Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study.

In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose-dependent increase in dialysate (0.3 mg kg(-1): 999±287%; 0.5 mg kg(-1): 1320±432%; 1.0 mg kg(-1): 2355±1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6±6%; 0.5 mg kg(-1): -16±4%; 1.0 mg kg(-1): -24±2%) as measured with PET. The relationship between amphetamine-induced peak ΔDA and Δ[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction.

Acquisition and baseline performance of working memory tasks by adolescent rhesus monkeys.

Adolescence is a transitional stage of development characterized by protracted refinements in the neural circuits required for adult level proficiency of working memory. Because impaired working memory is a hallmark feature of several psychiatric disorders that have their onset during adolescence, model systems that can be used to assess the maturation of working memory function, and of disease-related risk factors that disrupt its development, are of particular importance. However, few studies have investigated the maturation of working memory in nonhuman primates. Thus in the present study, we adapted two working memory tests that are among the most widely used in human and adult nonhuman primates, for adolescent rhesus monkeys. Using a touch-screen apparatus, monkeys were trained on a spatial delayed-response task to assess spatial working memory and a delayed match-to-sample task to assess object working memory. The results indicate that adolescent rhesus monkeys readily and efficiently acquire the ability to perform touch-screen based, complex tests of working memory. These data establish that distinct components of adult prefrontal cortex-dependent cognitive functions can be effectively modeled and evaluated in adolescent monkeys. As such, this approach should be useful for assessing the influence of environmental risk factors on the protracted maturation of working memory in adolescent macaques.

Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.

Cocaine abusers show impaired performance on cognitive tasks that engage prefrontal cortex. These deficits may contribute to impaired control and relapse in abusers. Understanding the neuronal substrates that lead to these deficits requires animal models that are relevant to the human condition. However, to date, models have mostly focused on behaviors mediated by subcortical systems. Here we evaluated the impact of long-term self-administration of cocaine in the rhesus monkey on cognitive performance. Tests included stimulus discrimination (SD)/reversal and delayed alternation tasks. The chronic cocaine animals showed marked deficits in ability to organize their behavior for maximal reward. This was demonstrated by an increased time needed to acquire SDs. Deficits were also indicated by an increased time to initially learn the delayed alternation task, and to adapt strategies for bypassing a reliance on working memory to respond accurately. Working memory per se (delay dependent performance) was not affected by chronic self-administration. This pattern of cognitive deficits suggests dysfunction that extends beyond localized prefrontal cortical areas. In particular, it appears that temporal cortical function is also compromised. This agrees with other recent clinical and preclinical findings, and suggests further study into addiction related dysfunction across more widespread cortical networks is warranted.

Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use.

Using a model of recreational cocaine consumption, we have determined in four rhesus monkeys the impact of self-administered cocaine on mesolimbic and sensorimotor striatal dopaminergic neurotransmission. The effects of cocaine repeated within a self-administration session and across multiple sessions over a 6 month period were determined by the use of fixed-ratio self-administration and microdialysis procedures. The exposure to cocaine was modest, with at most two 0.5 mg/kg infusions permitted in each weekly session. Within a cocaine self-administration session, acute tolerance to the ability of cocaine to elevate extracellular striatal dopamine was observed. Over a period of 6 months of repeated self-administration, there was a significant increase in the impact of a fixed dose on extracellular dopamine, indicating that neurochemical sensitization to the effects of self-administered cocaine occurs in primates. A pronounced dopaminergic response to noncontingent cocaine was also observed, with no increases in extracellular dopamine in response to an unexpected saline substitution, indicating that the neurochemical response to self-administered cocaine is primarily caused by direct pharmacological effects of the drug rather than by conditioning to external environmental cues. These results highlight the contrast in time-dependent changes in neurochemical responsiveness to cocaine, depending on whether within-session or between-session comparisons are made. They also demonstrate that recreational levels of cocaine consumption can result in neurochemical sensitization, an enduring change in brain function that may contribute to addiction.

Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys.

Studies were conducted to determine the impact of self-administered cocaine on extracellular striatal dopamine in four rhesus monkeys. The extent to which external cue conditioning contributed to the effects of cocaine and whether there is activation of striatal dopaminergic neurotransmission during drug-seeking behavior was also examined. Microdialysis measurements were made at 2 min intervals in sensorimotor (dorsolateral) and mesolimbic (central and ventromedial) striatum. A fixed-ratio schedule of reinforcement was used, with cocaine availability signaled by a visual cue. Studies examined the effects of cocaine or cocaine cues against a drug-free baseline. Large (fivefold to eightfold) increases in extracellular dopamine after a self-administered infusion of 0.5 mg/kg cocaine were quite rapid and matched the time course of reported subjective effects in human laboratory studies. To determine if conditioning to external cues contributed to the cocaine-induced increases, saline was substituted for cocaine in the infusion, leaving all other visual and auditory stimuli unchanged. No increase in extracellular dopamine in either sensorimotor or mesolimbic striatal subdivisions was observed. Extracellular dopamine during extended periods of drug-seeking behavior triggered by a visual cue was determined in both central and ventromedial striatum. This procedure also did not result in any measurable changes in extracellular dopamine. These studies demonstrate rapid and pronounced pharmacological actions of self-administered cocaine. No apparent conditioned component of those actions was associated with external environmental cues, suggesting that cues that trigger drug-seeking behavior in nonhuman primates do not cause conditioned increases in mesolimbic striatal dopamine.

Applications of microdialysis methodology in nonhuman primates: practice and rationale.

This review provides a comprehensive summary of the use of microdialysis procedures in nonhuman primates. Using these methods in primates is feasible, including both the anesthetized and awake preparations. The latter permit neurochemical sampling during complex information processing and behavioral performance. The close homology in structure and function between human and nonhuman primate brain makes using nonhuman primates particularly appealing, and the literature suggests that their use has provided instances of unique insight into brain structure and function. The continued use of these methods in areas such as the neurobiology of addiction, affective disorders, and psychosis will help in our ever-increasing understanding of the complex pathophysiologies of these disorders.

Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence.

RATIONALE: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. OBJECTIVE: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. METHODS: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. RESULTS: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. CONCLUSIONS: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed.

Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus.

Despite substantial differences between species in the organization and elaboration of the cortical dopamine innervation, little is known about the pharmacological response of cortical or striatal sites to antipsychotic medications in nonhuman primates. To examine this issue, rhesus monkeys were chronically implanted with guide cannulae directed at the principal sulcus, medial prefrontal cortex, premotor cortex, and caudate nucleus. Alterations in dopamine release in these discrete brain regions were measured in response to administration of clozapine or haloperidol. Clozapine produced significant and long-lasting increases in dopamine release in the principal sulcus, and to a lesser extent, in the caudate nucleus. Haloperidol did not produce a consistent effect on dopamine release in the principal sulcus, although it increased dopamine release in the caudate. Clozapine's preferential augmentation of dopamine release in the dorsolateral prefrontal cortex supports the idea that clozapine exerts its therapeutic effects in part by increasing cortical dopamine neurotransmission.

Effects of repeated amphetamine treatment on regional GABAA receptor binding.

The present study examined the effects of repeated exposure to amphetamine on GABAA receptor binding in cortical and subcortical areas. The goal of the study was to determine whether changes in specific binding were related to behavioral sensitization. Animals were exposed to either saline (0.3 ml, s.c.; n=12) or d-amphetamine (2.5 mg/kg, s.c.; n=12) for 6 consecutive days and sacrificed after a 14-day withdrawal period. Differences in GABAA receptor binding in these two groups of animals were assessed using the GABAA receptor antagonist [3H]SR 95531. To verify that the preceding treatment regimen led to the development of behavioral sensitization, a separate set of animals (n=8/group) was exposed to the same regimen and challenged with d-amphetamine (2.5 mg/kg, s.c.) after the 14-day withdrawal period. As expected, preexposure to amphetamine led to the development of amphetamine sensitization. There were no differences in GABAA receptor binding in animals preexposed to saline and amphetamine in the prefrontal cortex, caudate-putamen, hypothalamus, or cerebellum. These findings do not provide support for the idea that changes in GABAA receptor binding in the medial prefrontal cortex or various subcortical areas are related to the development of behavioral sensitization.

Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates.

The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (alpha MPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [123I]IBZM and [123I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D2 antagonists, but the affinity of [123I]IBZM (KD-0.4 nM) is lower than that of [123I]IBF (KD 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D2 receptors following amphetamine injection. [123I]IBZM binding to D2 receptors was more affected than [123I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [123I]IBZM, we observed an excellent correlation between reduction of D2 receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with alpha MPT significantly reduced the effect of amphetamine on [123I]IBZM binding to D2 receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain.

Alcohol plus cocaine: the whole is more than the sum of its parts.

Cocaethylene, an active metabolite that arises through hepatic transesterification of cocaine when cocaine and ethanol are used together, shares many neurochemical and pharmacological properties with cocaine. Cocaethylene is similar to cocaine in its properties as an indirect dopamine agonist, and human subjects cannot distinguish its effects from those of cocaine. Cocaethylene, and especially its isopropyl analog, are more selective indirect dopamine agonists than cocaine, with relatively weak potency at the serotonin transporter. Cocaethylene may contribute to the manifestations and consequences of combined cocaine and ethanol use, although its relative importance remains unclear.

Novelty-associated locomotion: correlation with cortical and sub-cortical GABAA receptor binding.

The present study was designed to determine whether variability in GABA (eta-aminobutyric acid)A receptor binding in cortical and subcortical brain regions was correlated with locomotor activity in a novel environment. Twenty four animals were rated for locomotor activity in a novel circular runway. Eight days later, locomotor activity was assessed following 1.5 mg/kg amphetamine sulfate (i.p.). After four to six days, animals were killed and samples were pooled in groups of four animals ranked according to novely locomotor score, and specific binding of the GABAA receptor antagonist [2-(3'-carboxy-2'-propyl)-3-amino-6-p-methoxy phenylpyridazinium bromide] ([3H]SR95531) was determined. Significant negative correlations were seen between specific ([3H]SR95531) binding and novelty induced locomotion in the cingulate and prefrontal cortices, and in the ventral pallidum. A near-significant negative correlation was seen in the striatum. Correlation coefficients between locomotion scores in the novel environment and specific [3H]SR95531 binding were: cingulate cortex, R = -0.91, P = 0.012; prefrontal cortex, R = -0.85, P = 0.032; ventral pallidum, R = -0.85, P = 0.030; striatum, R = -0.73, P = 0.097; and nucleus accumbens, R = -0.09, P = 0.85. The positive correlation between novelty- and amphetamine-induced locomotion was also quite high (R = 0.95, P = 0.004). These results are discussed in terms of their relevance to potential biochemical correlates of drug abuse vulnerability.

Effect of ethanol on extracellular 5-HT and glutamate in the nucleus accumbens and prefrontal cortex: comparison between the Lewis and Fischer 344 rat strains.

The present study investigated the impact of systemic (i.p.) ethanol administration on extracellular levels of serotonin and glutamate in the prefrontal cortex and the nucleus accumbens in Lewis and Fischer 344 rat strains using in vivo microdialysis. At 1.0 g/kg, ethanol elicited a significant increase in nucleus accumbens-dialysate levels of both 5-HT (44% +/- 16, P = 0.002) and glutmate (90% +/- 43, P = 0.009) in Lewis rats. In Fischer rats, there was no increase in 5-HT (6% +/- 7: P = 0.5), and a trend toward an increase in glutamate (88% +/- 46: P = 0.1). The 0.5 and 2.0 g/kg doses did not result in any significant change in extracellular 5-HT or glutamate in the nucleus accumbens or prefrontal cortex of either strain. The basal levels of glutamate, in both brain regions, were significantly lower in Lewis than in Fischer 344 rats. The basal levels of 5-HT were also lower in the nucleus accumbens of Lewis rats. These findings suggest that enhanced sensitivity of the mesoaccumbens 5-HT or glutamate systems to ethanol and/or inherent low basal levels of 5-HT or glutamate activity may be associated with the predisposition to alcohol-drinking behavior seen in Lewis rats.

Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization.

Interactions between serotonin (5-HT) and dopamine (DA) neuronal systems in the prefrontal cortex (PFC) may be important in the pathophysiology of cognitive disorders such as schizophrenia. We have examined the effect of 5-HT, applied locally through a microdialysis probe, on extracellular DA in the PFC, and compared the response to that observed in the striatum. 5-HT in concentrations of 1 to 10 microM increased extracellular DA dose-dependently to a greater extent in the PFC than in the striatum. The PFC response was pharmacologically characterized to determine the 5-HT receptor subtype mediating the increase in DA levels. The coperfusion of selective 5-HT2A and 5-HT3 antagonists MDL 100,907 ((R-(+)-(2,3-dimethoxyphenyl)-1-[2(4-flourophenylethyl)]-4- piperidine-methanol) and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate), respectively, with 5-HT failed to significantly attenuate the 5-HT induced increase of extracellular DA. Furthermore, the local application of the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl aminopropane did not yield an increase in extracellular DA. On the other hand, coperfusion of the selective 5-HT1B/1D antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide)) with 5-HT completely blocked the effect of 5-HT alone. Infusion of the selective 5-HT1B agonists CP 93,129 (3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one) and CP 94,253 (3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrolo[3,2-b]pyridine) resulted in a significant increase in extracellular DA and the effect of CP 93,129 was attenuated by coperfusion of GR 127935. The results obtained demonstrate a functional interaction between DA and 5-HT pathways in the PFC, with evidence of potential mediation by the 5-HT1B receptor subtype.

The role of serotonin in the actions of psychostimulants: molecular and pharmacological analyses.

Cocaine is a highly abused psychostimulant which is a local anesthetic and inhibitor of the reuptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE). This manuscript details a brief summary and the primary conclusions of several presentations geared to present recent pharmacological analyses of the interaction of cocaine with 5-HT systems. These data illustrate the complexity of actions for cocaine in the brain and emphasize that, to fully understand the mechanisms which underlie its potent behavioural effects, the impact of this drug on 5-HT function as well as the interactions between 5-HT and the function of DA mesolimbic pathways must be considered.

Effect of ethanol on extracellular dopamine in nucleus accumbens: comparison between Lewis and Fischer 344 rat strains.

The purpose of this study was to examine the differential effects of intraperitoneal ethanol on the mesoaccumbens dopamine (DA) system in Fischer 344 and Lewis rat strains, utilizing microdialysis in awake animals. At the lowest dose tested (0.5 g/kg), there were no changes in extracellular DA in the nucleus accumbens in either strain. There was a differential response to the intermediate dose of 1 g/kg ethanol, with an 84% increase in extracellular DA in the Fischer, but no change in Lewis rats. The highest dose administered (2 g/kg) did not induce significant increases in DA in either strain. These data demonstrate that the mesoaccumbens DA systems of Fischer and Lewis rat strains differ in their susceptibility to activation by ethanol, and suggest that the higher alcohol preference of Lewis rats is not associated with an enhanced DAergic response to acute experimental administration of ethanol.

Cocaine and cocaethylene: effects on extracellular dopamine in the primate.

Cocaine and cocaethylene (a psychoactive metabolite of concurrent cocaine and ethanol consumption) were studied in the anesthetized vervet monkey. The ability of each to elevate extracellular DA in the caudate nucleus was assessed using microdialysis probes acutely lowered through chronic guide cannulae. Blood samples were also collected to determine plasma levels of the two drugs. Doses of 1.5 mumol/kg cocaine (equivalent to 0.5 mg/kg cocaine-HCl) and cocaethylene were administered intravenously. Microdialysis and blood samples were collected at 5-min intervals immediately following drug administration. Both drugs caused a maximal four-fold increase in extracellular DA during the 5- to 10-min period following drug administration. This is the first report of cocaine (and cocaethylene) induced alterations in extracellular DA in primates. The abilities of cocaine and cocaethylene to produce euphoria are being compared in ongoing clinical research studies. The potential use of these results for interpreting the neurochemical basis of any differences in those studies is discussed.

Excitatory amino acid antagonists attenuate the effects of cocaine on extracellular dopamine in the nucleus accumbens.

The effect of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate excitatory amino acid antagonists on systemic cocaine-induced increases in extracellular dopamine was examined. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor subtype antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and N-methyl-D-aspartate receptor antagonists, 2-amino-5-phosphonovalerate and dizocilpine, were infused via a microdialysis probe placed in the nucleus accumbens. The local infusion of 2-amino-5-phosphonovalerate (500 microM), dizocilpine (50 microM) and CNQX (100 microM), started 80 min before cocaine injection, significantly inhibited the cocaine-induced increase in extracellular dopamine. The CNQX blockade was dose-dependent with respect to both CNQX concentration infused and dose of cocaine administered. Simultaneous infusion of the two antagonists (500 microM 2-amino-5-phosphonovalerate and 100 microM CNQX) did not lead to further reductions in the effects of cocaine when compared to either antagonist alone. Our results suggest that both N-methyl-Daspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate subtypes of excitatory amino acid antagonist receptors may contribute to the stimulatory effect of cocaine on extracellular dopamine in the nucleus accumbens.

Differences in bioavailability between cocaine and cocaethylene and their implications for drug-reward studies.

Cocaethylene, a psychoactive metabolite resulting from combined ethanol/cocaine consumption, is of interest because its psychostimulant properties may partially underlie combined cocaine/ethanol use, and because it has the potential for use as a probe of drug reward mechanisms due to its enhanced selectivity at monoamine uptake sites compared to cocaine. To determine the relative systemic bioavailabilities of cocaine and cocaethylene, sequential plasma samples were obtained from awake rats following drug administration. Following intravenous administration of 3 mumol/kg (molar equivalent of 1 mg/kg cocaine-HCl), both drugs achieved similar time courses and areas under the plasma concentration versus time curve. In contrast, intraperitoneal administration of 44 mumol/kg (molar equivalent of 15 mg/kg cocaine HCl) showed peak plasma levels, and the area under the plasma concentration vs time curve for cocaine to be approximately twice that for cocaethylene. Comparison of dose corrected areas under the curve of the two routes of administration for each drug indicated that relative systemic bioavailability of cocaethylene following intraperitoneal administration is only 58% that of cocaine. In addition, the elimination of both cocaine and cocaethylene was found to be slower following intraperitoneal administration compared to the intravenous route. The implications of these results are discussed with respect to the relative potency of these two compounds, as inferred from behavioral, drug reward, and lethality studies. Also, the differences noted will need to be taken into account when making mechanistic interpretations from comparative drug reward studies.