cp-94253 and Cocaine-Related-Disorders

The 5-HT. We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA.. Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21-60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions).. Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion.. CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT

Topics: Animals; Cocaine; Cocaine-Related Disorders; Cues; Female; Locomotion; Male; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Recurrence; Reinforcement, Psychology; Self Administration; Serotonin 5-HT1 Receptor Agonists; Time Factors

Studies examining serotonin-1B (5-HT1B) receptor manipulations on cocaine self-administration and cocaine-seeking behavior initially seemed discrepant. However, we recently suggested based on viral-mediated 5-HT1B-receptor gene transfer that the discrepancies are likely due to differences in the length of abstinence from cocaine prior to testing. To further validate our findings pharmacologically, we examined the effects of the selective 5-HT1B receptor agonist CP 94,253 (5.6 mg/kg, s.c.) on cocaine self-administration during maintenance and after a period of protracted abstinence with or without daily extinction training. We also examined agonist effects on cocaine-seeking behavior at different time points during abstinence. During maintenance, CP 94,253 shifted the cocaine self-administration dose-effect function on an FR5 schedule of reinforcement to the left, whereas following 21 days of abstinence CP 94,253 downshifted the function and also decreased responding on a progressive ratio schedule of reinforcement regardless of extinction history. CP 94,253 also attenuated cue-elicited and cocaine-primed drug-seeking behavior following 5 days, but not 1 day, of forced abstinence. The attenuating effects of CP 94,253 on the descending limb of the cocaine dose-effect function were blocked by the selective 5-HT1B receptor antagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating 5-HT1B receptor mediation. The results support a switch in 5-HT1B receptor modulation of cocaine reinforcement from facilitatory during self-administration maintenance to inhibitory during protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medication for treating cocaine dependence.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Extinction, Psychological; Male; Piperidones; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Reinforcement Schedule; Self Administration; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Spiro Compounds; Substance Withdrawal Syndrome; Time Factors

In order to substantiate the concept that cocaine behavioral effects may be influenced by serotonin (5-HT)1B receptors, male Wistar rats were trained to self-administer cocaine intravenously (0.5 mg/kg/injection), and were systemically pretreated with the selective 5-HT1B receptor antagonist N-[3-[3-(dimethylamine)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641), or with the agonist 5-propoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) before test session during the maintenance phase. The effects of the 5-HT1B receptor ligands on a control reinforcer (food)-induced self-administration and on basal locomotor activity were also assessed. SB 216641 (2.5-7.5 mg/kg) was inactive in altering the cocaine (0.5 mg/kg/injection)-maintained responding and at the highest dose (7.5 mg/kg) it did not alter the self-administration of a cocaine dose on the descending limb of the cocaine (0.125-0.5 mg/kg/injection) dose-effect function. On the other hand, CP 94253 (2.5-7.5 mg/kg) attenuated the cocaine (0.5 mg/kg/injection)-maintained responding with a significant inhibitory effect seen at 7.5 mg/kg, while its doses of 2.5-5 mg/kg potently reduced the self-administration of cocaine (0.125-0.25 mg/kg/injection), in a manner similar to the effect produced by increasing the unit dose of cocaine. The inhibitory effects of CP 94253 (5 mg/kg) on the cocaine (0.125 or 0.25 mg/kg/injection) self-administration were blocked by SB 216641 (7.5 mg/kg). Food reinforcing potential was not altered when either SB 216641 or CP 94253 was given in a dose range between 2.5-7.5 mg/kg. Moreover, none of the 5-HT1B receptor ligands altered horizontal locomotor activity while CP 9253 significantly reduced vertical activity. Our present findings extend previous observations that tonic activation of 5-HT1B receptors is not required for cocaine reinforcement while pharmacological stimulation of 5-HT1B receptors enhances such a property of the psychostimulant. Furthermore, we demonstrated that 5-HT1B receptor agonist-induced enhancement of cocaine reward was independent of an alteration in natural reinforcement.

Topics: Animals; Behavior, Animal; Benzamides; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Eating; Injections, Intravenous; Ligands; Male; Motor Activity; Oxadiazoles; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Reinforcement Schedule; Reward; Self Administration; Serotonin Antagonists; Serotonin Receptor Agonists

Recent studies have shown that antagonists of serotonin (5-HT)1B receptors attenuate cocaine-induced locomotor hyperactivity, whereas agonists enhance reinforcing and discriminative stimulus effects of the psychostimulant. The present study was designed to determine how 5-HT1B receptor ligands affected the development or the expression phase of sensitization to the cocaine-induced locomotor response in rats. In Experiment 1, rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either saline, GR 127935 (5-HT1B antagonist), CP 94,253 (5-HT1B agonist) or GR 127935 + CP 94,253. On day 10, they received a challenge dose of cocaine (10 mg/kg). In Experiment 2, animals received either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with saline, GR 127935, CP 94,253 or GR 127935 + CP 94,253, on day 10. In Experiment 3, rats received either saline, cocaine or CP 94,253 for 5 days; on day 10 they received challenge doses of CP 94,253 or cocaine. In rats treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was about twice as high as that observed after its first administration. The effect evoked by cocaine challenge was further increased in animals treated repeatedly with CP 94,253 + cocaine, but not with GR 127935 + CP 94,253 + cocaine. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine or GR 127935 + cocaine (Experiment 1). In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently increased when that drug was combined with CP 94,253, but not with GR 127935 + CP 94,253. No difference was observed in the locomotor response of rats challenged with cocaine or GR 127935 + cocaine (Experiment 2). When rats were treated repeatedly with cocaine, a challenge dose of CP 94,253 produced an about threefold increase in the locomotor effect compared to the animals treated likewise with saline (Experiment 3). Our results indicate that 5-HT1B receptors are involved in neither the development nor the expression of sensitization to cocaine-induced locomotor hyperactivity. On the other hand, they also show that pharmacological activation of 5-HT1B receptors enhances both phases of this phenomenon, and that repeated administration of cocaine leads to an increased functional reactivity of these receptors.

Topics: Animals; Cocaine-Related Disorders; Discrimination Learning; Drug Interactions; Drug Tolerance; Male; Motivation; Motor Activity; Oxadiazoles; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The effects of serotonin1B [5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- benzamide (p-MPPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Indoles; Injections, Intraventricular; Male; Oxadiazoles; Piperazines; Pyridines; Pyrroles; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Self Administration; Serotonin Antagonists; Serotonin Receptor Agonists