Cocaine-induced Locomotor Stimulation Research Articles

Effects of NMDA receptor blockers on cocaine-stimulated locomotor activity in mice

Effects of MK-801 and ketamine, N-methyl- d-aspartate (NMDA) receptor blockers, on cocaine-stimulated locomotor activity were investigated in male Swiss–Webster mice. MK-801 (0.25, 0.5, 1.0 and 2.5 mg/kg), ketamine (10, 25 and 50 mg/kg) or saline was injected 20 min before cocaine (5, 10 and 20 mg/kg i.p.). Locomotor activity was measured for 30 min immediately following cocaine treatment. All doses of the drugs were also tested for ability to depress or stimulate locomotor activity in the naive (no cocaine-treated) mice. Cocaine produced a dose-dependent increase in locomotor activity that was blocked dose-dependently by MK-801 or ketamine. The blockade by MK-801 was more prominent than by ketamine. Our results may suggest that cocaine-induced locomotor stimulation in mice is modulated via NMDA receptor mediated mechanisms.

Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release

It has been reported that kappa-opioids produce greater analgesia in women than in men. Sex differences are also apparent in drug-induced behaviors. Repeated administration of cocaine (25 mg/kg) produced a greater locomotor and sensitization response in C57BL/6By female mice. It was examined whether the increased sensitization in females to repeated cocaine administration was related to differences in kappa-opioid responses. The effects of the kappa agonist U62066 (spiradoline mesylate) on cocaine-induced locomotor stimulation in vivo and NMDA-mediated dopamine release in vitro were measured. In male, but not female mice, U62066 (1 mg/kg) given 30 min before cocaine potentiated the locomotor stimulation of an acute cocaine administration. U-62066 did not affect the development of locomotor sensitization with repeated cocaine administration (25 mg/kg s.c., once daily for 3 days), and a further enhanced response was not seen on days 2 and 3. It was then examined whether dopamine release, measured in vitro, plays a role in sex dependent differences in kappa-opioid- or NMDA-modulated dopaminergic function. In tissue perfusion studies, the in vitro NMDA (25 μM)-evoked release of labelled dopamine from striatum was lower in females (fractional release=5.4±0.4 and 4.0±0.4 in male and female mouse striatum). U62066 (1 μM) and ibogaine (1 μM), an indole alkaloid claimed to be useful in the treatment of drug addiction that acts in part at the kappa-opioid receptor, both reduced the NMDA (25 μM)-evoked release of dopamine. Inhibition of the release was significantly greater in tissue from male mice. Prior in vivo cocaine administration did not alter the NMDA-evoked dopamine release. Our studies indicate that kappa-opioid and NMDA receptor activity show differences between female and male mice that may account for differences in cocaine-induced behaviors, but do not exclude the role of other hetereoceptors modulating dopamine release.

2beta-Substituted analogues of 4'-iodococaine: synthesis and dopamine transporter binding potencies.

A series of 2beta-substituted analogues of 4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2beta-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenylphosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The binding affinity of 4'-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4'-iodococaine (3). Hydroxylation of 8 at the 2'-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.

Ethanol Modulates Cocaine-Induced Behavioral Change in Inbred Mice

We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg 21 or 2.0 g kg 21 ethanol plus 5, 15, or 30 mg kg 21 cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol’s effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans.

Cocaine stimulant effects vary with cocaine levels in medial prefrontal cortex.

Rats treated with 10 mg kg-1 cocaine exhibited hyperlocomotion. Individual variation in the magnitude of this response was not correlated with serum cocaine concentration. Brain cocaine concentration, particularly in the medial prefrontal cortex, was highly correlated with the cocaine-induced locomotor stimulant effect. These findings indicate that variation in the uptake of cocaine into the brain is a critical variable in determining individual variation in its stimulant effects.

Excitatory amino acids and the actions of cocaine

Antagonists of the N-methyl- d-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Ibogaine antagonizes cocaine-induced locomotor stimulation in mice

Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [ 3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC 50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.

Chronic cocaine administration sensitizes behavioral but not neuroendocrine responses

Many behavioral responses to cocaine become progressively exaggerated with chronic treatment. Most studies have focused on cocaine-induced locomotor stimulation and changes in the dopamine projection systems which mediate these actions. However, it is not clear if a uniform ‘sensitization’ develops in all dopamine systems during chronic stimulant administration. To test this possibility the neuroendocrine actions of cocaine which are mediate, in part, by hypothalamic dopamine neurons were evaluated after chronic cocaine administration. Treatment of rats with cocaine (15 mg/kg, 2×/day) markedly enhanced the locomotor response to cocaine after 3 and 7 days of chronic administration. In contrast, neither the stimulation of adrenocorticotropic hormone (ACTH)/corticosterone (CS) secretion nor the slight inhibition of prolactin caused by acute cocaine administration changed, although a small elevation of basal corticosterone secretion was observed after 7 days. These findings suggest that the marked sensitization observed in other dopamine systems does not occur in the hypothalamic dopamine neurons thought to mediate the neuroendocrine responses to cocaine during chronic administration, despite recently described commonalities in uptake and autoreceptor functions in these dopamine cell populations. This contrast suggests a role for long loop feedback systems unique to telencephalic dopamine systems or region-specific neurochemical adaptations in cocaine sensitization.

Metaphit, a receptor acylator, inactivates cocaine binding sites in striatum and antagonizes cocaine-induced locomotor stimulation in rodents

The PCP analog metaphit, a proposed PCP receptor acylator, produced a concentration-dependent loss of the number of high-affinity [ 3H] cocaine binding sites in rodent striatum. In addition, 24 h after administration of metaphit, a dose of 25 mg/kg of cocaine was not effective in stimulating locomotor behavior of rodents. The results suggest that metaphit antagonizes cocaine-induced locomotor stimulation by acylating cocaine binding sites on dopaminergic nerve terminals.

Effect of caffeine on cocaine locomotor stimulant activity in rats.

The effect of caffeine on the locomotor stimulant activity induced by intravenous cocaine in rats was investigated. Low doses of caffeine (20 mg/kg IP) potentiated the locomotor activity induced by 1, 2.5 mg/kg intravenous doses of cocaine and higher doses of caffeine (50, 100 mg/kg IP) had no significant effect. The locomotor stimulant effect of 20 mg/kg IP dose of caffeine per se in vehicle was significantly higher and that with 100 mg/kg dose significantly lower than that of the vehicle control. Thus caffeine produced dose-dependent effects on cocaine-induced locomotor stimulant activity, with low dose potentiating and higher doses having no significant effect on such activity. Pharmacokinetic or dispositional factors did not appear to play a role in potentiation of cocaine locomotor stimulant activity by caffeine.