Eric B. Thorndike

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.

Gender differences in the behavioral effects of methamphetamine

The effects of methamphetamine were tested in male and female rats on two different behavioral tasks. Following habituation to a locomotor activity chamber, female rats were more sensitive to the locomotor activating effect of i.p. methamphetamine (0.1-3.0 mg/kg) than were male rats. A similar effect has been observed for other psychomotor stimulants, including cocaine and amphetamine. However, males and females did not differ on methamphetamine-induced place preference following eight conditioning trials with a wide range of doses (0.1-5.6 mg/kg). These results suggest that males and females differ in their response to methamphetamine for only some behavioral tasks.

Persistent palatable food preference in rats with a history of limited and extended access to methamphetamine self‐administration

Recent studies have shown that when given a mutually exclusive choice between cocaine and palatable foods, most rats prefer the non‐drug rewards over cocaine. Here, we used a discrete choice procedure to assess whether palatable food preference generalizes to rats with a history of limited (3 hours/day) or extended (6 or 9 hours/day) access to methamphetamine self‐administration. On different daily sessions, we trained rats to lever‐press for either methamphetamine (0.1–0.2 mg/kg/infusion) or palatable food (five pellets per reward delivery) for several weeks; regular food was freely available. We then assessed food‐methamphetamine preference either during training, after priming methamphetamine injections (0.5–1.0 mg/kg), following a satiety manipulation (palatable food exposure in the home cage) or after 21 days of withdrawal from methamphetamine. We also assessed progressive ratio responding for palatable food and methamphetamine. We found that independent of the daily drug access conditions and the withdrawal period, the rats strongly preferred the palatable food over methamphetamine, even when they were given free access to the palatable food in the home cage. Intake of methamphetamine and progressive ratio responding for the drug, both of which increased or escalated over time, did not predict preference in the discrete choice test. Results demonstrate that most rats strongly prefer palatable food pellets over intravenous methamphetamine, confirming previous studies using discrete choice procedures with intravenous cocaine. Results also demonstrate that escalation of drug self‐administration, a popular model of compulsive drug use, is not associated with a cardinal feature of human addiction of reduced behavioral responding for non‐drug rewards.

Blocking of conditioning to a cocaine-paired stimulus: Testing the hypothesis that cocaine perpetually produces a signal of larger- than-expected reward

According to a recent account of addiction, dopaminergic effects of drugs like cocaine mimic the neuronal signal that occurs when a natural reward has a larger value than expected. Consequently, the drugs expected reward value increases with each administration, leading to an over-selection of drug-seeking behavior. One prediction of this hypothesis is that the blocking effect, a cornerstone of contemporary learning theory, should not occur with drug reinforcers. To test this prediction, two groups of rats were trained to self-administer cocaine with a nose-poking response. For 5 sessions, a tone was paired with each self-administered injection (blocking group), or no stimulus was paired with injection (non-blocking group). Then, in both groups, the tone and a light were both paired with each injection for 5 sessions. In subsequent testing, the light functioned as a conditioned reinforcer for a new response (lever-pressing) in the non-blocking group, but not the blocking group. Thus, contrary to prediction, pre-training with the tone blocked conditioning to the light. Although these results fail to support a potentially powerful explanation of addiction, they are consistent with the fact that most conditioning and learning phenomena that occur with non-drug reinforcers can also be demonstrated with drug reinforcers.

A stimulus-control account of regulated drug intake in rats

RationalePatterns of drug self-administration are often highly regular, with a consistent pause after each self-injection. This pausing might occur because the animal has learned that additional injections are not reinforcing once the drug effect has reached a certain level, possibly due to the reinforcement system reaching full capacity. Thus, interoceptive effects of the drug might function as a discriminative stimulus, signaling when additional drug will be reinforcing and when it will not.ObjectiveThis hypothetical stimulus control aspect of drug self-administration was emulated using a schedule of food reinforcement.Materials and methodsRats’ nose-poke responses produced food only when a cue light was present. No drug was administered at any time. However, the state of the light stimulus was determined by calculating what the whole-body drug level would have been if each response in the session had produced a drug injection. The light was only presented while this virtual drug level was below a specific threshold. A range of doses of cocaine and remifentanil were emulated using parameters based on previous self-administration experiments.ResultsResponse patterns were highly regular, dose-dependent, and remarkably similar to actual drug self-administration.ConclusionThis similarity suggests that the emulation schedule may provide a reasonable model of the contingencies inherent in drug reinforcement. Thus, these results support a stimulus control account of regulated drug intake in which rats learn to discriminate when the level of drug effect has fallen to a point where another self-injection will be reinforcing.

Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats.

The cardiovascular effects produced by 3,4‐methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.

Discriminative Stimulus Effects of Nicotine and Chronic Tolerance

Tolerance to discriminative stimulus (DS) effects of drugs, as observed by a shift of the dose-response curve to the right, has been observed with many addictive drugs (e.g. amphetamine, cocaine and morphine). Chronic administration of nicotine has been reported to produce tolerance to the locomotor depressant effects and aversive stimulus properties of nicotine; however, the DS effects of nicotine have not been examined for development of tolerance following chronic treatment. We report on experiments utilising a cumulative-dosing drug discrimination paradigm. Eight, male Sprague-Dawley rats were trained to discriminate nicotine (0.4 mg/kg s.c.) from saline under a fixed ratio (FR 10) schedule for food reinforcement. Multiple training sessions were given daily, and once criteria was met, cumulative doses of nicotine (0.025-1.2 mg/kg s.c.) were evaluated. Rats acquired the nicotine discrimination after 80 sessions. During this period, rats developed tolerance to the rate-depressing effects of nicotine after 20 nicotine-training sessions. Chronic treatments of nicotine in the rats home cage for 7 days during suspended training failed to shift the dose-response curve for nicotine. Increasing the frequency to three daily injections also had no effect on nicotine discrimination. Furthermore, continuous infusions of nicotine (6.4 mg/kg/day) delivered via osmotic minipumps failed to shift the dose-response curve. No physical signs of withdrawal were apparent, particularly on lever responding, following removal of the minipump. These results suggest that under the conditions described, chronic tolerance to nicotines DS does not develop readily.

Combined effects of THC and caffeine on working memory in rats

BACKGROUND AND PURPOSE Cannabis and caffeine are two of the most widely used psychoactive substances. Δ9‐Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short‐term memory. Caffeine, a non‐selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory.

Conditioned suppression with cocaine as the unconditioned stimulus.

A conditioned-suppression procedure was used to study drug conditioning using cocaine as the unconditioned stimulus (UCS). Rats were first trained to nose poke for food-reinforcement during daily 60-min sessions. At least 1 week following jugular vein catheterization, a 5-min tone-light compound stimulus was presented 30 min into the food-reinforcement session. Two minutes after the onset of the stimulus, either 0 (saline), 1.0, 3.0 or 5.6 mg/kg cocaine, was administered i.v. to separate groups of rats. For another group, the stimulus was presented, and the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion (i.e., at different times). After 5 days of training a test was given with the tone-light stimulus presented alone. No disruption of responding during the tone-light stimulus was observed in the saline and 1.0 mg/kg cocaine groups or for the unpaired group. When the tone-light stimulus was paired with 5.6 mg/kg cocaine; however, it produced nearly a 50% reduction in responding, which then gradually extinguished when the stimulus was presented alone for 5 days. The 3.0 mg/kg cocaine group produced intermediate suppression. When the tone-light compound stimulus was shortened to 70 s and the interstimulus interval (ISI) was 0, 30, or 60 s in three separate groups of rats, the most robust conditioned suppression was observed at the 60 s ISI. Therefore, the conditioned suppression procedure, using 3.0 or 5.6 mg/kg i.v. cocaine doses as the UCS, produced robust conditioning effects comparable to other drugs and more conventional reinforcers. The conditioned suppression procedure may be a useful model for studying the classically conditioned effects of cocaine.

Pharmacological Mechanisms Underlying the Cardiovascular Effects of the “Bath Salt” Constituent 3,4‐Methylenedioxypyrovalerone (MDPV)

3,4‐Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats.