Effect of serotonin (5-HT) 1B receptor ligands on cocaine sensitization in rats

Abstract

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.

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

“…The modulation of cocaine-induced behavioural sensitization by 5-HT receptor ligands has been previously observed in mice. 54 For example, 5-HT receptor antagonists [55][56][57][58] inhibit cocaine-induced behavioural sensitization, suggesting that the central 5-HT system plays an important role in this effect.…”

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

“…Modifications in serotonin function may be involved in the processes that underlie "behavioral sensitization" (Cunningham et al, 1992;Filip et al, 2001;Przegalinski et al, 2001). Behavioral sensitization is the enhancement of locomotor hyperactivity and stereotypies demonstrated upon challenge with cocaine during withdrawal from repeated, intermittent cocaine administration (for review, see Vanderschuren and Kalivas, 2000).…”

“…A repeated cocaine treatment regimen of 10 mg/kg/day for 5 days has previously been shown to induce locomotor sensitization when expression is measured 5 days after the last treatment injection Przegalinski et al, 2001). To examine the ability of the 5-HT 2 R ligands to alter acquisition of cocaine sensitization, the ligands were administered before each daily injection of cocaine during the repeated treatment regimen, whereas the ability of the 5-HT 2 R ligands to alter expression of sensitization was determined via administration of the ligands before challenge with cocaine 5 days after the termination of repeated cocaine treatment.…”

Serotonin1BReceptors in the Ventral Tegmental Area Modulate Cocaine-Induced Increases in Nucleus Accumbens Dopamine Levels

“…Several lines of evidence indicate that 5-hydroxytryptamine (serotonin) (5-HT) systems heavily modulate mesolimbic DA activity. Indeed, the VTA receives a dense serotonergic innervation, and serotonergic manipulations in the VTA modulate the behavioral and neurochemical effects produced by cocaine (for review, see Walsh and Cunningham, 1997).A growing body of evidence indicates that 5-HT 1B receptors play an important role in modulating the behavioral, neurochemical, and cellular effects of cocaine Cunningham, 1995, 1997;Parsons et al, 1998Parsons et al, , 1999Rocha et al, 1998;Castanon et al, 2000;Przegalinski et al, 2001). Although the neural mechanisms involved in these processes have not been elucidated, several recent studies implicate the VTA as an important locus for the modulatory influence of 5-HT 1B receptors on cocaine-induced behaviors.…”