Biomedical subjects

Charles W Schindler

Publications and source records attributed to Charles W Schindler.

At least 19 recordsLinked to original sources

PubMed2006

Effects of stress modulation on morphine-induced conditioned place preferences and plasma corticosterone levels in Fischer, Lewis, and Sprague-Dawley rat strains.

RATIONALE: There is a direct relationship between hypothalamic-pituitary-adrenal axis (HPA) reactivity and susceptibility to drug use in outbred rats. Specifically, manipulations that increase or decrease HPA activity also increase or decrease drug intake, respectively. Interestingly, this relationship has not been established in the inbred Fischer (F344) and Lewis (LEW) rat strains that are often used as animal models of susceptibility to drug use. OBJECTIVE: The present study investigated the effects of manipulations known to affect HPA activity on morphine-induced conditioned place preference (CPP) in male LEW, F344, and Sprague-Dawley (SD) rats. MATERIALS AND METHODS: In experiment 1, animals were exposed to an injection of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and 2-h restraint stress prior to the conditioning of a morphine-induced place preference (1, 4, or 10 mg/kg subcutaneous). In experiment 2, animals were chronically exposed to corticotropin-releasing hormone type 1 receptor antagonist, antalarmin, prior to CPP training. The effects of DMCM/restraint and antalarmin on corticosterone levels were examined in experiments 3 and 4. RESULTS: In outbred rats, DMCM/restraint increased both HPA activity and morphine-induced CPP, while antalarmin decreased CPP and produced a slight, but nonsignificant, decrease in corticosterone levels. In the inbred rats, however, DMCM/restraint increased plasma corticosterone yet decreased place preferences in the LEW strain, and antalarmin treatment decreased plasma corticosterone but increased place preferences in the F344 strain. CONCLUSIONS: These data suggest that the relationship between stress and drug use may be nonmonotonic. The use of these inbred strains in genetic analysis of drug addiction may require reexamination.

Animals↗

PubMed2006

Cocaine self-administration under variable-dose schedules in squirrel monkeys.

Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration. However, drug intake eventually became "dysregulated" after extensive training (100-300 sessions), with relatively short pauses following all doses. Dose-sensitivity was restored by adding a 60-s timeout period after each injection, suggesting that dysregulation occurred because the monkeys developed a tendency to self-administer another injection before the previous injection had been adequately distributed. Finally, when the response requirement under the variable-dose schedule was increased from 1 to 10, both the post-injection pause and the rate of responding following the pause ("run rates") were found to vary with dose. The dose-dependency of run rates suggests that post-injection pauses reflect not only motivational factors, such as satiety, but also the direct effects of cocaine on leverpressing.

Animals↗

PubMed2006

Peri-response pharmacokinetics of remifentanil during a self-administration session indicates that neither blood nor brain levels are titrated.

An individual's drug abuse pattern is determined by a multitude of factors. Among these, simple pharmacological determinants of within-binge drug consumption are sorely underinvestigated. We therefore determined if within-session operant responsing to the ultra-short-acting mu opioid agonist remifentanil (RMF) was determined by blood or brain RMF levels or changes thereof. Our peri-response analysis did not detect any "threshold" RMF level, either in blood or in the nucleus accumbens (NAc) core as a deep brain region that might determine a rat's "decision" to re-emit a response during a multiple-injection drug self-administration session. The peri-response analysis also failed to find any peak RMF level, either in blood or in the NAc core, which could serve as a "ceiling" level. Thus, our findings strongly suggest that titration of blood or brain RMF levels does not determine a rat's intra-session operant response.

Animals↗

PubMed2005

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.

Animals↗

PubMed2005

Intravenous butyrylcholinesterase administration and plasma and brain levels of cocaine and metabolites in rats.

Butyrylcholinesterase is a major cocaine-metabolizing enzyme in humans and other primates, catalyzing hydrolysis to ecgonine methylester. Increasing butyrylcholinesterase activity may be a treatment for cocaine addiction. We evaluated the effect of 30-min pretreatment with horse-derived butyrylcholinesterase (5-15,000 U i.v.) or with the selective butyrylcholinesterase inhibitor cymserine (10 mg/kg i.v.) on the metabolism of cocaine (17 mg/kg i.p.) in anesthetized rats. Venous blood samples were collected for two hours after cocaine administration and later assayed for cocaine and metabolites by gas chromatography/mass spectroscopy. Whole brains were collected after the last blood sample and similarly assayed. Butyrylcholinesterase significantly increased plasma and brain ecgonine methylester levels and decreased cocaine plasma half-life from 26.2 min (saline) to 16.4 min (15,000 U). Butyrylcholinesterase had no significant effect on plasma or brain cocaine or benzoylecgonine levels. Cymserine had no effect on any variable. These findings suggest that butyrylcholinesterase treatment may have benefits in enhancing cocaine metabolism and in increasing levels of ecgonine methylester, which may have a protective action against cocaine.

Animals↗

PubMed2005

Conditioned inhibition of cocaine seeking in rats.

Despite its potential relevance to the treatment of drug abuse, conditioned inhibition of drug seeking has not been systematically investigated before. In this study, rats could self-administer cocaine by lever pressing whenever a click or tone was present. Responding was not reinforced when a light was present. The light was presented simultaneously with the click (i.e., in an excitatory context) in 1 group, but the light was always presented alone in another group. When it was later presented in compound with the tone, the light was a highly effective conditioned inhibitor, suppressing cocaine seeking by 92% in the former group and by 74% in the latter. These results suggest ways to improve cue-oriented behavioral treatments for drug abuse.

Animals↗

PubMed2005

Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists.

1. The cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) were investigated in rats implanted with telemetry transmitters for the measurement of blood pressure and heart rate. 2. Intraperitoneal (i.p.) injections of the adenosine A1 receptor agonist CPA led to dose-dependent decreases in both blood pressure and heart rate. These effects of 0.3 mg kg(-1) CPA were antagonized by i.p. injections of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethyl-xanthine (CPT), but not by i.p. injections of the adenosine A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3). Injections (i.p.) of the peripherally acting nonselective adenosine antagonist 8-sulfophenyltheophylline (8-SPT) and the purported nonselective adenosine antagonist caffeine also antagonized the cardiovascular effects of CPA. 3. The adenosine A2A agonist CGS 21680 given i.p. produced a dose-dependent decrease in blood pressure and an increase in heart rate. These effects of 0.5 mg kg(-1) CGS 21680 were antagonized by i.p. injections of the adenosine A2A receptor antagonist MSX-3, but not by i.p. injections of the antagonists CPT, 8-SPT or caffeine. 4. Central administration (intracerebral ventricular) of CGS 21680 produced an increase in heart rate, but no change in blood pressure. MSX-3 given i.p. antagonized the effects of the central injection of CGS 21680. 5. These results suggest that adenosine A1 receptor agonists produce decreases in blood pressure and heart rate that are mediated by A1 receptors in the periphery, with little or no contribution of central adenosine A1 receptors to those effects. 6. The heart rate increasing effect of adenosine A2A agonists appears to be mediated by adenosine A2A receptors in the central nervous system. The blood pressure decreasing effect of adenosine A2A agonists is most probably mediated in the periphery.

Adenosine↗

PubMed2005

Human cocaine-seeking behavior and its control by drug-associated stimuli in the laboratory.

Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory-visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though self-reports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drug-related environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.

Adult↗

PubMed2004

Lorazepam reinstates punishment-suppressed remifentanil self-administration in rats.

RATIONALE: We recently described a reinstatement procedure that models relapse to drug abuse in cases where abstinence results from aversive consequences of drug use. The potential value of this punishment-based model of relapse depends on its sensitivity to relapse-inducing events that are ineffective in the widely used extinction-based model. OBJECTIVES: It is known that certain drugs can have anti-punishment effects, but these drugs have not been tested in the punishment-based reinstatement procedure. Therefore, the effects of the benzodiazepine, lorazepam, were examined using punishment-based and extinction-based reinstatement procedures. METHODS: Rats self-administered the opioid, remifentanil (4 microg/kg per infusion). Two punishment groups were trained with response-contingent footshock that suppressed baseline rates of responding to zero. In an extinction group, remifentanil delivery was discontinued, and baseline responding stabilized at a low rate (mean=0.06 responses/min). Lorazepam (0.08-10 mg/kg, IP) was given during test sessions with the shock contingency discontinued for both punishment groups. Remifentanil delivery was maintained during testing in one punishment group but not the other. RESULTS: Lorazepam reinstated self-administration responding in both punishment groups but not in the extinction group. Priming injections of heroin reinstated responding in both the punishment and extinction groups, but combining heroin and lorazepam did not enhance reinstatement. CONCLUSIONS: This is the first demonstration that a trigger for relapse may have different effects depending on whether aversive conditioning contributed to the achievement of abstinence. It may be important to consider potential anti-punishment effects of both abused drugs and therapeutic agents in the treatment of individuals with a history of drug abuse.

Analgesics, Opioid↗

PubMed2004

Lack of adenosine A1 and dopamine D2 receptor-mediated modulation of the cardiovascular effects of the adenosine A2A receptor agonist CGS 21680.

Some behavioral and biochemical effects of the systemically administered adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) in rats are potentiated by adenosine A(1) receptor agonists and counteracted by dopamine D2 receptor agonists. In the present study we compared potentiating and antagonistic interactions between CGS 21680 and adenosine A(1) and dopamine D2 receptor agonists on motor activity and on cardiovascular responses (arterial blood pressure and heart rate). The motor-depressant effects produced by CGS 21680 (0.5 mg/kg, i.p.) were potentiated by the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA, 0.3 mg/kg, i.p.) and counteracted by the dopamine D2 receptor agonist quinpirole (0.5 mg/kg, i.p.). In contrast, neither CPA nor quinpirole significantly modified the decrease in arterial pressure or the increase in heart rate induced by CGS 21680. However, the adenosine A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3, 3 mg/kg, i.p.) counteracted both the motor-depressant and cardiovascular effects of CGS 21680. Therefore, the effects of the systemically administered adenosine A(2A) receptor agonist CGS 21680 on cardiovascular function, in contrast to its effects on motor behavior, appear to be independent of the effects of adenosine A(1) and dopamine D2 receptor activity.

Adenosine↗

PubMed2004

Chronic methamphetamine increases fighting in mice.

A propensity for violent behaviors to develop in chronic methamphetamine (METH) abusers has been noted. The idea that increased aggressiveness might result from chronic METH administration was tested in mice after chronic (long-term intermittent, 8 weeks) or single exposures to the drug. A single injection of METH (6 mg/kg) did not augment fighting. In contrast, chronic METH administration significantly increased the number of animals that initiated bite attacks. This regimen also shortened the latency before the first attack. Latency before the first attack was shorter at 20 h after the METH injection than at 15 min after injection. Locomotor activity was not different at 20 h after METH injection, indicating that increased fighting was not secondary to METH-induced hyperactivity. METH-induced increases in fighting were not related to the duration of persistent sniffing after the initial encounter with an intruder since the duration of this behavior was significantly increased at 15 min after METH but not at 20 h post drug. These results indicate that repeated injections of METH can increase fighting behaviors and also alter social interactions in mice. Thus, intermittent administration of METH might be useful as a pharmacological model to study the biochemical and molecular bases of aggressiveness.

Aggression↗

PubMed2003

Reduced cardiovascular effects of methamphetamine following treatment with selegiline.

Selegiline is a specific MAO-B inhibitor. As MAO-B has been shown to be significantly involved in the metabolism of dopamine in certain regions of the primate brain, selegiline has been proposed for use in the treatment of drug addiction. Selegiline is also metabolized in vivo to l-methamphetamine. Therefore, when given in combination with psychostimulants such as d-methamphetamine, there is the potential for adverse effects. To study this possibility, squirrel monkeys were treated with chronic selegiline and tested with two doses of d-methamphetamine (0.1 and 1.0 mg/kg, i.v.). Following at least 7 days of treatment with once daily 0.3 mg/kg i.m. selegiline, the effects of methamphetamine on blood pressure and heart rate were no different than the effects of methamphetamine observed prior to selegiline treatment. However, following at least 10 days of treatment with 1.0 mg/kg i.m. selegiline, the effects of methamphetamine on blood pressure and heart rate were significantly reduced. Both methamphetamine and amphetamine were detected in plasma following chronic selegiline treatment. When monkeys were given an acute selegiline injection prior to methamphetamine, reduced cardiovascular effects were also seen. These results indicate that selegiline can be used safely even in combination with methamphetamine, as the cardiovascular effects of the drug combination were no greater than either drug alone, and were actually reduced at the higher selegiline dose.

Animals↗

PubMed2003

Abuse liability and stimulant properties of dextromethorphan and diphenhydramine combinations in rats.

RATIONALE: The abuse of over-the-counter (OTC) medications has been widely reported. However, there are few preclinical studies examining the behavioral effects of OTC medications at higher, abused doses. OBJECTIVES: The objectives of the current study were to determine whether the anti-histamine diphenhydramine (DIP) and the antitussive dextromethorphan (DEX), either alone or in combination, would have stimulant properties and be self-administered in animals. METHODS: For drug self-administration, naive rats with no history of exposure to other drugs were trained to self-administer i.v. DEX+DIP (0.5+0.5, 1+1 or 2+2 mg/kg per injection), DEX alone (1 mg/kg) or DIP (1 mg/kg) alone under five-response fixed-ratio (FR) schedule with a 30-s time-out after each injection in 2-h sessions 3-5 days a week. Separate groups of rats were tested on locomotor activity. After 8 consecutive days of habituation, naive rats were injected with 3, 10, or 30 mg/kg DEX or DIP alone i.p., or in combination of 3+3 mg/kg, 10+10 mg/kg, or 30+30 mg/kg DEX+DIP i.p. Saline was injected i.p. during the intervening days. Locomotor activity was measured for each session. RESULTS: DEX+DIP combinations were self-administered, but the drugs alone were not. The acquisition of DEX+DIP self-administration was rapid with a majority of rats reaching the final FR5 schedule in 22-23 sessions. The total i.v. combination dose for each final scheduled session ranged from 40 mg/kg to 160 mg/kg DEX+DIP. Significant increases in locomotor activity were observed for DIP, an effect that was significantly enhanced when DIP was given in combination with DEX. Significant mortality was also observed for the drug combination at each dose tested when given i.v., with the highest mortality following the highest dose (2+2 mg/kg). When given i.p., no mortality was observed. CONCLUSIONS: These results show that combinations of DEX and DIP have stimulant properties and are self-administered by animals. Abuse of this combination in humans would be expected.

Animals↗

PubMed2003

Variability of drug self-administration in rats.

RATIONALE: Although temporal patterns of drug self-administration in animals are known to be highly regular, this regularity has rarely been quantified or systematically compared across reinforcers. OBJECTIVES: Over a range of unit doses, this study assessed: (1) the within-subject variability of inter-infusion intervals (latencies); (2) the estimated whole-body drug level at the time of self-infusion; (3) the within-subject variability of these drug levels; and (4) the statistical dependence between successive latencies, to determine whether regularity is maintained by compensatory, moment-to-moment adjustment of latencies. METHODS: Rats were trained with cocaine (10-1000 microg/kg per infusion, IV), remifentanil (an ultra-short acting opioid; 0.25-32 microg/kg per infusion, IV), or food (20-180 mg/delivery). RESULTS: Within subjects, latencies were most consistent from infusion to infusion at unit doses on the descending limb of the dose-response curve. However, the drug level at the time an infusion was initiated was actually least consistent at these doses. Sequential latencies showed only a weak autocorrelation for both drugs. CONCLUSION: These results suggest that highly consistent response patterns are not simply a product of precise titration of drug levels. The weak autocorrelation between sequential latencies suggests that temporal regularity of responding is not maintained through compensatory adjustments of post-infusion pauses.

Analgesics, Opioid↗

PubMed2003

Enabling role of adenosine A1 receptors in adenosine A2A receptor-mediated striatal expression of c-fos.

When striatal neurons are strongly activated they produce adenosine, which activates nearby adenosine A1 receptors (A1Rs) and adenosine A2A receptors (A2ARs). Although the effects of A1R or A2AR activation on neural activity in the striatum have been examined separately, the effects of coactivating both receptors has not been investigated. Using c-Fos immunohistochemistry as an indicator of neural activity, we examined the effects of coactivation of A1Rs and A2ARs on neural activity and their mechanism of interaction in the caudate-putamen, nucleus accumbens (NAc) and prefrontal cortex in rats. Administration of a motor-depressant dose of the A2AR agonist CGS 21680 (0.5 mg/kg i.p.) did not significantly induce c-fos expression in any of these brain regions. Administration of a motor-depressant dose of the A1R agonist CPA (0.3 mg/kg, i.p.) produced a small but significant induction of c-fos expression only in the shell of the NAc. Coadministration of CGS 21680 and CPA produced a synergistic induction of c-fos expression in the caudate-putamen, cingulate cortex, and especially the NAc. In the shell of the NAc administration of CPA significantly decreased extracellular dopamine levels measured by in vivo microdialysis and blocked CGS 21680-induced increases in dopamine levels. Because it has been previously shown that activation of dopamine D2 receptors (D2Rs) by endogenous dopamine blocks A2AR-mediated c-fos expression, it is hypothesized that the enabling role of A1Rs in A2AR-mediated striatal c-fos expression is related to the A1R-mediated inhibition of dopamine release.

Adenosine↗

PubMed2003

Stimulus control of cocaine self-administration.

Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior.

Animals↗

PubMed2002

Reinstatement of punishment-suppressed opioid self-administration in rats: an alternative model of relapse to drug abuse.

RATIONALE: Animal models of relapse to drug abuse typically assess the ability of various manipulations to reinstate responding that has ceased due to non-reinforcement (extinction). However, there is a lack of information concerning the reinstatement of responding that has ceased for reasons other than extinction. OBJECTIVES: This study examined the ability of response-independent reinforcer delivery (priming) to reinstate food- or drug-reinforced responding that had been suppressed by response-contingent footshock (punishment). METHODS: Nose-poke responding by separate groups of rats was reinforced with food (45 mg/delivery) or intravenous remifentanil (4 micro g/kg per infusion), a short-acting micro -opioid agonist. After either 3 or 27 days of training (with 100 reinforcers/day), a punishment contingency was introduced that rapidly suppressed responding. Then, the punishment contingency was discontinued, and half the rats received priming. RESULTS: Priming by non-contingent delivery of food or remifentanil significantly reduced the number of sessions required for responding to resume. There were no significant differences in this effect between short-term and long-term training or between food- and drug-trained groups. CONCLUSIONS: Self-administration responding that has been suppressed by punishment can be reinstated by priming, and it can eventually resume even without priming. Under the conditions studied here, priming after punishment had effects qualitatively similar to those typically seen after extinction. This punishment/reinstatement procedure may be useful for comparing the effects of other manipulations known to affect behavior in the extinction/reinstatement model of relapse.

Analgesics, Opioid↗

PubMed2002

Second-order schedules of drug self-administration in animals.

On a second-order schedule, a subject responds according to one schedule (the unit schedule) for a brief presentation of a stimulus such as a light. Responding by the subject on this unit schedule is then reinforced according to another schedule of reinforcement. Second-order schedules of drug injection allow the study of more complex behavioral sequences than do simple schedules and may more accurately reflect the human drug-abuse situation. Much of the early work in this area used primates as subjects and focused on the behavioral variables controlling responding. It was shown that long sequences of behavior could be maintained on second-order schedules with relatively infrequent injections of drug and that the second-order, brief-stimulus presentations were critical to the acquisition and maintenance of responding. Also, the continued presentation of the brief stimulus in extinction often led to prolonged extinction behavior. These studies clearly showed that environmental stimuli greatly influence drug self-administration behavior under second-order schedules. The focus of much of the more recent work with second-order schedules has been on the evaluation of pharmacological treatments for drug addiction, both as antagonist and substitution therapies. Both types of potential therapies have shown promise in these preclinical models of addictive behavior. The recent extension of second-order self-administration studies to rats as subjects has facilitated the investigation of neural mechanisms involved in this behavior. While this use of second-order schedules is a relatively recent phenomenon, significant contributions have already been made in identifying neural mechanisms critical to second-order schedule drug self-administration. This active area of research holds great promise for delineating specific brain regions critical to different aspects of drug addiction.

Animals↗