An investigation of the psychopharmacology of timing behaviour in the rat

Interval timing behaviour refers to the ability of animals and humans to adapt their behaviour to temporal regularities in their environments. Two important classes of interval timing behaviour are temporal discrimination (discriminating between the durations of external events) and temporal differentiation (behavioural adaptation during an ongoing interval). It has been known for many years that drugs that affect central dopaminergic function can alter both forms of timing behaviour. More recently, evidence has been accumulated which shows that manipulation of central 5-hydroxytryptaminergic (5-HTergic) function can also influence interval timing behaviour. The experiments described in this thesis examined the effects of drugs acting at some subtypes of 5-HT receptors on temporal discrimination and temporal differentiation in the rat. Chapter 1 contains a review of the relevant literature. First, the anatomy, biochemistry and receptor pharmacology of the 5-HTergic system is outlined, and a selective review of the role of 5-HT in some behaviours relevant to this project is presented. This is followed by an overview of the behavioural methodology that has been used to study timing behaviour in animals, and an account of the major theories of timing behaviour. Finally, the behavioural pharmacology of timing behaviour is reviewed. Chapters 2-7 describe a series of experiments examining the effects of drugs acting at 5-HT1A, 5-HT2A/2C, and 5-HT3 receptors on temporal discrimination and temporal differentiation. Experiment 1 examined the effect of the 5-HT3 receptor agonist m-chlorophenylbiguanide (m-CPBG) and the non-selective agonist quipazine on temporal discrimination performance in the discrete-trials psychophysical procedure. Quipazine produced a dose-dependent disruption of temporal discrimination, consisting of a rightward displacement and flattening of the fitted psychometric function, reflected in a significant increase in the values of the indifference point T50 and the Weber fraction. m-CPBG had no significant effect on either T50 or the Weber fraction. The effects of quipazine were completely abolished by the 5-HT2A receptor antagonist ketanserin, but not by the 5-HT3 receptor antagonist topanyl 3,5-dichlorobenzoate (MDL-72222), indicating that the effect of quipazine was mediated by 5-HT 2A, and not 5-HT 3 receptors. In experiment 2, the effects of quipazine and m-CPBG were examined on temporal differentiation performance in the free-operant psychophysical procedure. Quipazine dose-dependently displaced the psychometric function to the left, reducing the value of T50, and significantly increased the Weber fraction. m-CPBG had no effect on the parameters of the function. The effects of quipazine were reversed by co-administration of ketanserin, but not by co-administration of MD L-72222. These results suggest that while 5-HT 2A receptor stimulation has a robust influence on temporal differentiation, 5-HT3 receptor stimulation does not. Experiment 3 further examined the effect of 5-HT2A receptor stimulation on temporal discrimination. The 5-HT 2A/2C receptor agonist 2,5- dimethoxy-4-iodoamphetamine (DOI) increased the Weber fraction and tended to increase T50. Ketanserin and the highly selective 5-HT2A receptor antagonist (± )2,3-dimethoxyphenyl-1-(2-( 4-piperidine )-methanol) (MDL-I00907) fully antagonized the effects of DOI The results indicate that DOI disrupts temporal discrimination via stimulation of 5-HT2A receptors. Experiment 4 examined whether intra-striatal injection of DOI would affect temporal discrimination, and whether the effect of systemically administered DOI on temporal discrimination would be blocked either by MDL-100907 or by 8-( 5 -(2, 4-dimethoxy-5 -( trifluoromethylphenylsulphonamido )phenyl-5-oxopentyl)-1 ,3,8- riazaspiro( 4.5)decane-2,4-dione RS- 102221: a selective 5-HT2C receptor antagonist), administered directly into the dorsal striatum. Intra-striatal injection of DOI did not affect temporal discrimination. Systemically administered DOI disrupted temporal discrimination; this effect was not attenuated by intra-striatal injection of MDL-100907 or RS102221, suggesting that the 5-HT2 receptors that mediate DOI's effect on temporal discrimination are not located in the dorsal striatum. Experiments 5 and 6 examined the effects of intra-striatally administered DOI, MDL-100907 and RS-102221 on temporal differentiation. In experiment 5, systemic injection of DOI significantly reduced T50. This effect was antagonized by systemically administered MDL-100907. In experiment 6, intra-striatally administered DOI had no significant effect on T50 or the Weber fraction. Intra-striatal injections of MDL-100907 and RS-102221 did not alter temporal differentiation, and failed to reverse the effects of systemically administered DOI. The results suggest that the 5-HT2 receptor population responsible for DOI’s effect on temporal differentiation is not located in the dorsal striatum. Experiment 7 examined the effect of a 5-HT1A and a 5-HT2A receptor agonist on another widely-used temporal differentiation schedule, the fixed interval peak procedure. The 5-HT1A receptor agonist 8-hydroxy-2-( di-n-propylamino) tetralin (8-0H-DPAT) and the 5-HT2A/2C receptor agonist DOI had similar effects on performance: both agonists displaced the peak function to the left and reduced the peak time, tpeak. The effect of 8-0H-DPAT was antagonized by the selective 5-HT1A receptor antagonist N-[2-( 4-[2-methoxyphenyl]- 1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY- 100635), and the effect of DOI by the 5-HT2A receptor antagonist ketanserin, respectively. These results, taken together with previous findings with the free-operant psychophysical procedure, suggest that 5-HT1A and 5-HT2A receptors mediate similar effects on temporal differentiation. The final chapter (Chapter 8) summarizes the findings from the project, and discusses their implications for the putative role of 5-HT in interval timing and for current theoretical accounts of timing. It is argued that current models of timing behaviour that assume the existence of a unitary 'pacemaker-driven' internal clock may have difficulty accommodating the finding that the same drug can have qualitatively different effects on temporal discrimination and temporal differentiation. Some possible directions for future research in this area are also discussed.