Contrasting interactions of pipradrol, d-amphetamine, cocaine, cocaine analogues, apomorphine and other drugs with conditioned reinforcement

144

Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an a-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of a-1 adrenoceptors, b-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.

Section: Discussionmentioning

confidence: 55%

Methylphenidate Disrupts Social Play Behavior in Adolescent Rats

Vanderschuren

Trezza

Griffioen-Roose

et al. 2008

144

“…MDMA is an amphetamine derivative that produces greater release of 5-HT relative to dopamine (Rothman et al, 2001). It is likely that MDMA-induced suppression of responding for a conditioned reinforcer is due to enhanced 5-HT since 5-HT indirect agonist suppress, and dopamine indirect agonist enhance, responding for conditioned reinforcers (Robbins et al, 1983;Fletcher, 1995). Furthermore, the SB 242,084-induced reversal of this effect suggests it is mediated via increased stimulation of 5-HT 2C receptors.…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of 5-HT Receptor Subtypes in Cue and Cocaine Reinstatement of Cocaine-Seeking Behavior in Rats

Burmeister

Lungren

Kirschner

et al. 2003

101

The 5-HT indirect agonist, d-fenfluramine, attenuates cue reinstatement of extinguished cocaine-seeking behavior. To investigate the role of 5-HT receptor subtypes in this effect, we examined whether the attenuation is reversed by either a 5-HT 1A , 5-HT 2A/C , or 5-HT 2C receptor antagonist. We also examined the effects of the antagonists alone on both cue and cocaine-primed reinstatement. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, i.v.) paired with light and tone cues underwent daily extinction sessions during which responding had no consequences. We then examined the effects of WAY 100635 (0-1.0 mg/kg, s.c.), ketanserin (0-10.0 mg/kg, i.p.), or SB 242,084 (0-1.0 mg/kg, i.p.) with and without d-fenfluramine (1.0 mg/kg, i.p.) pretreatment on cue reinstatement. Subsequently, we examined the effects of the antagonists on cocaine-primed (7.5 or 15.0 mg/kg, i.p.) reinstatement. The 5-HT 1A antagonist, WAY 100635, failed to alter cue reinstatement, but attenuated cocaine reinstatement. Conversely, the 5-HT 2A/C antagonist, ketanserin, attenuated cue reinstatement, but failed to alter cocaine reinstatement. The 5-HT 2C -selective antagonist, SB 242,084, did not alter cue or cocaine reinstatement, but was the only drug that reversed the d-fenfluramine-induced attenuation of cue reinstatement. The findings suggest that stimulation of 5-HT 1A receptors plays a critical role in cocaine-primed, but not cue, reinstatement. Furthermore, 5-HT 2A and 5-HT 2C receptors may play oppositional roles in cue reinstatement. The SB 242,084 reversal of the d-fenfluramine attenuation suggests that stimulation of 5-HT 2C receptors inhibits cue reinstatement, whereas the ketanserin-induced attenuation of cue reinstatement suggests that decreased stimulation of 5-HT 2A receptors inhibits this behavior.

“…In contrast, methamphetamine increased both responding and break points even when food was not delivered. The effects of methamphetamine when food was not delivered could be attributed to either (1) a nonspecific enhancement of motor activity, (2) an enhancement of the conditioned-reinforcing effects of the food-paired exteroceptive stimuli (see (Robbins et al, 1983), or (3) an increase in 'hunger' comparable to increasing the level of food deprivation, although this would be unlikely because methamphetamine is generally an appetite suppressant. In contrast, THC and morphine did not increase responding and break points at all when food was not delivered.…”

Section: Figurementioning

confidence: 99%

Motivational Effects of Cannabinoids and Opioids on Food Reinforcement Depend on Simultaneous Activation of Cannabinoid and Opioid Systems

Solinas

Goldberg

2005

162

130

Strong functional interactions exist between endogenous cannabinoid and opioid systems. Here, we investigated whether cannabinoidopioid interactions modulate motivational effects of food reinforcement. In rats responding for food under a progressive-ratio schedule, the maximal effort (break point) expended to obtain 45 mg pellets depended on the level of food deprivation, with free-feeding reducing break points and food-deprivation increasing break points. Delta-9-tetrahydrocannabinol (THC; 0.3-5.6 mg/kg intrapeitoneally (i.p.)) and morphine (1-10 mg/kg i.p.) dose-dependently increased break points for food reinforcement, while the cannabinoid CB1 receptor antagonist rimonabant (SR-141716A; 0.3-3 mg/kg i.p.) and the preferential mu-opioid receptor antagonist naloxone (0.3-3 mg/kg i.p.) dose-dependently decreased break points. THC and morphine only increased break points when food was delivered during testing, suggesting that these treatments directly influenced reinforcing effects of food, rather than increasing behavior in a nonspecific manner. Effects of THC were blocked by rimonabant and effects of morphine were blocked by naloxone, demonstrating that THC's effects depended on cannabinoid CB1 receptor activation and morphine's effects depended on opioid-receptor activation. Furthermore, THC's effects were blocked by naloxone and morphine's effects were blocked by rimonabant, demonstrating that mu-opioid receptors were involved in the effects of THC and cannabinoid CB1 receptors were involved in the effects of morphine on food-reinforced behavior. Thus, activation of both endogenous cannabinoid and opioid systems appears to jointly facilitate motivational effects of food measured under progressive-ratio schedules of reinforcement and this facilitatory modulation appears to critically depend on interactions between these two systems. These findings support the proposed therapeutic utility of cannabinoid agonists and antagonists in eating disorders.