Activation of 5-HT_1B receptors in the nucleus accumbens reduces self-administration of amphetamine on a progressive ratio schedule

Abstract

Brain serotonin interacts with dopamine function in a complex fashion. Previous work from our laboratory showed that activation of 5-HT_1B receptors within the nucleus accumbens attenuates the ability of amphetamine to increase responding for conditioned reinforcement. The primary purpose of these experiments was to determine the impact of 5-HT receptor stimulation, with particular focus on 5-HT_1B receptors in the nucleus accumbens on the reinforcing effect of amphetamine. To this end several experiments determined the effects of injecting 5-HT, and various 5-HT agonists, into the nucleus accumbens on responding for intravenous infusions of amphetamine (60 μg/kg) delivered according to a progressive ratio schedule of reinforcement. Both 5-HT (2.5, 5 and 10 μg) and the selective 5-HT_1B receptor agonist CP93,129 (0.625, 1.25 and 2.5 μg) dose-dependently reduced responding for amphetamine. Injections of 5-HT but not CP93,129 also reduced responding for food under a similar PR schedule. The 5-HT_1A agonist 8-OH-DPAT (5 μg) and the nonselective 5-HT₂ agonist DOI (10 μg) failed to alter amphetamine self-administration. Pretreatment with the selective 5-HT_1B/1D receptor antagonist GR127935 (3 mg/kg) attenuated the ability of 5-HT and CP93,129 to reduce amphetamine self-administration following their injection into the nucleus accumbens. These results extend our previous findings that increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT_1B receptors is particularly important in this regard.

Introduction

The behavioural effects of psychomotor stimulants such as amphetamine include increased locomotor activity and potentiated responding for conditioned reinforcers. Such drugs are also self-administered indicating that they possess primary reinforcing, or rewarding, effects. Experiments involving intracranial microinjections of amphetamine, or dopamine-depleting lesions have demonstrated that these behavioural effects of amphetamine are mediated in large part by increased dopamine neurotransmission in the nucleus accumbens. Infusion of amphetamine into the nucleus accumbens stimulates locomotor activity (e.g., Pijnenburg et al., 1976) and increases responding for conditioned reinforcement (e.g., Taylor and Robbins, 1986, Fletcher, 1995, Fletcher, 1996, Fletcher and Korth, 1999a). Animals will also self-administer amphetamine directly into the nucleus accumbens (Hoebel et al., 1983). All of these behaviours are also blocked by 6-hydroxydopamine-induced depletion of dopamine in the nucleus accumbens Kelly and Iversen, 1976, Lyness et al., 1979, Taylor and Robbins, 1986. While the mesolimbic dopamine system represents the primary neurochemical substrate for mediating the behavioural effects of amphetamine, other neurotransmitters systems interact with dopamine. One such neurotransmitter is 5-hydroxtryptamine (5-HT; serotonin), and a large body of evidence indicates that, in general, 5-HT modulates the activity of dopaminergic systems (see reviews by Kelland and Chiodo, 1996, Saito et al., 1996), although the nature of this modulation is complex depending upon the 5-HT receptor subtype involved (Barnes and Sharp, 1999). Not surprisingly then, the behavioural effects of amphetamine can be altered by treatments which alter 5-HT function.

Amphetamine-stimulated locomotion (Hollister et al., 1976), responding for Conditioned reinforcement (Fletcher, 1995) and intravenous self-administration of amphetamine Porrino et al., 1989, Lyness et al., 1980, Smith et al., 1986 are reduced by systemic administration of indirect agonists of 5-HT neurotransmission including tryptophan, 5-hydroxtryptophan, fenfluramine and fluoxetine. Cocaine self-administration is also reduced by such indirect 5-HT agonists Carroll et al., 1990, McGregor et al., 1993, Richardson and Roberts, 1991. These findings are indicative of a general inhibitory role of 5-HT systems on psychomotor stimulant-induced behavioural effects. However, because of the use of systemic injection of nonselective and indirect 5-HT agonists they do not shed any light on either the neuroanatomical locus of 5-HT modulation of amphetamine effects or the identity of the 5-HT receptor subtypes that may be involved in mediating these effects. With regard to the issue of where in the brain 5-HT may modulate the effects of psychomotor stimulants evidence suggests that the nucleus accumbens may be one important site. Several studies have shown that infusion of 5-HT into this site inhibits the locomotor stimulant effect of amphetamine Carter and Pycock, 1978, Costall et al., 1979, or of dopamine itself (Jones et al., 1981). The ability of amphetamine to potentiate responding for Conditioned reinforcement is also attenuated by 5-HT infusions into the nucleus accumbens (Fletcher, 1996). Data obtained from experiments involving microdialysis have shown that 5-HT acting through multiple receptor subtypes can influence DA levels in the nucleus accumbens and/or dorsal striatum Benloucif and Galloway, 1991, Benloucif et al., 1993, Parsons and Justice, 1993, Saito et al., 1996. However, very few experiments have documented the effects of specific 5-HT receptor agonists injected into the nucleus accumbens on amphetamine-mediated behaviours.

Recently we reported that a selective 5-HT_1B receptor agonist CP93,129 (Macor et al., 1990) reduced the effects of amphetamine on responding for Conditioned reinforcement (Fletcher and Korth, 1999a). A specific action involving 5-HT_1B receptors was further demonstrated by the ability of the 5-HT_1B/1D antagonist GR127935 (Skingle et al., 1996) to block the action of CP93,129. Additionally the nonselective 5-HT₂ agonist DOI and the selective 5-HT_1A agonist 8-OH-DPAT did not alter the effect of amphetamine. All of these results point to an important role for 5-HT_1B receptors in the nucleus accumbens in modulating the activity of amphetamine on responding for Conditioned reinforcement.

Recent experiments have documented changes in drug reinforcement, primarily involving cocaine, following genetic or pharmacological manipulation of 5HT_1B receptor function. Mice lacking the 5-HT_1B receptor gene show enhanced self-administration of cocaine Rocha et al., 1997, Rocha et al., 1998, a finding that is broadly in keeping with the ability of 5-HT_1B agonists injected into the nucleus accumbens to reduce the behavioural effect of amphetamine. In contrast self-administration of cocaine (Parsons et al., 1998), though not amphetamine (Fletcher and Korth, 1999b), is enhanced by systemic injections of 5-HT_1B receptor agonists in a manner consistent with an increase in the reinforcing efficacy of cocaine. Given our findings that 5-HT and 5-HT_1B agonists infused into the nucleus accumbens block the ability of amphetamine to potentiate responding for conditioned reinforcement the aim of the work described here was to determine the effects of these manipulations on amphetamine self-administration. Specifically, we examined the effects of 5-HT, and of CP93,129 in rats self-administering amphetamine on a progressive ratio schedule. The effects of these manipulations on responding for food were also examined in an attempt to define the behavioural specificity of these manipulations.