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Drugs that modulate the effective level of dopamine (DA) in cortico-striatal circuits have been shown to alter the perception of time in the seconds-to-minutes range. How this relationship changes as a function of repeated experience with the reinforcement contingencies and the gradual adaptation of the underlying neural circuits remains unclear.The present study examined the clock-speed enhancing effects of methamphetamine (MAP 0.5 or 1.0 mg/kg, ip) in groups of rats that received different levels of baseline training (20, 60, or 120 sessions) on a 50-s peak-interval (PI) procedure before initial drug administration.A curvilinear relationship was observed such that rats that received either minimal or intermediate levels of training (or=60 sessions) displayed dose- x training-related horizontal leftward shifts in their timing functions, suggesting that the speed of the internal clock was increased. In contrast, rats that had received an extended level of training (or=120 sessions) did not show this "classic" DA agonist curve-shift effect, but instead displayed a dose-dependent disruption of temporal control after MAP administration. A transition from DA-sensitive to DA-insensitive mechanisms is proposed to account for the loss of control of clock speed, as timing behaviors associated with the PI procedure gradually become learned habits through the strengthening of DA-glutamate connections.

Drugs that increase dopamine (DA) transmission have been shown to produce an overestimation of time in duration production procedures as exhibited by horizontal leftward shifts of the psychophysical functions. However, the generality of these results has been inconsistent in the literature.The present report evaluates the effects of five doses of methamphetamine (MAP) (0.5-1.5 mg/kg, i.p.) on two duration production procedures, the single duration peak-interval (PI) procedure and the multiduration tri-peak procedure in rats.We replicated and extended prior results by showing a dose-dependent proportional overestimation of time that was equivalent on both procedures (i.e., subjects behaved as though they expected reinforcement to be available earlier in real time). Single-trials analyses demonstrated that the reduction in peak rate that is often observed after MAP administration is due to an increase in the proportion of trials in which responding occurred at very low rates and without temporal control. However, these low-rate trials were not the source of the leftward shift in the temporal estimates. Rather, we found that the leftward shift of the PI functions was due to proportional changes in the placement of temporally controlled high-rate responding, which is consistent with a DA-mediated alteration in clock speed.

Several lines of evidence suggest that nicotine may be useful in treating the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). The current study was an acute, placebo-controlled double-blind experiment to determine whether nicotine might be useful as an alternative treatment of adults with ADHD symptomatology. Six smokers and 11 nonsmokers who were outpatient referrals for ADHD were diagnosed by DSM-IV criteria. Measures of treatment effect included the Clinical Global Impressions (CGI) scale, Hopkins' symptom check list (SCL-90-R), the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT), the Stroop test, and an interval-timing task. The smokers underwent overnight deprivation from smoking and were given a 21 mg/day nicotine skin patch for 4.5 h during a morning session. The nonsmokers were given a 7 mg/day nicotine skin patch for 4.5 h during a morning session. Active and placebo patches were given in a counter-balanced order approximately 1 week apart. Nicotine caused a significant overall nicotine-induced improvement on the CGI. This effect was significant when only the nonsmokers were considered, which indicated that it was not due merely to withdrawal relief. Nicotine caused significantly increased vigor as measured by the POMS test. Nicotine caused an overall significant reduction in reaction time (RT) on the CPT, as well as, with the smokers, a significant reduction in another index of inattention, variability in reaction time over trial blocks. Nicotine improved accuracy of time estimation and lowered variability of time-estimation response curves. Because improvements occurred among nonsmokers, the nicotine effect appears not to be merely a relief of withdrawal symptoms. It is concluded that nicotine deserves further clinical trials with ADHD.

The effects of clozapine (0.6, 1.2, and 2.4 mg/ kg) and haloperidol (0.03, 0.06, and 0.12 mg/kg) on the timing of 10, 30, and 90-s intervals were characterized in rats. Each drug's effect on timing behavior was assessed following intraperitoneal injections using a variant of the peak-interval procedure. Although haloperidol proportio- nately shifted peak times rightward in a manner consistent with a decrease in clock speed, clozapine exerted the op- posite effect and proportionately shifted peak times left- ward in a manner consistent with an increase in clock speed. These results support the proposal that typical an- tipsychotic drugs such as haloperidol and atypical anti- psychotic drugs such as clozapine exert differential effects on dopaminergic, serotonergic, and glutamatergic systems within the cortex and striatum, two brain regions shown to be crucial for interval timing.

Nicotine has been shown to improve attentiveness in smokers and attenuate attentional deficits in Alzheimer's disease patients, schizophrenics and adults with attention-deficit/hyperactivity disorder (ADHD). The current study was conducted to determine whether nicotine administered via transdermal patches would improve attentiveness in non-smoking adults without attentional deficits. The subjects underwent the nicotine and placebo exposure in a counterbalanced double-blind manner. Measures of treatment effect included the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT) of attentiveness and a computerized interval-timing task. The subjects were administered a 7 mg/day nicotine transdermal patch for 4.5 h during a morning session. Nicotine significantly increased self-perceived vigor as measured by the POMS test. On the CPT, nicotine significantly decreased the number of errors of omission without causing increases in either errors of commission or correct hit reaction time. Nicotine also significantly decreased the variance of hit reaction time and the composite measure of attentiveness. This study shows that, in addition to reducing attentional impairment, nicotine administered via transdermal patches can improve attentiveness in normal adult non-smokers.