Faculty Bibliography

The route of administration influences the reinforcing effects of cocaine. Here we assessed whether there were differences in the efficacy of cocaine to block the dopamine transporters (major target for cocaine's reinforcing effects), as a function of route of administration. Positron emission tomography and [11C]cocaine, a dopamine transporter radioligand, were used to compare the levels of dopamine transporter blockade induced by intravenous, smoked and intranasal cocaine in 32 current cocaine abusers. In parallel, the temporal course for the self-reports of 'high' were obtained. Cocaine significantly blocked dopamine transporters. The levels of blockade were comparable across all routes of administration and a dose effect was observed for intravenous and intranasal cocaine but not for smoked cocaine. For equivalent levels of cocaine in plasma and DAT blockade, smoked cocaine induced significantly greater self reports of 'high' than intranasal cocaine and showed a trend for a greater effect than intravenous cocaine. The time to reach peak subjective was significantly faster for smoked (1.4+/-0.5 min) than for intravenous cocaine (3.1+/-0.9 min), which was faster than intranasal cocaine (14.6+/-8 min). Differences in the reinforcing effects of cocaine as a function of the route of administration are not due to differences in the efficacy of cocaine to block the dopamine transporters. The faster time course for the subjective effects for smoked than intravenous and for intravenous than for intranasal cocaine highlights the importance of the speed of cocaine's delivery into the brain on its reinforcing effects

Large numbers of in vitro studies and microdialysis studies suggest that dopaminergic regulation of striatal acetylcholine (ACh) output is via inhibitory dopamine D2 receptors and stimulatory dopamine D1 receptors. Questions remain as to the relative predominance of dopamine D2 versus D1 receptor modulation of striatal ACh output under physiological conditions. Using positron emission tomography, we first demonstrate that norchloro[18F]fluoroepibatidine ([18F]NFEP), a selective nicotinic ACh receptor (nAChR) ligand, was sensitive to changes of striatal ACh concentration. We then examined the effect of quinpirole (D2 agonist), raclopride (D2 antagonist), SKF38393 (D1 agonist), and SCH23390 (D1 antagonist) on striatal binding of [18F]NFEP in the baboon. Pretreatment with quinpirole increased the striatum (ST) to cerebellum (CB) ratio by 26+/-6%, whereas pretreatment with raclopride decreased the ST/CB ratio by 22+/-2%. The ratio of the distribution volume of [18F]NFEP in striatum to that in cerebellum, which corresponds to (Bmax/K(D)) + 1 (index for nAChR availability), also showed a significant increase (29 and 20%; n = 2) and decrease (20+/-3%; n = 3) after pretreatment with quinpirole and raclopride, respectively. However, both the D1 agonist and antagonist had no significant effect. This suggests that under physiological conditions the predominant influence of endogenous dopamine on striatal ACh output is dopamine D2, not D1, receptor-mediated

Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. CONCLUSIONS: The blunted response to alcohol in cocaine abusers contrasts with their enhanced sensitivity to benzodiazepines suggesting that targets other than GABA-benzodiazepine receptors are involved in the blunted sensitivity to alcohol and that the toxicity from combined cocaine-alcohol use is not due to an enhanced sensitivity to alcohol in cocaine abusers. The blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers

Extracts of Ginkgo biloba have been reported to reversibly inhibit both monoamine oxidase (MAO) A and B in rat brain in vitro leading to speculation that MAO inhibition may contribute to some of its central nervous system effects. Here we have used positron emission tomography (PET) to measure the effects of Ginkgo biloba on human brain MAO A and B in 10 subjects treated for 1 month with 120 mg/day of the Ginkgo biloba extract EGb 761, using [11C]clorgyline and [11C]L-deprenyl-D2 to measure MAO A and B respectively. A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambdak3, a model term which is a function of the concentration of catalytically active MAO molecules. Ginkgo biloba administration did not produce significant changes in brain MAO A or MAO B suggesting that mechanisms other than MAO inhibition need to be considered as mediating some of its CNS effects

OBJECTIVE: Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. METHOD: Thirty-seven healthy volunteers aged 24-86 years underwent positron emission tomography scans after injection of [(11)C]raclopride to assess dopamine D(2) receptors and [(18)]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D(2) receptors-pixel-by-pixel correlations and correlations in preselected regions of interest-were then compared. RESULTS: D(2) receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D(2) receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). CONCLUSIONS: These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of 'high' in cocaine abusers. In this study, we measured DAT occupancies after intravenous methylphenidate and assessed whether they also were associated with the 'high'. Occupation of DAT by intravenous MP was measured with PET using [11C]cocaine, as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as measure of DAT availability. In parallel, self-reports of 'high' were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED50 of 0.075 mg/kg. DAT occupancies were significantly correlated with the 'high' (p <.03). However, four of the eight subjects, despite having significant levels of DAT blockade, did not perceive the 'high'. Methylphenidate is as effective as cocaine in blocking DAT in the human brain (cocaine ED50 = 0.13 mg/kg), and DAT blockade, as for cocaine, was also associated with the 'high'. However, the fact that there were subjects who despite significant DAT blockade did not experience the 'high' suggests that DAT blockade, although necessary, is not sufficient to produce the 'high'

OBJECTIVES: Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the 'high'. The present experiments were conducted to examine dose-occupancy and dose-effect relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry. METHODS: Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection in mice from the displacement of in vivo binding of [(3)H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus. RESULTS: The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy, previously measured in human and baboons using [(11)C]cocaine or [(11)C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at the same dose and the same degree of dopamine-transporter receptor occupancy. CONCLUSIONS: The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced 'high' in human subjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have very similar psychopharmacological properties