The exact mechanism of action of cocaine responsible for its abuse potential is uncertain. The major biochemical action of cocaine is to inhibit the activity of transporter proteins for noradrenaline (NA), dopamine (DA) and serotonin (5-HT), leading to a non-selective inhibition of monoamine reuptake and thus, the modulation synaptic transmission at both pre- and post-synaptic sites in a variety of brain areas. Previous studies have generally ascribed cocaine's abuse liability and reinforcing effects to the inhibition of DA uptake and the associated enhancement of dopaminergic neurotransmission. However, other studies have examined the ability of 5-HT system to modulate cocaine's reinforcing effects. For example, enhancement of 5-HT neurotransmission through the administration of the 5-HT precursor L-tryptophan or the 5-HT uptake inhibitor fluoxetine has been reported to decrease indices of cocaine self-administration. Conversely, depletion of 5-HT by administration of the selective serotonergic neurotoxin 5,7-DHT increases the apparent reinforcing efficacy of cocaine. These are global manipulations of the serotonergic system, but in order to understand how 5-HT can modulate complex behaviors, it is important to be able to dissect the contribution of individual receptor subtypes to these receptors. Among the 5-HT receptors that are affected by cocaine is the 5-HT1B receptor. Compounds displaying affinity for 5-HT1B receptor partially substitute for the discriminative stimulus effects of cocaine. Also, a series of recent experiments points toward a role of 5-HT1B receptors modulating the activity of DA neurons. Injection of non-selective 5-HT1B receptor agonist into the ventral tegmental area resulted in an increase in DA release in this area. The recently developed transgenic mouse lacking 5-HT1B receptors offers the opportunity to determine the role that this receptor plays in the reinforcing effects of cocaine. This grant proposal is to test the hypothesis that 5-HT1B receptors are mainly implicated in the cocaine's reinforcing efficacy. This hypothesis will be tested through a series of experiments having the following aims: 1. characterization of differential reinforcing efficacy of cocaine between wild-type mice and mice lacking the 5-HT1B receptors. This will be accomplished by testing both counterparts in the cocaine IV self-administration in a progressive ratio (PR) schedule. 2. characterization of the specificity of the reinforcing effects of cocaine in mice lacking the 5-HT1B receptors. This will be accomplished by testing both counterparts in a PR schedule reinforced by food.
| Rocha, B A; Fumagalli, F; Gainetdinov, R R et al. (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1:132-7 |
| Rocha, B A; Odom, L A; Barron, B A et al. (1998) Differential responsiveness to cocaine in C57BL/6J and DBA/2J mice. Psychopharmacology (Berl) 138:82-8 |
