Cocaine accumulates in dopamine‐rich regions of primate brain after I.V. Administration: Comparison with mazindol distribution

Abstract

Pharmacological and neurochemical evidence suggest that brain dopamine systems, and the dopamine transporter in particular, contribute significantly to the behavioral effects and reinforcing properties of cocaine. The first objective of this study was to determine whether the brain distribution of cocaine supports these conclusions. A high resolution neuroanatomical map of cocaine disposition in brain after i.v. administration was developed. [3H]Cocaine ([3H](-)-cocaine) was administered to squirrel monkeys (Saimiri sciureus) at a trace dose (0.001 mg/kg) and at doses at or above the threshold for producing behavioral effects (0.1 mg/kg, 0.3 mg/kg). After 15 min, ex vivo autoradiography revealed the highest accumulation of [3H]cocaine in dopamine-rich brain regions, including the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle. The norepinephrine-rich locus coeruleus, the hippocampus, and amygdala also accumulated large quantities of [3H]cocaine. Moderately high levels were found in the stria terminalis, medial septum, substantia nigra, and other regions. Lowest levels were found in the cerebellum. A high and positive correlation was established for the brain distribution of [3H]cocaine administered at trace or at behaviorally relevant doses (r: 0.94; P < 0.001). To determine whether radioactivity represented [3H]cocaine or its metabolic products, tissue extracts from brain regions with high levels of cocaine were subjected to thin layer chromatography using two solvent systems. In caudate-putamen, nucleus accumbens, cortex, and hippocampus, radioactivity comigrated with standard [3H]cocaine. In substantia nigra, less than 70% of the radioactivity comigrated with [3H]cocaine, suggesting that cocaine metabolites are generated more rapidly in the substantia nigra than in other brain regions. The second objective was to determine the brain distribution of mazindol, a potent norepinephrine and dopamine transport inhibitor with low abuse liability in humans. The disposition of intravenously administered [3H]mazindol in brain (0.001 mg/kg, 0.007 mg/kg) was surveyed by ex vivo autoradiography. In sharp contrast to [3H]cocaine distribution, the highest accumulation of [3H]mazindol was localized in the norepinephrine-rich pineal gland, discrete regions of the hypothalamus (paraventricular nucleus, supraoptic nucleus), and the locus coeruleus. Moderately high levels were detected in the caudate-putamen, nucleus accumbens, and other regions. The following conclusions were drawn: (1) Although dopamine-rich brain regions are principal targets of cocaine after i.v. administration to the nonhuman primate, other prominent targets of cocaine (locus coeruleus, hippocampus, and amygdala) may contribute to the acute and chronic effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)

Selegiline Effects on Cocaine-Induced Changes in Medial Temporal Lobe Metabolism and Subjective Ratings of Euphoria

“…The PET data suggest that the reduction in this subjective response to cocaine by selegiline may involve altering the effect of cocaine on amygdala metabolism and reducing hippocampal metabolic activity. This supposition is consistent with findings from some animal studies (Lyons et al 1996;Madras and Kaufman 1994;Pontieri et al 1995;Stein and Fuller 1993;Imperato et al 1993a;Hsu et al 1996;Wilson et al 1994;Whitelaw et al 1996). These changes seemed to be specific to the limbic region, because they were not present in the thalamus control region.…”

“…These effects consist of increasing dopamine availability by reducing dopamine breakdown through MAO-B inhibition, increasing levels of betaphenylethylamine (another MAO-B specific substrate) resulting in increased synaptic dopamine release and decreasing dopamine reuptake, and enhancing catecholaminergic neuron activity (Paterson et al 1995;Knoll et al 1996) (for review see Gerlach et al 1996). Dopamine agonists with higher abuse potential have also been reported, by addicts who relapsed while being treated with these agents, to reduce the reinforcing subjective experience of euphoria produced by cocaine (Rothman 1995;Rothman et al 1996).Animal studies have shown that limbic structures, such as the hippocampus and amygdala, are important in the brain's response to psychostimulants (Stein and Fuller 1993;Imperato et al 1993a;Madras and Kaufman 1994;Pontieri et al 1995;Lyons et al 1996;Hsu et al 1996;Wilson et al 1994;White 1996;Whitelaw et al 1996), human PET studies of cue-induced cocaine craving have shown activation in the medial temporal lobe (Childress et al 1995;Grant et al 1996), and human functional magnetic resonance imaging studies have shown that changes in these regions are associated with subjective effects in cocaine infusion experiments (Breiter et al 1997). In the current study, we focused on limbic structures of the medial temporal lobe (amygdala and hippocampus), and for the purpose of evaluating the specificity of the limbic findings, we also examined the thalamus as a comparison region.…”

“…Animal studies have shown that limbic structures, such as the hippocampus and amygdala, are important in the brain's response to psychostimulants (Stein and Fuller 1993;Imperato et al 1993a;Madras and Kaufman 1994;Pontieri et al 1995;Lyons et al 1996;Hsu et al 1996;Wilson et al 1994;White 1996;Whitelaw et al 1996), human PET studies of cue-induced cocaine craving have shown activation in the medial temporal lobe (Childress et al 1995;Grant et al 1996), and human functional magnetic resonance imaging studies have shown that changes in these regions are associated with subjective effects in cocaine infusion experiments (Breiter et al 1997). In the current study, we focused on limbic structures of the medial temporal lobe (amygdala and hippocampus), and for the purpose of evaluating the specificity of the limbic findings, we also examined the thalamus as a comparison region.…”

Role of Dopamine, the Frontal Cortex and Memory Circuits in Drug Addiction: Insight from Imaging Studies

“…The abnormal activation of the thalamus in dependent subjects, but not in controls, and its significant association with MP-induced cocaine craving suggests that abnormal activation of thalamic DA pathways may participate in the expression of this unique behavior of the addicted subject. The thalamus has a relatively high uptake of cocaine (Madras & Kaufman, 1994), it is sensitive to DA D2 receptor mediated effects of cocaine (Shyu, Kiritsy-Roy, Morrow, & Casey, 1992), and one of its nuclei, the mediodorsal, which receives DA projections (Groenewegen, 1988) appears to be involved in conditioned reinforcement (Mc Alonan, Robbins, & Everitt, 1993). However, because the specific to nonspecific binding ratio of […”

Complete Republication: National Association of Medical Examiners Position Paper: Recommendations for the Investigation, Diagnosis, and Certification of Deaths Related to Opioid Drugs

“…Drugs may distribute unevenly throughout organs such as the liver or brain because of variations in blood flow, bio-accumulation, and other factors, further complicating interpretation [26]. Death certificate data are often used to determine priorities in public health.…”