Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central ₁-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil,l-ephedrine andd-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by ₁-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil andl-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil required very high doses: modafinil was over 200 times less potent thand-amphetamine and was also less potent thanl-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.     

Comparative behavioral profile of cocaine and norcocaine in rats and monkeys

The effects of cocaine and norcocaine were compared using locomotor activity, fixed-ratio 100 (FR 100) and fixed-interval 4 min (FI 4 min) food reinforcement and free feeding paradigms in rat and intravenous self-administration tests in rhesus monkeys. Cocaine was shown to significantly increase locomotor activity at doses of 20 and 40 mg/kg, while norcocaine had no effect at these doses and produced convulsions and death at 60 and 80 mg/kg. Both compounds significantly reduced food consumption at one or more of the doses tested. Cocaine and norcocaine at doses of 20 and 40 mg/kg, produced decreases in FR responding. Cocaine at doses of 10, 20, and 40 mg/kg, produced increases in FI responding; norcocaine had no effect following 10 mg/kg and decreased responding at 20 and 40 mg/kg. Cocaine (0.2 mg/kg/inj) and norcocaine (0.5, 0.2, 0.8 mg/kg/inj) maintained intravenous self-administration in all three monkeys tested. The data indicate that norcocaine is a pharmacologically active metabolite of cocaine which could account for some of the activity heretofore attributed to cocaine. However, the lack of any stimulatory effect of norcocaine or locomotor activity and the lack of increased responding produced by norcocaine on fixed-interval behavior suggest that norcocaine differs qualitatively from cocaine.     

Experimental studies of the abuse potential of d,l-glaucine·1.5-phosphate in rhesus monkeys

d-Glaucine is an alkaloid derived from Glaucium flavum, which is as effective as codeine as an antitussive. d,l-Glaucine·1.5 phosphate is a synthetic compound related to d-glaucine. The ability of ,l-glaucine·1.5 phosphate to maintain responding in rhesus monkeys was assessed in 2 procedures. In the first study responding was maintained under a fixed-ratio 10 schedule of codeine delivery during daily 3-hr sessions. When d,l-glaucine·1.5 posphate (0.05–0.4 mg/kg) was substituted for codeine, responding was not maintained. In the second procedure, monkeys given 23-hr/day access to 0.5–1.0 mg/kg under a fixed-ratio schedule did not self-administer d,l-glaucine·1.5 phosphate above saline levels even after a 21-day period of programmed injections. Following the period of programmed injections, there were no signs of opiate withdrawal following the administration of naloxone. These results indicate that the abuse potential of td,l-glaucine·1.5 phosphate is low relative to codeine.     

The effect of novelty on amphetamine self-administration in rats classified as high and low responders

Rationale Rats categorized as high responders (HR) based on their activity in an inescapable novel environment self-administer more amphetamine than low responder (LR) rats. Previous research has also demonstrated that novel stimuli presented during the amphetamine self-administration session decreases the number of infusions earned.Objectives This study determined whether individual differences in response to inescapable or free-choice novelty differentially predict the ability of novel stimuli to decrease amphetamine self-administration. Further, this study determined whether novel stimuli maintained the ability to reduce self-administration with repeated presentations, and whether the effect of novel stimuli varied as a function of the unit dose of amphetamine tested.Methods Male rats were screened for their response in inescapable and free-choice novelty tests. Following initial training using a high unit dose of amphetamine (0.1 mg/kg per infusion), the dose was reduced (0.03 mg/kg per infusion), and novel stimuli were presented in the operant conditioning chamber on four separate sessions. In experiment 2, novel stimuli were presented during several sessions at a variety of amphetamine doses (0.003, 0.01, 0.03, and 0.056 mg/kg per infusion).Results Four repeated presentations of novel stimuli reduced amphetamine self-administration with no significant loss in the effect of novel stimuli across repeated presentations. In experiment 2, novel stimuli reduced amphetamine self-administration at low unit doses (0.003 mg/kg and 0.01 mg/kg per infusion), and rats classified as HR based on their activity in inescapable novel stimuli were more disrupted by novel stimuli than LR rats.Conclusions These results suggest that repeated presentation of novel stimuli can reduce amphetamine self-administration at low unit doses and that HR rats are more sensitive than LR rats to non-drug stimuli that compete with responding for amphetamine.     

Effects of phencyclidine and methylphenidate on d-amphetamine-induced behaviors in reserpine pretreated rats

The effects and interactions of phencyclidine (PCP), methylphenidate and d-amphetamine on locomotor activity, stereotyped behavior and ataxia in reserpine- and vehicle-pretreated rats were examined. The behaviors of rats receiving PCB alone or in combination with other drugs were quantified along three dimensions (locomotor activity, stereotyped behavior, and ataxia) on scales developed in this laboratory. The behaviors of groups receiving methylphenidate and/or d-amphetamine in treatment combinations other than those including PCP were quantified using a well known d-amphetamine behavioral rating scale. PCP, methylphenidate and d-amphetamine each induced significant increases in locomotor activity and stereotyped behavior when administered alone. Reserpine was found to antagonize PCP-induced locomotor activity and stereotyped behavior, and methylphenidate-induced stereotyped behavior at a dose which either potentiated or had no significant effect upon d-amphetamine-induced behavior (depending upon the scale used). Reserpine also potentiated PCP-induced ataxia. Whereas PCP potentiated the locomotor activity induced by d-amphetamine in both reserpine- and vehicle-pretreated subjects, methylphenidate marginally antagonized d-amphetamine-induced stereotypy in reserpine-pretreated subjects, PCP-induced ataxia in reserpine pretreated subjects appeared moderately reduced in subjects also receiving d-amphetamine. In general, the behavioral effects of PCP appear to be more similar to those of methylphenidate than to those of d-amphetamine, but differences are also found between PCP and methylphenidate. The results are discussed in relation to a behavioral model recently proposed as a method for differentiating indirect dopamine agonists on the basis of their neurochemical mechanisms of action.     

Structure-activity relationships of met5- and leus-enkephalin analogues

1. The effect of various analogues of met5- and leu5-enkephalin were determined on the reduction in twitch height of the electrically-stimulated longitudinal muscle preparation of the guinea-pig ileum and of the isolated mouse vas deferens. 2. In the guinea-pig ileum, D-alanine2-met5-enkephalin was the most potent whereas leu5-enkephalin was the most potent in the mouse vas deferens. 3. The met5-enkephalin analogues were more effective in reducing the twitch height of the ileum than they were in depressing that of the vas deferens preparation. The leu5-enkephalin analogues were more potent in their effects on the mouse vas deferens than they were on the guinea-pig ileum. 4. When a peptide bond is replaced by a glycol bond as in glycol2-3-leu5-enkephalin there is a marked reduction in opiate-like activity. 5. Substitution of a D-alanine residue for the glycine2 residue, as in D-alanine2-met5-enkephalin, increases the duration and potency of opiate-like activity. 6. These results confirm that modification of either met5- or leu5-enkephalin can alter the opiate-like potency of the resulting analogues. It appears that an intact tyrosyl residue of leu5-enkephalin is essential for such activity and that substitution of a D-alanine2 residue for the glycine2 residue confers resistance to enzymatic degradation on the met5-enkephalin peptide. In addition, the glycine2-3 peptide bond is essential for opiate-like activity.     

Structure-activity relationships for hepatocyte toxicity and electrophilic reactivity of alpha,beta-unsaturated esters, acrylates and methacrylates

Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, electrophile reactivity towards biological nucleophiles could serve as an important correlate for toxic effects such as hepatocyte death. To determine if reactivity correlates with rat hepatotoxicity, alpha,beta-unsaturated esters, consisting of acrylates and methacrylates, that are inherently electrophilic and exhibit widely varying degrees of reactivity were investigated. Reactivity was measured using simple assays with glutathione and butylamine as surrogates for soft thiol and hard amino biological nucleophile targets. A linear relationship was observed between hepatotoxicity and thiol reactivity only, while no amine reactivity was observed. Structure-activity relationships were also investigated, with results showing toxicity was well modeled by electronic parameters E(LUMO) and partial charge of the carbon atoms in the reactive center. No relationship was observed between toxicity and logP. These results suggest that differences in hepatocyte toxicity of acrylates and methacrylates can be related to their electrophilic reactivity which corresponds to their ability to deplete GSH and protein thiols.     

Assessment of mazindane,a pro-drug form of mazindol,in assays used to define cocaine treatment agents

The current studies compared mazindane (5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1a] isoindole) hydrogen sulfate, a water soluble pro-drug of mazindol (5-(4-chlorophenyl-2,3-dihydro-5H-imidazo [2,1-a] isoindol-5-ol), with mazindol in assays used to define cocaine treatment agents. Both compounds enhanced motor activity (LMA) in Swiss Webster mice with ED(50) values of 2.5 mg/kg i.p. for mazindane and 3.9 mg/kg i.p. for mazindol. At 25 mg/kg mazindane displayed toxic effects and death while mazindol was effect/death free at 50 mg/kg. In Sprague-Dawley rats trained to discriminate cocaine from saline both compounds fully substituted for cocaine with mazindane being fourfold more potent in the total session (0.33 vs. 1.3 mg/kg i.p.) and first reinforcer (0.29 vs. 1.2 mg/kg i.p). Complete substitution was observed in rhesus monkeys trained to discriminate cocaine from saline with ED(50) values for mazindane (0.134 mg/kg i.m.) and mazindol (0.119 mg/kg i.m.). Mazindol exhibited little or no activity at 10(-5) M in inhibiting radioligand binding at 14 neurotransmitter sites while mazindane gave weak activity at the histamine H(1) and 5-hydroxytryptamine 5-HT(3) sites. These results demonstrate that mazindane could be a useful alternative to mazindol as a pharmacological tool because of its similar profile of activity and enhanced water solubility.     

Behavioral pharmacology of local anesthetics: Reinforcing and discriminative stimulus effects

The reinforcing properties of several short-acting esteratic local anesthetics were determined in rhesus monkeys experienced in the IV self-administration of cocaine. In addition, the discriminative stimulus properties of these and several other local anesthetics of both the ester and amide class were determined in rats trained to discriminate procaine from saline in a 2-lever operant task. IV delivery of chloroprocaine, dimethylprocaine or dimethocaine maintained responding above vehicle levels in most monkeys while propoxycaine, piperocaine and dimethylaminoethanol (Deanol) failed to maintain self-administration behavior. Thus some, but not all, short-acting esteratic local anesthetics are positive reinforcers in rhesus monkeys. In addition, it is unlikely that the reinforcing effects of dimethylprocaine are mediated by its metabolite dimethylaminoethanol. In rats, all local anesthetics tested except piperocaine and procainamide resulted in responding on the procaine-appropriate lever indicating procaine-like discriminative stimulus effects for these compounds. In addition, injections of d-amphetamine resulted in principally procaine lever responding. All local anesthetics that were self-administered by rhesus monkeys had discriminative stimulus effects in rats that were similar to those of procaine. However, not all local anesthetics that were procaine-like in rats were self-administered by rhesus monkeys. These data may represent a separation of these two stimulus properties for local anesthetics although other variables such as species differences may play a role.