Connections Between Interval Timing Neuropharmacology And Drug Abuse

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Drugs that increase the effective level of dopamine in the brain, such as cocaine and methamphetamine, are among the most commonly abused drugs today (Stahl, 2000). The connection between interval timing and drug abuse comes from the fact that dopaminergic drugs cause predictable distortions in timing and time perception. The dopamine agonist, methamphetamine, causes a leftward shift in psychophysical timing functions that is proportional in size to the duration of the interval being timed (e.g., Meck, 1983, 1996). This result is compatible with the hypothesis that increasing the effective level of dopamine in the brain causes an increase in the speed of the pacemaker or oscillatory processes used for timing: if the pacemaker is caused to run faster than when a time interval was first learned, then participants will think that feedback is due earlier than it actually is, and consequently timing functions will be horizontally shifted to the left.

Genetic modifications of the dopamine system can be made in various ways, including the deletion of the gene coding for the dopamine reuptake transporter (DAT), which leads to an increase in the synaptic levels of dopamine. The DAT mediates uptake of dopamine into neurons and is a major target for cocaine and amphetamine (e.g., Carboni et al., 2001). Since its cloning, much information has been obtained regarding the structure and function of the DAT. Binding domains for dopamine and various blocking drugs (e.g., cocaine) are likely formed by interactions with multiple amino acid residues, some of which are separate in the primary structure, but lie close together in the still unknown tertiary structure. The DAT gene is expressed only in the central nervous system within a small subset of neurons (i.e., dopamine-containing neurons) and not in glia cells. DAT expression is more restricted, for instance, than the expression of genes encoding dopamine biosynthetic enzymes (e.g., tyrosine hydroxylase and aromatic amino acid decar-boxylase) or dopamine receptors. DAT therefore provides an excellent marker for most dopamine neurons and their projections. In the rodent, DAT mRNA is found in great abundance within midbrain dopamine neurons of the substantia nigra, with somewhat lower expression in the ventral tegmental nuclei and adjacent nuclei. Within the hypothalamus, DAT is expressed within the A13 (zona incerta) and, to a lesser extent, the A14 (periventricular) and A12 (arcuate nucleus) cell groups, but not other tyrosine hydroxylase-positive cell groups. Moderate DAT expression is also seen in the A16 cell group of the olfactory bulb. DAT mRNA is not found in regions devoid of dopamine cell bodies or within dopamine nerve terminals. The major sites of DAT expression correspond well with the brain regions known to be involved in interval timing (Gibbon et al., 1997).

Gene-dosage effects of the DAT can be observed. Wild-type mice (+/+) have a normal (100%) level of the DAT. There is 50% expression of the DAT in heterozygous mice (+/-) and a total lack of the DAT in homozygous mice (-/-). Dopamine stays in the synapse 100 times longer in -/- mice than in +/+ mice. Mice without the DAT are five to six times more active than wild-type mice and have been used as an animal model of cocaine and amphetamine addiction, attention deficit hyper-activity disorders, and schizophrenia (see Cevik, this volume; Gainetdinov and

Caron, 2001; Gainetdinov et al., 1999, 2001a, 2001b). Recently, mice deficient in the DAT have been shown to have altered timing behavior consistent with the dopaminergic regulation of temporal integration in the seconds-to-minutes range (see Cevik, this volume; Sasaki et al., 2002).

Other molecular mechanisms underlying the role of dopamine in interval timing may be studied using catechol-o-methyltransferase (COMT) deficient mice. Although there are many proteins involved in the biological actions of dopamine, COMT, because it metabolizes released dopamine primarily in the prefrontal cortex may be a critical marker for schizophrenia and cognitive functions such as interval timing (Egan et al., 2001).

It is reasonable to assume that abuse of methamphetamine by humans causes a similar speeding up of the clock to the increases observed in the laboratory with birds and rodents. Given the above evidence that interval timing is important both in the assessment of rate of reinforcement and in classical conditioning, it has been hypothesized that timing distortions could be important in understanding the mind-altering properties of dopaminergic drugs (see Buhusi, this volume; Cevik, this volume; Paule et al., 1999). Other psychoactive substances (e.g., marijuana and its active ingredient tetrahydrocannabinol) have been shown to alter time perception as a function of their effects on cortical and cerebellar blood flow (e.g., Mathew et al., 1998).

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