Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats

Abstract

In this experiment we examined the effect of a serotonin receptor (5-HT1A) agonist and antagonist WAY-100635 (N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received sham lesions. They were trained to press two levers (A and B) in 50-s trials, in which reinforcement was contingent upon responding on A in the first half, and B in the second half, of the trial. Logistic psychophysical curves were fitted to the relative response rate data (percent responding on B, %B), for derivation of timing indices [T50 (time corresponding to %B=50%), slope, Weber fraction] following WAY-100635, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and 300 microg/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200 microg/kg, s.c.) reduced T50 without affecting the Weber fraction. WAY-100635 (300 microg/kg) abolished the effect of 8-OH-DPAT on T50 in both the lesioned and sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala, nucleus accumbens and hypothalamus of the lesioned group were <20% of those in the sham-lesioned group; catecholamine levels were unaffected. The results confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant psychophysical schedule, reducing T50, and indicate that this effect of 8-OH-DPAT is mediated by postsynaptic 5-HT1A receptors.

Effect of quinpirole on timing behaviour in the free-operant psychophysical procedure: evidence for the involvement of D2 dopamine receptors

“…In agreement with previous findings with Stubbs' freeoperant psychophysical procedure (Stubbs 1976;Bizo and White 1994a, b;Chiang et al 1998Chiang et al , 1999Chiang et al , 2000aMachado and Guilhardi 2000;Body et al 2002Body et al , 2003Body et al , 2004Body et al , 2006aCheung et al 2006), response rate on lever A declined, while response rate on lever B increased, as a function of time from trial onset, this being reflected in an increasing percentage of total responding being devoted to lever B (%B) as the trial progressed. The trial duration used in these experiments was 50 s, and the 'transition point', when reinforcer allocation was transferred from lever A to lever B, was 25 s from trial onset.…”

“…Because a single variable-interval 30-s schedule was in operation throughout the standard trials, it might be expected that the value of T 50 would be close to 25 s from trial onset (Bizo and White 1994a, b). However, previous studies using the constrainedswitching version of the free-operant psychophysical procedure that was used in these experiments have generally reported values of T 50 that are considerably shorter than the 'transition point' (Chiang et al 1998(Chiang et al , 1999(Chiang et al , 2000aBody et al 2002Body et al , 2003Body et al , 2004Body et al , 2006aCheung et al 2006). In agreement with these earlier findings, the values of T 50 seen under the vehicle treatment condition in the present experiments ranged between 17.4 and 22.4 s.…”

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors

“…In agreement with previous findings using Stubbs' freeoperant psychophysical procedure (Stubbs 1976;White 1994a, b, 1997;Chiang et al 1998Chiang et al , 1999Chiang et al , 2000aMachado and Guilhardi 2000;Body et al 2002Body et al , 2003Body et al , 2004Body et al , 2006aCheung et al 2006), response rate on lever A declined, while response rate on lever B increased, as a function of time from trial onset, this being reflected in an increasing percentage of total responding being devoted to lever B (%B) as the trial progressed. The absolute rate of responding on lever B tended to decline towards the end of the trial.…”

Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms

“…Performance in the free-operant psychophysical procedure was similar to that seen in previous studies with this schedule (Stubbs 1976;Bizo and White 1994a,b;Chiang et al 1998Chiang et al -2000aMachado and Guilhardi 2000;Body et al 2002Body et al -2004Body et al , 2006aCheung et al 2006), as exemplified by an increasing proportion of responding allocated to lever B (%B) as a function of time from the trial onset. Initial treatment with DOI (0.25 mg kg −1 ) reduced T 50 in the present experiments, which is consistent with previous findings (Body et al 2003(Body et al , 2004(Body et al , 2006a.…”