Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT2C receptor stimulation and 5-HT2A receptor blockade
Highlights
► Amphetamine, cocaine and MK801 increased impulsivity in the 5-CSRT test. ► The 5-HT2C receptor agonist Ro60-0175 reduced this drug-induced impulsive action. ► The 5-HT2A receptor antagonist M100907 reduced this drug-induced impulsive action. ► These drugs did not impair attention, motivation or motor aspects of performance.
Introduction
Brain serotonin function has long been linked to impulsivity in humans and in laboratory animals. Twenty-five years ago Soubrie (1986) proposed a major role for brain 5-HT systems in mediating behavioural inhibition and response control, and specifically hypothesized that lowering 5-HT function leads to increased impulsive behaviour (Soubrie, 1986). Work conducted since then has consistently provided support for a link between impulsivity and 5-HT function but has shown that the nature of this link is complex, and that the initial view that low 5-HT activity induces impulsive behaviour is too simple (Dalley et al., 2008, Dalley et al., 2002, Evenden, 1999a, Evenden, 1999b, Fletcher et al., 2009, Hollander and Rosen, 2000, Pattij and Vanderschuren, 2008, Winstanley et al., 2004a). Two factors in particular seem to contribute to this complicated relationship between serotonergic activity and impulsive behaviour.
The first relates to the fact that impulsivity is not a unitary construct and that 5-HT may play differing roles in different facets of impulsive behaviour (Evenden, 1999b, Winstanley et al., 2004a). For example, serotonergic manipulations seem to have inconsistent effects on impulsive choice, defined operationally as the tendency to choose small immediate rewards over larger but delayed rewards (Winstanley et al., 2004a, Wogar et al., 1993). A second form of impulsivity has been termed impulsive action; implicit in this form of impulsivity is the idea of loss of control over responding, a failure of behavioural inhibition, or acting prior to having all of the necessary information needed to guide responding. The expression of such motorically-based impulsive action seems to be especially susceptible to changes in 5-HT function. Impulsive action is frequently measured in the 5-choice serial reaction time (5-CSRT) test (Dalley et al., 2008, Robbins, 2002). In this task rats earn reinforcement by detecting and correctly responding to brief visual stimuli randomly occurring in one of five spatial locations. Although the 5-CSRT test was developed primarily as a test of visual attention, this task can also measure impulsive action, measured as premature or anticipatory responses that occur after the onset of a trial, but prior to stimulus presentation. Numerous studies have now demonstrated that rats chronically depleted of 5-HT (Harrison et al., 1997a, Harrison et al., 1997b, Winstanley et al., 2003b), or with acute reductions in serotonergic activity arising from the raphe nuclei (Carli and Samanin, 2000) show poor inhibitory control in that they tend to make premature responses before the light stimuli have been presented. Similar findings have been also found in other operant-conditioning based behavioural tasks that require inhibition of prepotent responses (Fletcher, 1993, Fletcher, 1994, Fletcher, 1995).
The second important factor is the type of receptor through which 5-HT acts to modulate neuronal activity, and hence impulsive behaviour. The neuronal effects of 5-HT are mediated through multiple receptor subtypes, which are sub-classified into seven families (Barnes and Sharp, 1999). The 5-HT2 receptor family (5-HT2A/2B/2C receptors) is probably the most studied in terms of impulsive behaviour, and in particular with regard to impulsive action defined as premature responding in the 5-CSRT test. In this test the selective 5-HT2C receptor antagonist SB-242084 (Kennett et al., 1997) increases premature responding (Fletcher et al., 2007, Higgins et al., 2003, Winstanley et al., 2004b), an effect consistent with the effects of global 5,7-DHT lesions. Consistent with this finding activating 5-HT2C receptors reduced premature responding, and this effect is especially noticeable when baseline levels of impulsivity are high, for example when the inter-trial interval is unexpectedly lengthened. In contrast to these effects the 5-HT2A receptor antagonist M100907 reduced premature responding (Carli et al., 2004, Fletcher et al., 2007, Higgins et al., 2003, Winstanley et al., 2004b). Similar results have been found with ketanserin (Passetti et al., 2003, Ruotsalainen et al., 1997), which also blocks 5-HT2A receptors. Collectively these data show that reduced 5-HT function can induce or inhibit impulsive behaviour depending on which 5-HT receptor subtype is involved.
These opposing influences of 5-HT2A and 5-HT2C receptors extend also to other behaviours, and especially to some of the behaviours induced by psychomotor stimulants. Thus, locomotor activity induced by cocaine, amphetamine and methamphetamine is enhanced by 5-HT2C receptor antagonists, but reduced by 5-HT2A receptor antagonists (Filip et al., 2004, Fletcher et al., 2002, Fletcher et al., 2006, Kehne et al., 1996, McCreary and Cunningham, 1999, O’Neill et al., 1999, Steed et al., 2011). 5-HT2C receptor agonists also reduce the locomotor stimulant effects of cocaine (Filip et al., 2004, Grottick et al., 2000) and amphetamine (Marquis et al., 2007). These 5-HT2C receptor ligands also exert bi-directional effects on cocaine self-administration (Fletcher et al., 2002, Grottick et al., 2000), although 5-HT2A receptor antagonists do not seem to affect this behaviour (Fletcher et al., 2002, Nic Dhonnchadha et al., 2009). However the 5-HT2A receptor antagonist M100907 has been reported to attenuate reinstatement of cocaine-seeking behaviour that is induced by re-exposure to cocaine (Fletcher et al., 2002) or cocaine-associated cues (Nic Dhonnchadha et al., 2009); these effects are also observed with 5-HT2C receptor agonists (Fletcher et al., 2004, Fletcher et al., 2008, Grottick et al., 2000).
Another behavioural effect of cocaine and amphetamine is the induction of impulsive action, as seen by increased premature responses on the 5-CSRT test (Cole and Robbins, 1987, van Gaalen et al., 2006). Impulsive action is inhibited by 5-HT2C receptor agonists (Fletcher et al., 2007, Navarra et al., 2008), and by a 5-HT2A receptor antagonist (Fletcher et al., 2007, Higgins et al., 2003), and as described above both types of drugs also reduce some behavioural effects of cocaine and amphetamine. Therefore, the main purpose of the present studies was to examine whether a 5-HT2C receptor agonist Ro60-0175 (Martin et al., 1998, Porter et al., 1999), and a 5-HT2A receptor antagonist M100907 (Kehne et al., 1996) would block impulsive action induce by amphetamine and cocaine. The NMDA receptor antagonist MK801 (dizocilpine) also induces impulsive behaviour (Amitai and Markou, 2010, Grottick and Higgins, 2000). While this response is blocked by M100907 (Higgins et al., 2003), the effect of 5-HT2C receptor stimulation on the behavioural response to MK801 is not known. Therefore we additionally examined the effects of M100907 and Ro60-0175 on performance of the 5-CSRT test following treatment with MK801.
Section snippets
Subjects
Adult male Long-Evans rats (270–320 g) were obtained from Charles River Canada, (Saint-Constant, Quebec). Water was feely available in the home cage. Housing rooms were maintained on a 12 h light–dark cycle with lights on at 7 am. The work conformed to the guidelines of the Canadian Council on Animal Care, and were approved by the CAMH Animal Care Committee.
Apparatus
Testing was conducted in operant-conditioning boxes (Med Associates, St. Albans, VT) measuring 33 cm × 31 cm × 29 cm. The curved, rear
Experiment 1. Dose response effects for amphetamine, cocaine and MK801
Results are shown in Fig. 1 and Table 1, along with the statistical analyses. All three drugs significantly increased the number of premature responses, the main variable of interest for these experiments. The effect was significant at all doses of amphetamine and MK801, but only at the middle dose of cocaine. All drugs reduced the number of trials completed; the highest doses of cocaine and MK801 were especially disruptive, with animals completing about half of the available trials. The
Discussion
In keeping with previous findings, the psychomotor stimulants amphetamine and cocaine, as well as the NMDA receptor antagonist MK801 (dizocipline) increased premature responding measured in rats performing the 5–CSRT test (Cole and Robbins, 1987, Grottick and Higgins, 2000, Higgins et al., 2003, van Gaalen et al., 2006). In all cases the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 reduced these drug-induced increases in premature responding. Both serotonergic
Acknowledgement
This work was supported by an operating grant from CIHR to PJF.
References (68)
- et al.
Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia
Biol. Psychiatry
(2010) - et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999) - et al.
Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal
Behav. Brain Res.
(1989) - et al.
Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry
Pharmacol. Biochem. Behav.
(2008) - et al.
Biochemical and electrophysiological evidence that Ro60-0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors
Brain Res.
(2000) A comparison of the effects of dorsal or median raphe injections of 8-OH-DPAT in three operant tasks measuring response inhibition
Behav. Brain Res.
(1993)Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20 s schedule of food reinforcement
Brain Res.
(1995)- et al.
Differential effects of the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding
Neuropsychopharmacology
(2002) - et al.
Effects of 5-HT depletion in the frontal cortex or nucleus accumbens on response inhibition measured in the 5-choice serial reaction time test and on a DRL schedule
Behav. Brain Res.
(2009) - et al.
Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task
Behav. Brain Res.
(2000)