked to its ability to enhance dopaminergic neurotransmission by inhibiting DA uptake via transporter blockade (Ritz et al., 1987). The affinities of several cocainelike drugs for DA transporter correlate well with their potencies for supporting self-administration behavior (Ritz et al., 1987;Bergman et al., 1989). In humans, a significant correlation has been observed between DA transporter binding and the intensity of subjective effects produced by intravenous cocaine (Volkow et al., 1997). Cocaine affects neurotransmission in various brain DA systems, leading to a variety of behavioral effects. For example, the DA neurons of the substantia nigra pars compacta project to the caudate nucleus and putamen, the primate homologues of the rodent dorsal striatum (Parent et al., 1995), to modulate motor function. Facilitation of DA transmission in the nigrostriatal system...

Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n ϭ 4) discriminating ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n ϭ 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic ⌬ 9 -THC (1 mg/kg s.c. 12 h) treatment. ⌬ 9 -THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating ⌬ 9 -THC; the ED 50 values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32-3.2 mg/kg) produced surmountable antagonism of ⌬ 9 -THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA 2 /pK B values of 6.65, 6.68, and 6.79 in the presence of ⌬ 9 -THC, JWH-018, and JWH-073, respectively. In ⌬ 9 -THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED 50 value of rimonabant was 0.20 mg/kg. ⌬ 9 -THC (1-10 mg/kg), JWH-018 (0.32-3.2 mg/kg), and JWH-073 (3.2-32 mg/kg) dose-dependently attenuated the rimonabantdiscriminative stimulus (i.e., withdrawal). These results suggest that ⌬ 9 -THC, JWH-018, and JWH-073 act through the same receptors to produce ⌬ 9 -THC-like subjective effects and attenuate ⌬ 9 -THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulusoutcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than ⌬ 9 -THC.

Rationale: Previous studies show that selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, have a greater effect on ethanol-maintained responding compared with an alternative reinforcer. However, none of these studies matched baseline responding for reinforcers. Because behavioral effects of many drugs depend on the baseline response rate, the preferential effects of SSRIs may be due to different baseline response rates. Objectives: Fluvoxamine effects on ethanol-and foodmaintained responding were compared using a multiple schedule of behavior, providing matched baseline responding and allowing within-subject analysis in two strains of rats. Methods: The multiple schedule consisted of three consecutive 5-min, fixed-ratio five components (Food1, Ethanol, Food2). Fluvoxamine (3-30 mg/kg, i.p.) was administered 30 min presession. In Lewis rats, fluvoxamine effects were determined at several available ethanol concentrations [8, 16, 32, and 8% (w/v) redetermination]. In Sprague-Dawley rats, fluvoxamine effects were determined when the available ethanol concentration was 8% (w/v). Results: Baseline responding was stable and well matched under all conditions except 32% ethanol, when responding for ethanol was lower than for food. After the administration of 17.8 mg/kg fluvoxamine, ethanol-maintained responding was 15-33% lower than food-maintained responding in four of the five conditions tested. Breath ethanol assessments indicated that rats had blood ethanol levels of 33 mg/dl following responding for 8% ethanol. Conclusions: These results are in agreement with previous findings that SSRIs preferentially reduce ethanolmaintained responding and suggest this is not likely due to different baseline levels of responding between the comparison conditions. Further, these results support the hypothesis that alteration of synaptic serotonin can modulate ethanol reinforcement.

We have previously shown that using agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in three-dimensional quantitative structure-activity relationship studies (3D-QSAR) presents a unique opportunity for accuracy and precision in measurement. Thus, a comparison of affinity's structural determinants for a set of compounds at two different recombinant dopamine receptors represents an attainable goal for 3D-QSAR. A molecular database of bound conformations of 16 structurally diverse agonists was established by alignment with a high-affinity template compound for the D1 receptor, 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-benzazepin. A second molecular database of the bound conformations of the same compounds was established against a second template for the D2 receptor, bromocriptine. These aligned structures suggested three-point pharmacophore maps (one cationic nitrogen and two electronegative centers) for the two dopamine receptors, which differed primarily in the height of the nitrogen above the plane of the catechol ring and in the nature of the hydrogen-bonding region. The ln(1/KL) values for the low-affinity agonist binding conformation at recombinant D1 and D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA (comparative molecular field analysis) of the 16 aligned structures. The resulting CoMFA models yielded cross-validated R2 (q2) values (standard error of prediction) of 0. 879 (1.471, with five principal components) and 0.834 (1.652, with five principal components) for D1 and D2 affinity, respectively. The simple R2 values (standard error of the estimate) were 0.994 (0.323) and 0.999 (0.116), respectively, for D1 and D2 receptor. F values were 341 and 2465 for D1 and D2 models, respectively, with 5 and 10 df. The predictive utility of the CoMFA model was evaluated at both receptors using the dopamine agonists, apomorphine and 7-OH-DPAT. Predictions of KL were accurate at both receptors. Flexible 3D searches of several chemical databases (NCI, MDDR, CMC, ACD, and Maybridge) were done using basic pharmacophore models at each receptor to determine the similarity of hit lists between the two models. The D1 and D2 models yielded different lists of lead compounds. Several of the lead compounds closely resembled high-affinity training set compounds. Finally, homology modeling of agonist binding to the D2 receptor revealed some consistencies and inconsistencies with the CoMFA-derived D2 model and provided a possible rationale for features of the D2 CoMFA contour map. Together these results suggest that CoMFA-homology based models may provide useful insights concerning differential agonist-receptor interactions at related receptors. The results also suggest that comparisons of CoMFA models for two structurally related receptors may be a fruitful approach for differential QSAR.

The discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB(1)) receptors, whereas the effects of methanandamide or a metabolite of methanandamide are mediated at least in part by non-CB(1) receptors. The discriminative stimulus effects of Delta(9)-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.