Imaging of the brain cannabinoid system.

This review covers two major strategies for imaging of the brain cannabinoid system: autoradiography and in vivo neuroimaging. Cannabinoid receptors can be imaged directly with autoradiography in brain slices using radiolabeled cannabinoid receptor ligands. In addition, the effects of pharmacologic doses of unlabeled cannabinoid drugs can be autoradiographically imaged using indicators of blood flow or indicators of metabolism such as glucose analogs. Although cannabinoid imaging is a relatively new topic of research compared to imaging of other drugs of abuse, autoradiographic strategies have produced high-quality information about the distribution of brain cannabinoid receptors and the effects of cannabinoid drugs on brain metabolism. In vivo neuroimaging, in contrast to autoradiography, utilizes noninvasive techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) to image both the binding and the effects of drugs within living brain. These techniques are well developed; however, in vivo imaging of cannabinoid systems is in a very preliminary state. Early results have been promising yet hard to generalize. Definitive answers to some of the most important questions about cannabinoid drugs and their effects await development of suitable in vivo neuroimaging ligands for cannabinoid systems.

Study of brain uptake and biodistribution of [11C]toluene in non-human primates and mice.

Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain phamacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radio-tracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.

Mechanism of action of methylphenidate: insights from PET imaging studies.

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). We have used Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain. We have shown (a) that oral MPH reaches peak concentration in the brain 60-90 minutes after its administration, (b) that therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT), and (c) that of the two enantiomers that compose MPH, it is d-threo-methylphenidate (d-MPH) and not l-threo-methylphenidate (l-MPH) that binds to the DAT. We have also shown that therapeutic doses of MPH significantly enhance extracellular dopamine (DA) in the basal ganglia, which is an effect that appears to be modulated by the rate of DA release and that is affected by age (older subjects show less effect). Thus, we postulate (a) that MPH's therapeutic effects are in part due to amplification of DA signals, (b) that variability in responses is in part due to differences in DA tone between subjects, and (c) that MPH's effects are context dependent. Because DA enhances task specific neuronal signaling and decreases noise, we also postulate that MPH-induced increases in DA could improve attention and decrease distractibility; and that since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the 'interest it elicits' and thus improving performance.

Non-MAO A binding of clorgyline in white matter in human brain.

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.

Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence.

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [(11)C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12-17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.

Species differences in [11C]clorgyline binding in brain.

[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.

Effects of endogenous neurotransmitters on the in vivo binding of dopamine and 5-HT radiotracers in mice.

Several studies have indicated that the in vivo binding of D(2) receptor positron emission tomography radiotracers can, under some conditions, be influenced by competition with endogenous dopamine. The present study was undertaken to compare the extent to which the in vivo binding in mice of radiotracers to other amine neuroreceptors, namely D(1), 5-HT(2A) and 5-HT(1A) receptors, can also be modulated by neurotransmitter competition. For dopamine radiotracers we examined [3H]raclopride as a D(2) radiotracer and [3H]A69024 as a D(1) radiotracer. Striatal binding of both radiotracers was substantially reduced by administration of the dopamine releaser, amphetamine, although only at a high dose. [3H]raclopride was decreased more than [3H]A69024. Dopamine depletion with 4-hydroxybutyrate strongly increased [3H]raclopride binding but failed to increase [3H]A69024 binding. For 5-HT radiotracers we examined [3H]N-methylspiperone as a 5-HT(2A) radiotracer and [3H]WAY 100635 as a 5-HT(1A) radiotracer. Cortical binding of both radiotracers was unaffected by the 5-HT releaser, p-chloroamphetamine. [3H]WAY 100635 binding was additionally unaffected by 5-HT release with fenfluramine and by 5-HT depletion with p-chlorophenylalanine. In conclusion, of the four radiotracers examined, [3H]raclopride binding to D(2) receptors had greatest sensitivity to changes in endogenous neurotransmitter levels. [3H]A69024 binding to D(1) receptors was affected only by neurotransmitter increases. [3H]N-methylspiperone binding to 5-HT(2A) receptors and [3H]WAY 100635 binding to 5-HT(1A) receptors appeared insensitive to changes in neurotransmitter levels.

[(11)]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy.

Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [(11)C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [(11)C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [(11)C]cocaine.

A consideration of the dopamine D2 receptor monomer-dimer equilibrium and the anomalous binding properties of the dopamine D2 receptor ligand, N-methyl spiperone.

Some discrepancies between experimental results with the two D2 antagonists N-methyl spiperone (NMSP) and raclopride (RAC) have been observed. Among these are the observation that MK-801 increases NMSP binding but not RAC binding: pretreatment with reserpine increases RAC binding but decreases NMSP binding; and that the two ligands yield different values for Bmax. It has been observed that the D2 receptor can exist in both a monomer and dimer form and that a NMSP photolabel ligand binds primarily to the monomer form while a RAC-like photolabel ligand binds both. Using a model of the dimerization in which the equilibrium dissociation constant increases with increasing dopamine (DA) concentration, the free monomer concentration can be shown to go through a maximum value with increasing DA. Using this model with data from a baboon PET study, it can be shown that under certain conditions an increase in binding could be observed. Further research may show that there are clusters of D2 receptors forming oligomers with more than two receptors in which NMSP binds to more sites on clusters with fewer receptors. If increasing DA favors cluster with fewer receptors, an increase in NMSP binding sites may also occur under some circumstances with an increase in DA.

Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer's dementia.

One of the strategies in the treatment of Alzheimer's disease is the use of drugs that enhance cholinergic brain function, since it is believed that cholinergic dysfunction is one of the factors that contributes to cognitive deterioration. Positron emission tomography is a medical imaging method that can be used to measure the concentration, kinetics, and distribution of cholinergic-enhancing drugs directly in the human brain and assess the effects of the drugs at markers of cholinergic cell viability (vesicular transporters, acetylcholinesterase), at muscarininc and nicotinic receptors, at extracellular acetylcholine, at markers of brain function (glucose metabolism and blood flow), and on amyloid plaque burden in vivo in the brains of patients with Alzheimer's disease. In addition, these measures can be applied to assess the drugs' pharmacokinetic and pharmacodynamic properties in the human brain. Since the studies are done in living human subjects, positron emission tomography can evaluate the relationship between the drugs' biological, behavioral, and cognitive effects; monitor changes in brain function in response to chronic treatment; and determine if pharmacologic interventions are neuroprotective. Moreover, because positron emission tomography has the potential to identify Alzheimer's disease during early disease, it can be used to establish whether early interventions can prevent or delay further development.

Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers.

OBJECTIVE: Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to dopamine terminals. The authors evaluated if similar changes occur in humans and assessed if they were functionally significant. METHOD: Positron emission tomography scans following administration of [(11)C]d-threo-methylphenidate (a dopamine transporter ligand) measured dopamine transporter levels (a marker of dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function. RESULTS: Methamphetamine abusers showed significant dopamine transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine transporter reduction was associated with motor slowing and memory impairment. CONCLUSIONS: These results provide evidence that methamphetamine at dose levels taken by human abusers of the drug leads to dopamine transporter reduction that is associated with motor and cognitive impairment. These results emphasize the urgency of alerting clinicians and the public of the long-term changes that methamphetamine can induce in the human brain.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

OBJECTIVE: Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. METHOD: Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. RESULTS: Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. CONCLUSIONS: The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.

Effect of amphetamine-induced dopamine release on radiotracer binding to D1 and D2 receptors in rat brain striatal slices.

The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 microM, reduced [3H]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 microM amphetamine or 3.0 microM methamphetamine. Neither drug produced a significant effect on binding of [3H]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D2 but not D1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [3H]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [3H]raclopride binding by a low (3 microM) amphetamine concentration. At a higher (30 microM) amphetamine concentration the inhibition of [3H]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [3H]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine.

Resting brain metabolic activity in a 4 tesla magnetic field.

MRI is a major tool for mapping brain function; thus it is important to assess potential effects on brain neuronal activity attributable to the requisite static magnetic field. This study used positron emission tomography (PET) and (18)F-deoxyglucose ((18)FDG) to measure brain glucose metabolism (a measure of brain function) in 12 subjects while their heads were in a 4 T MRI field during the (18)FDG uptake period. The results were compared with those obtained when the subjects were in the earth's field (PET scanner), and when they were in a simulated MRI environment in the PET instrument that imitated the restricted visual field of the MRI experiment. Whole-brain metabolism, as well as metabolism in occipital cortex and posterior cingulate gyrus, was lower in the real (4 T) and simulated (0 T) MRI environments compared with the PET. This suggests that the metabolic differences are due mainly to the visual field differences characteristic of the MRI and PET instruments. We conclude that a static magnetic field of 4 T does not in itself affect this fairly sensitive measure of brain activity.

Sensitivity of binding of high-affinity dopamine receptor radioligands to increased synaptic dopamine.

PET and SPECT studies have documented that D2 radioligands of moderate affinity, but not radioligands of high affinity, are sensitive to pharmacological challenges that alter synaptic dopamine levels. The objective of this work was to determine whether the brain kinetics of high-affinity radioligands for dopamine D1 ([(3)H]SCH 23390) and D2 ([(123)I]epidepride) receptors were altered by a prolonged elevation of synaptic dopamine induced by the potent cocaine analog RTI-55. Mice were injected intravenously with radioligands either 30 min after or 4 h before intraperitoneal administration of RTI-55 (2 mg/kg). In separate experiments, the pharmacological effects of RTI-55 were assessed biochemically by measuring uptake of dopamine in synaptosomes prepared from RTI-treated mice and behaviorally by monitoring locomotor activity. Consistent with the expected elevation of synaptic dopamine, RTI-55 induced a long-lasting decrement in dopamine uptake measured ex vivo, and a prolonged increase in locomotor activity. RTI-55 injected prior to the radioligands induced a significant (P < 0.05) increase in striatal concentration of [(123)I]epidepride at 15 min, relative to saline-treated controls, but there were no differences between the two groups at later time-points. For [(3)H]SCH 23390, both initial striatal uptake and subsequent clearance were slightly increased by preadministration of RTI-55. Administration of RTI-55 4 h after the radioligands (i.e., when it was presumed that a state of near equilibrium binding of the radioligands had been reached), was associated with a significant reduction of striatal radioactivity for both radiotracers. Our results are consistent with increased competition between dopamine and radioligand for binding to both D1 and D2 receptors after treatment with RTI-55. We suggest that the magnitude of the competition is reduced by failure of the receptor binding of high-affinity radioligands to rapidly attain equilibrium.

Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281.

The goals of this study were to examine the relationship between intravenous doses of the cannabinoid CB1 receptor antagonist AM281 (N-(morpholin-4-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and the degree of occupancy of this receptor, and to relate occupancy to the ability of this compound to antagonize the sedative effects of the cannabinoid receptor agonist WIN 55,212-2. Occupancy was determined by measuring the ability of intravenous doses of AM281 to inhibit in vivo binding of [(131)I]AM281 in brain areas, and locomotor activity was assessed by measuring the rate of beam crossings in a photocell apparatus. As previously documented, WIN 55,212-2 (1 mg/kg, i.v.) significantly reduced locomotor activity at early times after administration. Co-injection of AM281 (0.3 mg/kg i/v) and WIN 55, 212-2 restored the rate of beam crossings to that seen on injection of vehicle. In addition, AM281 (0.3 mg/kg i/v) approximately doubled locomotor activity between 60-120 min when injected alone. The IC(50) value for displacement of [(131)I]AM281 by AM281 was 0.45 mg/kg. These observations confirm earlier indications that AM281 is a CB1 receptor antagonist or inverse agonist and suggest the existence of an endogenous cannabinoid tone that moderates exploratory locomotor activity.

Cannabinoid receptor-mediated inhibition of acetylcholine release from hippocampal and cortical synaptosomes.

In previous studies cannabinoid agonists have been found to inhibit and cannabinoid antagonists to enhance electrically-evoked [(3)H]-acetycholine (ACh) release in hippocampal slices. The present study was undertaken to determine if similar cannabinoid effects could be observed in synaptosomes. [(3)H]-ACh release was evoked by two methods, both sensitive to presynaptic receptor effects. The first involved the addition of 1.3 mM calcium following perfusion with calcium-free Krebs and the second the addition of 11 mM potassium following perfusion with normal Krebs. In hippocampal synaptosomes the 1.3 mM calcium-evoked release and the high potassium-evoked [(3)H]-ACh release were inhibited by the cannabinoid agonist, WIN 55212-2, by 59 and 39%, respectively, and with an EC(50) of approximately 1 nM. WIN 55212-2 produced a similar, although less potent, inhibition of [(3)H]-ACh release in cortical synaptosomes. No inhibitory effect of WIN 55212-2 on [(3)H]-ACh release in striatal synaptosomes was observed, supporting previous data collected in this area with brain slices. The cannabinoid antagonist, SR 141716A, produced a robust enhancement of 1.3 mM calcium-evoked [(3)H]-ACh release in hippocampal synaptosomes (EC(50)<0.3 nM) but had no effect on potassium-evoked release or on [(3)H]-ACh release in the cortex or striatum. In conclusion our data demonstrates the inhibitory effects of WIN 55212-2 observed on ACh release in brain slices can be observed in hippocampal and cortex synaptosomes, suggesting a direct action of these compounds on the synaptic terminals. The SR 141716A-induced enhancement of ACh release can similarly be observed in hippocampal synaptosomes and is probably due to an inverse agonist action at constitutively active receptors.

Comparison between intraperitoneal and oral methylphenidate administration: A microdialysis and locomotor activity study.

The therapeutic and stimulant properties of methylphenidate (MP), a drug commonly prescribed for the treatment of attention deficit hyperactivity disorder, have been attributed to increases in synaptic dopamine (DA) concentrations resulting from the blockade of DA transporters. In addition to obvious difficulties inherent in any interspecies comparison, interpretation of preclinical studies done with MP is further complicated by different routes of administration in animals (i.v. and i.p.) compared with humans (oral). In the present study we compared the effects of i.p. and intragastric (oral) MP both on rat nucleus accumbens DA assessed by in vivo microdialysis and on locomotor activity measured in a photocell apparatus. We also compared regional brain uptake and plasma levels of [(3)H]MP after administration of 5 mg/kg via both routes. Intraperitoneal MP (5 and 10 mg/kg) was approximately twice as potent as intragastric MP in terms of increasing extracellular DA levels and in stimulating locomotion. This was consistent with the higher brain uptake of [(3)H]MP when given i.p. rather than intragastrically. The dose of 2 mg/kg produced significant increases in both measurements when administered i.p., but not intragastrically. This study shows that relatively low doses of MP (2 mg i.p. and 5 mg intragastric) significantly increase extracellular DA and locomotor activity and indicates that the differences in the neurochemical and behavioral effects of MP between the intragastric and the i.p. routes are due to central drug bioavailability.

Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain.

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.