Cocaine Methiodide Research Articles

Cocaine hydrochloride, cocaine methiodide and methylenedioxypyrovalerone (MDPV) cause distinct alterations in the structure and composition of the gut microbiota

Cocaine is a highly addictive psychostimulant drug of abuse that constitutes an ongoing public health threat. Emerging research is revealing that numerous peripheral effects of this drug may serve as conditioned stimuli for its central reinforcing properties. The gut microbiota is emerging as one of these peripheral sources of input to cocaine reward. The primary objective of the present study was to determine how cocaine HCl and methylenedioxypyrovalerone, both of which powerfully activate central reward pathways, alter the gut microbiota. Cocaine methiodide, a quaternary derivative of cocaine that does not enter the brain, was included to assess peripheral influences on the gut microbiota. Both cocaine congeners caused significant and similar alterations of the gut microbiota after a 10-day course of treatment. Contrary to expectations, the effects of cocaine HCl and MDPV on the gut microbiota were most dissimilar. Functional predictions of metabolic alterations caused by the treatment drugs reaffirmed that the cocaine congeners were similar whereas MDPV was most dissimilar from the other two drugs and controls. It appears that the monoamine transporters in the gut mediate the effects of the treatment drugs. The effects of the cocaine congeners and MDPV on the gut microbiome may form the basis of interoceptive cues that can influence their abuse properties.

Conditioned Contribution of Peripheral Cocaine Actions to Cocaine Reward and Cocaine-Seeking

Cocaine has actions in the peripheral nervous system that reliably precede--and thus predict--its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood-brain barrier, to isolate the peripheral actions of cocaine and determine their central and behavioral effects in animals first trained to lever-press for cocaine hydrochloride (the centrally acting and abused form of the drug). We first confirmed with fast-scan cyclic voltammetry that cocaine methiodide causes rapid dopamine release from dopamine terminals in cocaine hydrochloride-trained rats. We then compared the ability of cocaine hydrochloride and cocaine methiodide to establish conditioned place preferences in rats with self-administration experience. While cocaine hydrochloride established stronger place preferences, cocaine methiodide was also effective and its effectiveness increased (incubated) over weeks of cocaine abstinence. Cocaine self-administration was extinguished when cocaine methiodide or saline was substituted for cocaine hydrochloride in the intravenous self-administration paradigm, but cocaine hydrochloride and cocaine methiodide each reinstated non-rewarded lever-pressing after extinction. Rats extinguished by cocaine methiodide substitution showed weaker cocaine-induced reinstatement than rats extinguished by saline substitution. These findings suggest that the conditioned peripheral effects of cocaine can contribute significantly to cocaine-induced (but not stress-induced) cocaine craving, and also suggest the cocaine cue as an important target for cue-exposure therapies for cocaine addiction.

On the speed of cocaine

. He is correct to suggest that the mesocorticolimbic dopamine system is heterogeneous and that the segments that are responsive to the unconditioned and conditioned effects of cocaine seem to be different. As he and others 3 impulse flow. We have not ignored the indi- rect evidence from voltammetry studies; our article cites and discusses two of the four ref- erences indicated by Aragona, and we stand by our earlier comments on those papers (which apply equally to the others). Second, Aragona argues that the primary (unconditioned) rewarding effect of cocaine is mediated by cocaine-induced dopamine release, not dopamine uptake blockade. However, he does not offer an explanation for the fact that nomifensine, a selective dopa- mine uptake inhibitor that lacks the major side-effects of cocaine, has (like cocaine itself) rewarding effects when locally injected into the ventral striatum 10 . Dopamine uptake inhibitors that are injected locally in this dopamine ter- minal field are unlikely to influence dopamine impulse flow. He also neglects to mention the recent evidence that cocaine is not rewarding in mice that lack the dopamine transporter 11 . More importantly, Aragona offers no sug- gestion as to the mechanism that underlies the increased dopamine transients that he observes. Although similar transients are seen when dopamine autoreceptor func- tion is blocked, does that necessarily mean that the release events caused by cocaine involve increased impulse flow? Could they not result from presynaptic control of dopa- mine release by glutamatergic input from the thalamus, prefrontal cortex, amygdala or hippocampus? And is it not possible that, whereas exteroceptive cocaine cues activate only the core of the accumbens, interoceptive cocaine cues may activate its shell as well? The effects of cocaine methiodide — which shares the peripheral but not the central effects of rewarding cocaine — have yet to be studied in the cocaine-trained animals that show conditioned glutamate input to the VTA 7

Potencies of Cocaine Methiodide on Major Cocaine Targets in Mice

Cocaine methiodide (CM), a charged cocaine analog, cannot pass the blood brain barrier. It has been assumed the effects of systemic CM represent cocaine actions in peripheral tissues. However, the IC50 values of CM have not been clearly determined for the major cocaine targets: dopamine, norepinephrine, and serotonin transporters, and sodium channels. Using cells transfected with individual transporters from mice and synaptosomes from mouse striatum tissues, we observed that the inhibition IC50 values for monoamine uptake by CM were 31-fold to 184-fold higher compared to cocaine at each of the transporters. In dorsal root ganglion neurons, cocaine inhibited sodium channels with an apparent IC50 of 75 µM, while CM showed no observable effect at concentrations up to 3 mM. These results indicate that an equal dose of CM will not produce an equivalent peripheral effect of cocaine.

Cocaine action on peripheral, non-monoamine neural substrates as a trigger of electroencephalographic desynchronization and electromyographic activation following i.v. administration in freely moving rats

Many important physiological, behavioral and subjective effects of i.v. cocaine (COC) are exceptionally rapid and transient, suggesting a possible involvement of peripheral neural substrates in their triggering. In the present study, we used high-speed electroencephalographic (EEG) and electromyographic (EMG) recordings (4-s resolution) in freely moving rats to characterize the central electrophysiological effects of i.v. COC at low doses within a self-administration range (0.25–1.0 mg/kg). We found that COC induces rapid, strong, and prolonged desynchronization of cortical EEG (decrease in alpha and increase in beta and gamma activity) and activation of the neck EMG that begin within 2–6 s following the start of a 10-s injection; immediate components of both effects were dose-independent. The rapid effects of COC were mimicked by i.v. COC methiodide (COC-MET), a derivative that cannot cross the blood–brain barrier. At equimolar doses (0.33–1.33 mg/kg), COC-MET had equally fast and strong effects on EEG and EMG total powers, decreasing alpha and increasing beta and gamma activities. Rapid EEG desynchronization and EMG activation was also induced by i.v. procaine, a structurally similar, short-acting local anesthetic with virtually no effects on monoamine uptake; at equipotential doses (1.25–5.0 mg/kg), these effects were weaker and shorter in duration than those of COC. Surprisingly, i.v. saline injection delivered during slow-wave sleep (but not during quiet wakefulness) also induced a transient EEG desynchronization but without changes in EMG and motor activity; these effects were significantly weaker and much shorter than those induced by all tested drugs. These data suggest that in awake animals, i.v. COC induces rapid cortical activation and a subsequent motor response via its action on peripheral non-monoamine neural elements, involving neural transmission via visceral sensory pathways. By providing a rapid neural signal and triggering neural activation, such an action might play a crucial role in the sensory effects of COC, thus contributing to the learning and development of drug-taking behavior.

Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release.

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.

Biodegradable hydrophobic–hydrophilic hybrid hydrogels: swelling behavior and controlled drug release

The objective of this work was to investigate a new family of hydrophobic–hydrophilic biodegradable hybrid hydrogels as drug carriers. A series of hydrophobic–hydrophilic biodegradable hybrid hydrogels was formulated via photo means from hydrophobic three-arm poly (ε-caprolactone) maleic acid (PGCL-Ma) and hydrophilic dextran maleic acid (Dex-Ma) precursors over a wide range of the two precursors' feed ratio (PGCL-Ma/Dex-Ma at 100:0, 70:30, 50:50, 30:70 and 0:100). A low-molecular-weight and hydrophilic drug, the α-7 agonist cocaine methiodide, was used as the model drug for the release study from the hybrid hydrogels in pH 7.4 phosphate buffer solution at 37°C. The swelling data of these hybrid hydrogels depended on the hydrophobic to hydrophilic precursors' feed ratio, and there were several-fold differences in swelling ratios between a pure hydrophilic Dex-Ma and a pure hydrophobic PGCL-Ma hydrogels. The presence of the hydrophobic PGCL-Ma component significantly reduced the initial burst swelling of the hybrid hydrogels. Depending on the two precursors' feed ratios, the swelling data during the early period obeyed either Fickian diffusion (for 50:50 PGCL-Ma/Dex-Ma hydrogel), non-Fickian or anomalous transport (for 70:30 and 100:0 PGCL-Ma/Dex-Ma), or relaxation-controlled (for 30:70 and 0:100 PGCL-Ma/Dex-Ma). A wide range of cocaine methiodide release profiles was achieved by controlling hydrophobic to hydrophilic precursors' feed ratios. Initial drug burst release was significantly reduced as the concentration of the hydrophobic PGCL-Ma component increased in the hybrid hydrogels. The bulk of cocaine methiodide released during the 160-h period was via diffusion-controlled mechanism, while degradation-controlled mechanism dominated thereafter.

The role of peripheral and central sodium channels in mediating brain temperature fluctuations induced by intravenous cocaine

While cocaine's interaction with the dopamine (DA) transporter and subsequent increase in DA transmission are usually considered key factors responsible for its locomotor stimulatory and reinforcing properties, many centrally mediated physiological and psychoemotional effects of cocaine are resistant to DA receptor blockade, suggesting the importance of other non-DA mechanisms. To explore the role of cocaine's interaction with Na+ channels, rats were used to compare locomotor stimulatory and temperature (NAcc, temporal muscle and skin) effects of repeated iv injections of cocaine (1 mg/kg) with those induced by procaine (PRO 5 mg/kg), a short-acting local anesthetic with negligible effect on the DA transporter, and cocaine methiodide (COC-MET 1.31 mg/kg), a quaternary cocaine derivative that is unable to cross the blood–brain barrier. While PRO, unlike cocaine, did not induce locomotor activation, it mimicked cocaine in its ability to increase brain temperature following the initial injection and to induce biphasic, down–up fluctuations following repeated injections. This similarity suggests that both these effects of cocaine may be driven by its action on Na+ channels, a common action of both drugs. While COC-MET also did not affect locomotor activity, it shared with cocaine and PRO their ability to increase brain temperature but failed to induce temperature decreases after repeated injections. These findings point toward activation of peripheral Na+ channels as the primary mechanism of rapid excitatory effects of cocaine and inhibition of centrally located Na+ channels as the primary mechanism for transient inhibitory effects of cocaine. DA receptor blockade (SCH23390 + eticlopride) fully eliminated locomotor stimulatory and temperature-increasing effects of cocaine, but its temperature-decreasing effects remained intact. Surprisingly, DA receptor blockade also altered the temperature fluctuations caused by PRO and COC-MET, suggesting that some of the central effects triggered via Na+ channels are in fact DA-dependent. Finally, repeated administration of PRO to animals that had previous cocaine experience led to conditioned locomotion and potentiated temperature-increasing effects of this drug. It appears, therefore, that, in addition to the central effects of cocaine mediated via interaction with the DA transporter and potentiation of DA uptake, interaction with peripheral and central Na+ channels is important for the initial physiological and, perhaps, affective effects of cocaine, likely contributing to the unique abuse potential of this drug.

The role of peripheral Na+ channels in triggering the central excitatory effects of intravenous cocaine

While alterations in dopamine (DA) uptake appear to be a critical mechanism underlying locomotor and reinforcing effects of cocaine (COC), many centrally mediated physiological and affective effects of this drug are resistant to DA receptor blockade and are expressed more quickly following an intravenous (i.v.) injection than expected based on the dynamics of drug concentration in the brain. Because COC is also a potent local anesthetic, its rapid action on Na+ channels may be responsible for triggering these effects. We monitored temperatures in the nucleus accumbens, temporal muscle and skin together with conventional locomotion during a single i.v. injection of COC (1 mg/kg), procaine (PRO, 5 mg/kg; equipotential anesthetic dose), a short-acting local anesthetic drug that, like COC, interacts with Na+ channels, and cocaine methiodide (COC-MET, 1.31 mg/kg, equimolar dose), a quaternary COC derivative that is unable to cross the blood-brain barrier. In this way, we explored not only the importance of Na+ channels in general, but also the importance of central vs. peripheral Na+ channels specifically. COC induced locomotor activation, temperature increase in the brain and muscle, and a biphasic temperature fluctuation in skin. Though PRO did not induce locomotor activation, it mimicked, to a greater degree, the temperature effects of COC. Therefore, Na+ channels appear to be a key substrate for COC-induced temperature fluctuations in the brain and periphery. Similar to PRO, COC-MET had minimal effects on locomotion, but mimicked COC in its ability to increase brain and muscle temperature, and induce transient skin hypothermia. It appears therefore that COC's interaction with peripherally located Na+ channels triggers its central excitatory effects manifested by brain temperature increase, thereby playing a major role in drug sensing and possibly contributing to COC reinforcement.

Assessment of the contributions of Na + channel inhibition and general peripheral action in cocaine-induced conditioned taste aversion

While the rewarding properties of cocaine appear to be mediated by its blockade of central monoamine uptake, the mechanisms and sites of action for cocaine's aversive effects have yet to be determined. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of Na + channel blockade in cocaine's aversive effects by comparing cocaine to the local anesthetic procaine at three doses (18, 32 and 50 mg/kg). Furthermore, the role of cocaine's peripheral actions in its aversive effects was examined by comparing cocaine to the quaternary analog cocaine methiodide (equimolar to the three doses of cocaine) in establishing CTAs. Procaine and cocaine methiodide each dose-dependently suppressed saccharin consumption, indicating that the aversive effects of cocaine are, in part, mediated by its inhibition of Na + channels and via its activity in the PNS. However, the fact that the aversions induced by procaine and cocaine methiodide were weaker than those induced by cocaine at each dose tested suggests other factors are involved in its aversive effects. Possible reasons for the weaker aversions induced by procaine and cocaine methiodide relative to cocaine were discussed.

Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain.

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI). Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB). Experimental results demonstrated that both CM (with doses of 2.5 and 7.5 mg/kg) and cocaine (with doses of 1.25 and 5.0 mg/kg) can induce a significant MABP change (30-80%). It was found that CM can only produce scattered, weak, and transient BOLD signals in a few voxels of the rat brain, and that these MABP-induced BOLD signals are not dose-dependent. In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically-induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain. The potential confounding factor of the MABP changes had little effect on the interpretation of drug-induced BOLD signal changes. These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity.

Specific activation of the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine.

Effects of cocaine and cocaine methiodide were evaluated on the homomeric alpha 7 neuronal nicotinic receptor (nAChR). Whereas cocaine itself is a general nAChR noncompetitive antagonist, we report here the characterization of cocaine methiodide, a novel selective agonist for the alpha 7 subtype of nAChR. Data from (125)I-alpha-bungarotoxin binding assays indicate that cocaine methiodide binds to alpha 7 nAChR with a K(i) value of approximately 200 nM while electrophysiology studies indicate that the addition of a methyl group at the amine moiety of cocaine changes the drug's activity profile from inhibitor to agonist. Cocaine methiodide activates alpha 7 nAChR with an EC(50) value of approximately 50 microM and shows comparable efficacy to ACh in oocyte experiments. While agonist effects are specific for the alpha 7 neuronal nAChR and are not observed with heteromeric neuronal or skeletal muscle nAChR, antagonist effects are present for heteromeric nAChR combinations. Studies of PC12 cells transiently transfected with human alpha 7 cDNA and expressing a variety of functional nicotinic receptor subtypes confirm the specificity of cocaine methiodide agonist effects. Our results indicate that a quaternary structural derivative of cocaine can be used as a specific agonist for the alpha 7 subtype of neuronal nicotinic receptor.

Mechanisms of cocaine-induced decreases in immune cell function

Cocaine has previously been shown to decrease mitogen-induced T lymphocyte proliferation in rats following intravenous administration. However, in this report, it is demonstrated that central administration of cocaine (1–50 μg) had no effect on lymphocyte proliferation responses. Similarly, the quaternary derivative, cocaine methiodide, also suppressed lymphocyte proliferation only when administered peripherally (6.5 mg/kg), and not centrally (1–20 μg). These results suggest that the effects of cocaine were mediated through a peripheral mechanism. Since significant elevations in plasma corticosterone were observed with all routes of administration of cocaine, the effects of cocaine did not appear to be due entirely to activation of the HPA axis. Instead, the peripheral administration of the local anesthetic, lidocaine (5 mg/kg) or the monoamine reuptake inhibitor, RTI-55 (2–5 mg/kg), produced significant suppressive effects on proliferation, suggesting that both of these peripheral activities of cocaine may be involved in the alteration of lymphocyte responses.

The influence of route of administration on the acute cardiovascular effects of cocaine in conscious unrestrained pregnant rats

The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term pregnant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutaneous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague–Dawley rats ( n = 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17–19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subsequent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23%↓) and MAP (37%↑) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4%↓, 6%↓) and MAP (2%↑, 15%↓) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of administration (PFV dias not PFV sys); IV cocaine increased (55%↑) whereas IG or SC cocaine decreased ∼35%↓) PFV dias. The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38%↑ vs. 37%↑), as were the effects on PFV dias (83%↑ vs. 55%↑). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of cocaine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal cardiovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3–6mg/kg) IV cocaine during GD8–21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not reproduce the cardiovascular component(s) of the expected physiological response to cocaine.

Antinociceptive Effects of Cocaine in Rhesus Monkeys

The antinociceptive effects of (−)cocaine, (+)cocaine, and cocaine methiodide administered alone and in combination with the mu-opioid agonist morphine were evaluated in rhesus monkeys. The shaved tails of four rhesus monkeys were exposed to warm water (42, 46, 50, and 54°C), and tail-withdrawal latencies (20-s maximum) from each temperature were determined. (−)Cocaine (0.032–1.8 mg/kg, SC) produced dose-dependent antinociceptive effects and enhanced the antinociceptive effects of morphine. Neither (+)cocaine nor cocaine methiodide (0.1–10 mg/kg, SC) produced antinociception or altered the effects of morphine. Pretreatment with the serotonin receptor antagonist mianserin (0.1–0.32 mg/kg, IM) produced dose-dependent rightward shifts in the dose–effect curve for (−)cocaine alone, and attenuated (−)cocaine-induced enhancement of the antinociceptive effects of morphine. However, mianserin (0.32 mg/kg, IM) did not alter the antinociceptive effects of morphine alone. These results suggest that in rhesus monkeys, the effects of cocaine on nociception may be steroselective and centrally mediated. These findings further suggest that the antinociceptive effects of cocaine in primates may be mediated at least in part by cocaine’s effects on serotonergic systems.

Pharmacological characterization of the enhancement of apomorphine-induced gnawing in mice by cocaine

The present study was designed to provide additional information on the behavioral and pharmacological mechanisms associated with the augmentation of apomorphine-induced gnawing in C57BL/6J mice. (−)-Cocaine enhanced apomorphine-induced gnawing at doses devoid of effects on gnawing when given alone. The effect was stereoselective, with (+)-cocaine devoid of activity in this test. Peripheral synapses may also not be critical to the cocaine enhancement, as cocaine methiodide, a charged species, was also without effect. The local anesthetic actions of cocaine were evaluated with lidocaine, a local anesthetic without prominent dopaminergic actions. Like (−)-cocaine, lidocaine augmented the gnawing response to apomorphine without increasing climbing or gnawing when given alone. (+)-Amphetamine enhanced apomorphine-induced gnawing but only at a high dose that increased gnawing by itself. The selective dopamine uptake blocker, GBR 12909, augmented apomorphine-induced gnawing without increasing gnawing when given alone; however, unlike cocaine or lidocaine, GBR 12909 increased climbing at doses that augmented the gnawing response. These data indicate that the cocaine-augmented gnawing response to apomorphine does not appear to be the result of psychomotor stimulation per se. Rather, this effect may be due to blockade of dopamine uptake and/or the local anesthetic actions of cocaine.

Assessment of the relative contribution of peripheral and central components in cocaine place conditioning

A balanced place conditioning paradigm was used to assess the contribution of peripheral and central factors mediating place conditioning induced by cocaine HCl. The first experiment was conducted to examine changes in locomotor activity and extracellular dopamine (DA) concentrations in the nucleus accumbens (NACC) following intraperitoneal (IP) injections of cocaine HCl (15 mg/kg) or cocaine methiodide (19.6 mg/kg). IP cocaine HCl significantly increased locomotor activity and extracellular NACC DA, whereas IP cocaine methiodide failed to increase either locomotor activity or extracellular DA in the NACC. In the second experiment, IP cocaine HCl (15 mg/kg) induced a significant conditioned place preference; however, neither IP procaine HCl (25 or 50 mg/kg) nor IP cocaine methiodide (4.9, 9.8, or 19.6 mg/kg) induced preferences for the drug-paired compartment. In the third experiment, intracerebroventricular (ICV) infusions of cocaine HCl (25 μg/2 μl) or cocaine methiodide (1 or 5 μg/2 μl) induced significant place conditioning for the drug-paired compartment. These results suggest place conditioning induced by cocaine HCl is mediated centrally and that the local anesthetic properties alone do not contribute to this effect to any significant degree.

Cocaine enhances one-way avoidance responding in mice

We reported previously that posttraining cocaine injections enhance subsequent performance of an automated jump-up avoidance response and trough avoidance response in rats. In the present study we examined the species generality of the cocaine enhancement by investigating the effects of posttraining cocaine injection on subsequent performance of a one-way active avoidance response in mice. Cocaine (30 mg/kg, IP) administered to mice immediately following completion of two escape-only trials on day 1 significantly enhanced avoidance response performance on day 2. Neither lidocaine nor cocaine methiodide, when administered in doses equimolar to the effective cocaine dose, altered performance on day 2. These data indicate that cocaine's enhancement of avoidance responding in mice probably is neither peripherally mediated nor attributable to its local anesthetic properties.

Effects of cocaine and its quaternary derivative cocaine methiodide on cardiovascular function in squirrel monkeys

The effects of cocaine and its quarternary derivative cocaine methiodide, which does not cross the blood-brain barrier, were studied on cardiovascular function in squirrel monkeys. In conscious monkeys, cocaine produced clear dose-dependent increases in blood pressure and heart rate, while cocaine methiodide did not. Both cocaine and cocaine methiodide enhanced the effects of norepinephrine in anesthetized animals, suggesting that both inhibit neuronal uptake of norepinephrine; cocaine was approximately 30 times more potent than cocaine methiodide. In anesthetized monkeys both cocaine and cocaine methiodide produced small, short duration pressor effects, although cocaine was at least 10 times more potent than cocaine methiodide. Cocaine's effects in anesthetized animals were clearly blunted in comparison to its effects in conscious animals. These effects of cocaine on blood pressure occurred at doses lower than those required to enhance norepinephrine's effects, indicating that the norepinephrine uptake blocking effects of the drugs cannot fully account for their cardiovascular effects. The greatly enhanced effect of cocaine in conscious animals and the finding that cocaine methiodide had little effect in conscious animals indicates that central mechanisms are involved in the effects of cocaine on cardiovascular function in conscious animals.

N-Modified analogs of cocaine: synthesis and inhibition of binding to the cocaine receptor

Cocaine methiodide (2), N-norcocaine (1b), N-benzyl-N-norcocaine (1c), and N-nor-N-acetylcocaine (1d) were synthesized and evaluated for their ability to inhibit binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester (WIN 35,428) to the cocaine receptor. The study showed that removal of the N-methyl group to give 1b, or replacement with the larger N-benzyl group to give 1c, has a relatively small effect on binding potency. In contrast, replacement of the N-methyl group by the acetyl moiety to give 1d, or the addition of a methyl group to give 2, reduces affinity for the receptor by a large factor. In order to gain preliminary information concerning the importance of the nitrogen location on the tropane ring system, the receptor binding affinity of 8-methyl-8-azabicyclo[3.2.1]octan-3 beta-ol benzoate (5, beta-tropacocaine) was compared to that of the isomeric 6-methyl-6-azabicyclo[3.2.1]octan-3 beta-ol benzoate (4d). The fact that both compounds have similar binding affinities for the cocaine receptor suggests that 3 beta-(benzoyloxy)-6-methyl-6-azabicyclo[3.2.1] octane-2-carboxylic acid methyl ester, which is isomeric with cocaine, may possess binding potency similar to cocaine.