α‐Adrenoceptor‐Mediated Modulation of 5‐HT₂ Receptor Agonist Induced Impulsive Responding in a 5‐Choice Serial Reaction Time Task

Abstract

The activation of 5-HT 2A receptors has been shown to enhance the probability of premature responding, regarded as a form of motor impulsive behaviour. At the behavioural level, the interaction of a-adrenoceptors and 5-HT 2 receptors has been linked to head twitch behaviour, regarded as an experimental model of compulsive behaviour. The aim was to determine whether the probability of premature responding induced by an excess activation of 5-HT 2A receptors can be modulated by the blockade of a 1 -or a 2 -adrenoceptors. In the experiments, the 5-choice serial reaction time task was used to measure attention and response control of the rats. The experiments assessed the effects of (∫)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) 0.1-0.2 mg/kg subcutaneously, a 5-HT 2A/2C agonist, and prazosin, an a 1 -adrenoceptor antagonist, alone or in combination, on the performance of rats. In an additional experiment to examine the possible role of the a 2 -adrenoceptors, a potent, selective and specific a 2 -adrenoceptor antagonist, atipamezole, was given alone or in combination with DOI. Results showed that DOI increased the probability of premature responses, but it did not affect the choice accuracy. Prazosin (0.1 or 0.3 mg/kg, subcutaneously), given on its own had no effects on probability of responding prematurely, but prazosin (0.3 mg/kg.) was able to attenuate the DOI-induced responding. Atipamezole (0.1 mg/kg, s.c.) did not attenuate the effect of DOI on probability of premature responding. When given at lower doses, DOI (0.03 mg/kg) and atipamezole (0.03 mg/kg) synergistically increased the probability of premature responding, whereas a higher dose of atipamezole (0.3 mg/kg) on its own increased the probability of responding prematurely, but this effect was not additive to that of 0.1 mg/kg DOI. These data indicate that 5-HT 2 receptor activation enhances impulsive responding and this effect can be diminished by the blockade of a 1 -adrenoceptors. Atipamezole, an a 2 -antagonist, enhances the probability of premature responding and shares the mechanism of action with the 5-HT 2 agonist in this respect. These results provide evidence for an interaction between the serotonergic 5-HT 2 receptors and aadrenoceptors in the modulation of response control to the motor impulsivity type of behaviour (premature responding) in addition to that of compulsory behaviour (head shakes) found previously.

Acute Serotonin and Dopamine Depletion Improves Attentional Control: Findings from the Stroop Task

“…These findings are consistent with a number of studies which have also found decreased Stroop interference following tryptophan depletion (Evers et al, 2006;Schmitt et al, 2000). A relationship between serotonin and attentional control is also supported by studies in rats using the 5 choice serial reaction time task (5-CSRTT) in which enhanced premature responses (a measure of failure of behavioral inhibition) have been noted under conditions of increased serotonin neurotransmission (Dalley et al, 2002;Koskinen et al, 2003;Koskinen and Sirvio, 2001), particularly in the infralimbic/prelimbic regions of the medial prefrontal cortex (Dalley et al, 2002). Similarly, it has been found that increased serotonergic function can increase premature responses in a behavioral inhibition task in healthy humans (Del-Ben et al, 2005).…”

The effects of serotonin and/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the three-choice serial reaction time task: a simple and valid model of impulsive action using rats

“…(Puumala et al, 1997;Koskinen et al, 2003). Nevertheless, it is difficult to conclude that the reduction of impulsive-like action observed in the present study is accounted by an increase in noradrenergic neurotransmission due to the blockade of the noradrenaline transporter because this transporter takes up not only extracellular noradrenaline but also dopamine in some specific brain regions such as the medial prefrontal cortex and the nucleus accumbens shell (Carboni et al, 1990;Pozzi et al, 1994;Yamamoto and Novotney, 1998).…”

Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression

“…It has been shown that stimulation of 5-HT 2A receptors facilitates DA release (Bortolozzi et al 2005) and that the impulsivityenhancing effects of DOI were attenuated by DA receptor blockade (Koskinen and Sirvio 2001;Koskinen et al 2003) raising the possibility of a 5-HT 2A -mediated activation of the dopaminergic system underlying deficient impulse control. However, DOI-induced impulsive overresponding seems to involve DA receptors only indirectly since intra-accumbens administration of DOI had no effect on premature responses (Koskinen and Sirvio 2001).…”