Second-order Schedule Research Articles

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine < RTI-336 < RTI-150 < RTI-113 < RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were self-administered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.

Dopaminergic mechanism of reward-related incentive learning: Focus on the dopamine d3 receptor

Dopamine D(3) receptors (Drd3) have been implicated in the control of responding by drug-related conditioned incentive stimuli. We review recent studies of the effects of Drd3 antagonists or partial agonists on the control of self-administration of intravenous (IV) cocaine, IV morphine and oral ethanol on reward-rich and lean schedules, in reinstatement tests, on second-order schedules and on the acquisition and expression of conditioned place preference (CPP) and conditioned motor activity. For comparison, related studies where conditioned stimuli are based on nutritional reward also are considered. When self-administration depends more heavily on conditioned cues for its maintenance, for example on second-order schedules or lean ratio schedules, Drd3 antagonists or partial agonists reduce responding. Although data are limited, similar effects may be seen for responding for cues based on drugs or nutritional rewards. Drd3 agents also block the ability of conditioned cues to reinstate responding for cocaine or food. Published results suggest that Drd3 plays a more important role in the expression than in the acquisition of a CPP or conditioned motor activity. The mechanism mediating the role of Drd3 in the control of responding by conditioned incentive stimuli remains unknown but it has been found that Drd3 receptors increase in number in the nucleus accumbens during conditioning. Perhaps Drd3 participates in the molecular mechanisms underlying the role of dopamine and of dopamine receptor subtypes in reward-related incentive learning.

Blockade of THC-Seeking Behavior and Relapse in Monkeys by the Cannabinoid CB1-Receptor Antagonist Rimonabant

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.

Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

Drug seeking under a second-order schedule of reinforcement depends on dopamine D₃ receptors in the basolateral amygdala.

Drug seeking under the control of drug-associated stimuli and its reinstatement after extinction can be decreased by systemic administration of dopamine D3 receptor antagonists. It is demonstrated that responding by rats on the active lever for cocaine under a 2nd-order schedule of reinforcement, under which responding is maintained by response-contingent cocaine-paired conditioned reinforcers, is markedly attenuated by infusion of the dopamine D3 receptor antagonist SB-277011-A into the amygdala (2 and 4 microg/0.3 microl). By contrast, infusions of SB-277011-A into the shell subregion of the nucleus accumbens and also into the dorsal striatum were without effect. These results show that the control over drug seeking by conditioned reinforcers depends on D3 receptor-dependent dopamine transmission in the amygdala.

κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms

Kappa opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that kappa agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the kappa agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the alpha(2)-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of kappa opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by kappa agonists.

5‐HT2C receptor activation inhibits appetitive and consummatory components of feeding and increases brain c‐fos immunoreactivity in mice

5-Hydroxytryptamine (5-HT)(2C) and 5-HT(1B) receptors are implicated in the inhibitory modulation of feeding behaviour. However, their respective, and possibly different, roles have not been clearly identified because of a lack of selective 5-HT(2C) receptor agonists. Here, using the putative, selective 5-HT(2C) receptor agonist VER23779, we show that its effects on feeding are fully reversed by pretreatment with a selective 5-HT(2C) receptor antagonist, but unaffected by pretreatment with either a 5-HT(1B) or a 5-HT(2A) receptor antagonist. In mice eating a palatable mash, feeding ends earlier, inactivity is increased but the behavioural satiety sequence is preserved. In a second-order schedule of reinforcement with an initial, non-food-reinforced appetitive phase, VER23779 produces a much greater relative reduction in appetitive responding than the 5-HT(1B) receptor agonist CP-94,253. Increased c-fos immunoreactivity patterns following VER23779 also differ from those described for CP-94,253, in particular showing strong activation of the basolateral amygdala. The different behavioural consequences of 5-HT(2C) and 5-HT(1B) receptor activation may relate to the patterns of c-fos immunoreactivity. In particular, the basolateral amygdala may have a role in maintaining response in the appetitive phase of the second-order schedule and also be susceptible to serotonergic modulation through activation of 5-HT(2C) receptors.

Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats

Nucleus accumbens glutamate transmission has been implicated in drug-seeking behavior, but the involvement of glutamate receptor subtypes in drug seeking maintained by drug-associated cues has not been fully investigated. This study examined the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-D-aspartate (NMDA) and mGlu5 receptor blockade in the nucleus accumbens core on cue-induced reinstatement of cocaine seeking. Wistar rats were trained to self-administer cocaine and associate a compound stimulus (light and tone) with the drug under an FR4(FR5:S) second-order schedule of reinforcement. After extinction, during which neither cocaine nor the compound stimulus was available, responding was reinstated by contingent presentations of the compound stimulus. The effects of the intra-accumbal AMPA/kainate receptor antagonist 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX; 0, 0.01, and 0.03 microg/side), the NMDA antagonist D-2-amino-5-phosphonopentanoate (D-AP5; 0, 1, and 2 microg/side), and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 0.5, and 1 microg/side) on reinstatement were examined in a within-subjects design. CNQX and D-AP5 attenuated cue-induced reinstatement of cocaine seeking dose-dependently. MPEP, however, decreased cocaine seeking only relative to baseline because also the saline vehicle included in the within-subjects series of injections decreased responding, possibly reflecting conditioned anhedonic effects of MPEP. In additional experiments, none of the antagonists attenuated locomotor activity or responding for sucrose pellets. The results suggest that cue-induced reinstatement of cocaine seeking after a period of withdrawal from cocaine is sensitive to AMPA/kainate and NMDA receptor antagonism in the nucleus accumbens core and give further evidence for the role of the accumbal glutamate transmission in modulation of drug-seeking behavior.

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.

Effects of d-Amphetamine and Buprenorphine Combinations on Speedball (Cocaine+Heroin) Self-Administration by Rhesus Monkeys

The simultaneous i.v. administration of heroin and cocaine, called a 'speedball,' is often reported clinically, and identification of effective pharmacotherapies is a continuing challenge. We hypothesized that treatment with combinations of a monoamine releaser d-amphetamine, and a mu partial agonist, buprenorphine, might reduce speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine+0.0032 mg/kg/inj heroin) and food (1 g banana-flavored pellets) were available during four daily sessions on a second-order schedule of reinforcement (fixed ratio (FR)2 (variable ratio (VR)16:S)). Monkeys were treated for 10 days with saline or ascending doses of d-amphetamine (0.0032-0.032 mg/kg/h)+buprenorphine (0.075 or 0.237 mg/kg/day) in combination. d-Amphetamine+both doses of buprenorphine produced an amphetamine dose-dependent decrease in speedball self-administration in comparison to the saline treatment baseline (P<0.01-0.001), but food-maintained responding did not change significantly. d-Amphetamine alone (0.032 mg/kg/h) significantly decreased both food (P<0.01) and speedball-maintained responding (P<0.05). During saline control treatment, speedball unit doses of 0.0032 mg/kg/inj cocaine+0.001 mg/kg/inj heroin were at the peak of the speedball dose-effect curve. Daily treatment with 0.01 mg/kg/h d-amphetamine+0.237 mg/kg/day buprenorphine produced a significant downward and rightward shift in the speedball dose-effect curve (P<0.01) and no significant effect on food-maintained responding. A significant decrease in speedball self-administration was sustained over 10 days of treatment. These findings are consistent with our previous reports and suggest that medication mixtures designed to target both the stimulant and the opioid component of the speedball may be an effective approach to polydrug abuse treatment.

Long-term cocaine self-administration under fixed–ratio and second-order schedules in monkeys

Studies in rodents have demonstrated that increased access to cocaine can result in increases in drug intake per unit time. The present studies characterized long-term changes in cocaine self-administration associated with quantitatively and qualitatively different conditions of cocaine availability in monkeys. Separate groups of rhesus monkeys (n = 6/group) self-administered cocaine (0.2 mg/kg per injection) under a fixed ratio (FR) 30 schedule for 3 h twice daily for two consecutive days each week for 1 year, or responded under a second-order FR 10 (fixed interval 3-min:S) schedule of 0.2 mg/kg per injection cocaine during daily sessions. After 18 weeks, probe sessions were conducted once per week, in which responding was maintained under a fixed interval (FI) 30-min schedule in the presence of distinct stimuli. Weekly cocaine intakes under the FR schedule were stable in three subjects, but increased progressively in three monkeys over 1 year. In contrast, response rates under the second-order schedule were low and stable over time. Responding under the FI 30-min schedule was higher for monkeys in the FR group and pattern of responding was not indicative of FI performance, perhaps due to experimental history. These data suggest that increases in cocaine intake can be observed under ratio schedules in monkeys. The use of an FI 30-min "probe" to assess changes in "drug seeking" appeared to be influenced by experimental history. These data may aid in the development of behavioral models of cocaine abuse, which focus on the compulsive nature of drug taking.

Context‐dependent prefrontal cortex regulation of cocaine self‐administration and reinstatement behaviors in rats

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.

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.

A MAJOR TRIO

A MAJOR TRIO

Cue-Induced Cocaine Seeking and Relapse Are Reduced by Disruption of Drug Memory Reconsolidation

Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challenge to the treatment of drug addiction. Here we show that blockade of drug memory reconsolidation, through infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala shortly before reexposure to a cocaine-associated stimulus but not simply to the training context, severely impaired subsequently cue-maintained cocaine seeking under a second-order schedule of reinforcement and abolished cue-induced reinstatement of and relapse to cocaine seeking. This reduction in relapse after disrupted memory reconsolidation was not only seen after several hundred pairings of the stimulus with self-administered cocaine, but older, as well as recent, memories were also disrupted. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.

The effects of eticlopride and the selective D 3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D 3 receptor is mainly expressed in regions of the brain associated with the limbic system. D 3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D 2 receptors. The purpose of the present studies was to evaluate the effects of a selective D 3 receptor antagonist and a non-selective D 2/D 3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01–0.3 mg/kg/injection) presentation. In one experiment ( n = 4), the schedule was a fixed-interval (FI) 3-min and a second study ( n = 6) was conducted using a second-order fixed-ratio 5 (FI 6-min : S) schedule. The D 3 antagonist PNU 99194-A (0.3–3.0 mg/kg), which is 14-fold selective for D 3 relative to D 2 receptors, or the D 2/D 3 antagonist eticlopride (0.001–0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D 3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.

Effects of N‐acetylcysteine on the behavioral‐stimulant, reinforcing, and neurochemical effects of cocaine in the squirrel monkey

The stimulant and reinforcing effects of cocaine have been attributed largely to its actions at the dopamine transporter. However, other neurotransmitters can modulate cocaine-induced increases in dopamine. In rodents, glutamate receptor function in the striatum and nucleus accumbens plays a major role in the behavioral pharmacology of cocaine. Withdrawal from repeated exposure to cocaine results in decreased levels of glutamate by decreased cystine-glutamate transporter function. Systemic administration of N-acetylcysteine (NAC), which restores cystine-glutamate function, normalized glutamate levels. In the present studies, we examined the stimulant effects of cocaine in squirrel monkeys using a fixed-interval schedule of reinforcement. Systemic administration of cocaine increased extracellular dopamine levels in the striatum of squirrel monkeys, as measured by in vivo microdialysis. Pretreatment with NAC did not alter the stimulant effects of cocaine, but dose-dependently decreased cocaine-induced increases in dopamine in the striatum. Self-administration behavior maintained by a second-order schedule of i.v. cocaine delivery in squirrel monkeys was not altered by pretreatment with NAC. Hence, drug interactions in neurochemistry were not reflected in behavioral measures. Supported by USPHS grants DA00517, DA15902, DA13326, DA12514 and RR00165.

SECOND‐ORDER SCHEDULES OF TOKEN REINFORCEMENT WITH PIGEONS: IMPLICATIONS FOR UNIT PRICE

Four pigeons were exposed to second-order schedules of token reinforcement, with stimulus lights serving as token reinforcers. Tokens were earned according to a fixed-ratio (token-production) schedule, with the opportunity to exchange tokens for food (exchange period) occurring after a fixed number had been produced (exchange-production ratio). The token-production and exchange-production ratios were manipulated systematically across conditions. Response rates varied inversely with the token-production ratio at each exchange-production ratio. Response rates also varied inversely with the exchange-production ratio at each token-production ratio, particularly at the higher token-production ratios. At higher token-production and exchange-production ratios, response rates increased in token-production segments closer to exchange periods and food. Some conditions were conducted in a closed economy, in which the pigeons earned all their daily ration of food within the session. Relative to comparable open-economy conditions, response rates in the closed economy were less affected by changes in token-production ratio, resulting in higher levels of food intake and body weight. Some of the results are consistent with the economic concept of unit price, a cost-benefit ratio comprised of responses per unit of food delivery, but most are well accounted for by a consideration of the number of responses required to produce exchange periods, without regard to the amount of reinforcement available during those exchange periods.

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

L-Deprenyl (selegiline) is used in the treatment of Parkinson's disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. L-Deprenyl is metabolized in the body to L-methamphetamine and L-amphetamine, suggesting that it may have abuse potential. The current study assessed whether L-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether L-deprenyl would alter drug-seeking behavior maintained by D-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of D-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of D-amphetamine (0.3-1.0 mg/kg), L-deprenyl (0.1-10.0 mg/kg), and D-deprenyl (0.1-3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg L-deprenyl intramuscularly 30 min prior to D-amphetamine baseline sessions. D-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. D-Deprenyl maintained high rates of drug-seeking behavior similar to D-amphetamine. L-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with L-deprenyl failed to alter drug-seeking behavior maintained by D-amphetamine. These results indicate that D-deprenyl, but not L-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by D-amphetamine, L-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.

In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys

Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. Similar to cocaine, other local anesthetics bind to the dopamine transporter (DAT) and inhibit DA uptake in rodent and monkey brain. Additionally, local anesthetics are self-administered in rhesus monkeys, indicative of abuse liability. The present study examined the reinforcing and DAT effects of the local anesthetics dimethocaine, procaine and cocaine using in vivo techniques. Monkeys were trained to respond under a second-order schedule for i.v. cocaine administration (0.10 or 0.30 mg/kg/infusion). When responding was stable, dimethocaine (0.030-1.7 mg/kg/ infusion) or procaine (0.10-10 mg/kg/ infusion) was substituted for the cocaine training dose. Dimethocaine administration produced higher response rates compared with that of procaine, and was a more potent reinforcer. Drug effects on behavior were related to DAT occupancy in monkey striatum during neuroimaging with positron emission tomography (PET). DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 66 and 82% and <10-41% for doses of dimethocaine and procaine that maintained maximum response rates, respectively. Finally, in vivo microdialysis in awake subjects determined drug-induced changes in extracellular DA in the caudate nucleus. There was close correspondence between peak increases in DA and DAT occupancy. Overall, reinforcing effects were consistent with DAT effects determined with in vivo techniques. The results further support a role for the DAT in the abuse liability of local anesthetics.