Caffeine preexposure sensitizes rats to the motor activating effects of cocaine

Rats were preexposed to caffeine or to water vehicle with nine daily injections (20 mg/kg, i.p.). On each of the 9 days, the motor activating response to the drug was assessed in open field boxes. On the tenth day, water and caffeine preexposed rats were challenged with a single injection of cocaine HCI (10 mg/kg, i.p.) or vehicle, and the activational effect of cocaine was assessed. The rats that had been pretreated with caffeine showed a larger response to cocaine than their vehicle treated counterparts, suggesting that caffeine exposure enhanced the response to cocaine. Since caffeine-preexposed rats responded to the vehicle injection on test day in much the same manner as rats that had received chronic injections of the water vehicle, it is unlikely that the increase in cocaine effect was due to carryover effects of the caffeine pretreatment or conditioned activity due to the preexposure. These data add to the literature base describing predisposing factors in cocaine sensitivity, and suggest that readily available stimulants, like caffeine, may serve to prime central systems that mediate the response to cocaine.     

Stereoselective effects of cocaine

The stereoselectivity of several effects of cocaine was examined. Traditional behavioral effects of psychomotor stimulants, including increases in locomotor behavior in mice, increases in rates of operant behavior maintained under fixed-interval schedules in monkeys, and discriminative stimulus effects in rats were assessed. Toxic effects, including convulsions and lethality, were assessed in mice. The (-)-enantiomer of cocaine produced increases in locomotor activity at doses at least 340-fold lower than the highest doses of the (+)-enantiomer that were inactive. Increases in operant behavior were also obtained at doses of the (-)-enantiomer that were at least 340-fold lower than the highest doses of the (+)-enantiomer that were inactive. The ED(50) value for the discriminative stimulus effects of the (-)-enantiomer was approximately 60-fold lower than the highest inactive doses of (+)-cocaine examined. In contrast, toxic effects were obtained with both enantiomers of cocaine, with (-)-cocaine approximately 8- or 13-fold more potent than its enantiomer in producing convulsions and lethality, respectively. These results indicate that there is a marked stereoselectivity in the psychomotor stimulant effects of cocaine, and additionally, that this stereoselectivity does not carry over to the toxic effects of cocaine, which appear to be mediated by different mechanisms.     

Prazosin attenuates the effects of cocaine on motor activity but not on schedule-controlled behavior in the rat.

The spontaneous motor activity of rats was measured following administration of cocaine alone and in combination with the centrally acting alpha 1-antagonist prazosin. Cocaine alone (18-42 mg/kg) increased motor activity in a dose-related manner. At doses of 1 and 1.8 mg/kg, prazosin attenuated the increases in motor activity produced by cocaine. In rats responding under a fixed-ratio discrimination procedure, cocaine (10-32 mg/kg) produced dose-dependent increases in percent errors and decreases in overall response rate. Across a range of doses (0.32-3.2 mg/kg), prazosin failed to antagonize the effects of cocaine on responding under the discrimination procedure. Rather, the combined effects were frequently greater than those obtained with cocaine alone. The data suggest that in rats activation of alpha 1-adrenergic systems may mediate the effects of cocaine on motor activity but not on schedule-controlled behavior.     

Ketoconazole reduces low dose cocaine self-administration in rats

Ketoconazole is an oral antimycotic agent approved by the FDA for the treatment of fungal disease which also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0.5 mg/kg per infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125-0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding. In fact, pretreatment with ketoconazole resulted in rates and patterns of self-administration at these doses that were indistinguishable from those observed during cocaine extinction. However, cocaine self-administration at the highest dose tested in these experiments (i.e. 0.5 mg/kg per infusion) was not significantly affected by ketoconazole. These data suggest the potential utility of ketoconazole or related drugs as adjuncts in the treatment of cocaine abuse and further underscore the role for corticosterone in cocaine reinforcement.     

Tolerance to the reinforcing effects of cocaine

This study tested the hypothesis that prolonged exposure to high doses of cocaine would produce tolerance to the reinforcing effects of cocaine. We determined the rate of administration of low doses of cocaine in rats and then exposed these subjects to high doses of cocaine (5mg) three-times a day for 1 week. This treatment caused a 2-fold faster intake of cocaine, and the lowest dose of cocaine that would maintain self-administration was double the previous threshold dose. To our knowledge this is the first controlled demonstration of tolerance to the reinforcing effects of cocaine produced by chronic exposure to the drug, and we suggest that this tolerance may be a key marker for the development of drug dependence.     

Ethanol consumption reduces the adverse consequences of self-administered intravenous cocaine in rats

Rationale Human drug users report that the initial positive effects of cocaine are followed by a dysphoric state characterized by anxiety and drug-craving. As a means of presumably attenuating these negative aftereffects, 50–90% of cocaine users choose to co-administer ethanol during cocaine binges. This co-administration reportedly prolongs the high and diminishes the low associated with cocaine use.Objective The current study was intended to assess whether this phenomenon could be modeled in the animal laboratory. We have previously shown that animals running a straight alley for an intravenous cocaine reward develop a unique approach-avoidance conflict behavior that is characterized by stop and retreat behaviors as the subjects approach the goal box. The retreats are thought to reflect the concurrent positive (reward) and negative (anxiety) associations with the goal box and can be dose-dependently reduced by pretreatment with diazepam, which presumably attenuates the anxiety stemming from the conflict.Methods To test the role of ethanol in reducing cocaine-induced anxiety, rats were trained to run a straight-arm alley for a single daily injection of cocaine (1.0 mg/kg IV).Results Rats that had the opportunity to then drink either an 8% or a 4% sucrose–ethanol solution immediately following their daily runway trial came to exhibit fewer retreats than rats that did not drink ethanol following their cocaine injection.Conclusions These results suggest that ethanol effectively reduces the development of approach-avoidance conflict in animals running an alley for IV cocaine, a result that may account for the prevalence of cocaine–ethanol co-administration in humans.     

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

Rationale Metabotropic glutamate receptors (mGluRs) were reported to regulate various behavioral effects of addictive drugs.Objective The present study evaluated the role of group I mGluRs in the progressive augmentation (“sensitization”) of the behavioral effects observed after repeated, intermittent cocaine exposure.Materials and methods After habituation to handling and baseline activity measurement (days 1–2), rats received eight injections of cocaine (10 mg/kg) or saline on days 3–6, 8–11, and then, were tested twice with acute saline and cocaine given in a counterbalanced manner on days 13 and 15. Before the test sessions, subjects were pretreated with mGluR1 antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine).Results Pretreatment with EMQMCM (2.5–10 mg/kg) but not MTEP (2.5–10 mg/kg) significantly reduced expression of the sensitized ambulatory motor activity of the cocaine-experienced animals acutely challenged with cocaine. Both EMQMCM and MTEP significantly reduced vertical motor activity across all cocaine/saline treatment conditions.Conclusions These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity.     

Respiratory effects of cocaine freebasing among habitual cocaine users.

Smoking of alkaloidal cocaine ("crack") has become increasingly prevalent in our society. Recent evidence suggests that crack smoking can cause acute respiratory symptoms, abnormalities in lung function and, in some instances, severe, life-threatening acute lung injury. To evaluate further the relationship between frequent cocaine smoking and respiratory symptoms and lung dysfunction, we studied a sample of 177 heavy, habitual smokers of freebase cocaine (mean 6.6 gm/wk for an average of 27 months) with or without concomitant smoking of tobacco and/or marijuana. Results in this sample were compared with those in a control sample of 75 age-, sex- and race-matched nonsmokers of cocaine who did or did not also smoke tobacco and/or marijuana. After controlling for the use of other smoked substances, heavy, habitual cocaine smoking was associated with the following: (1) a high frequency of acute respiratory symptoms (cough, black sputum, chest pain) in temporal association with freebase use; (2) an obstructive ventilatory abnormality involving the large airways; and (3) a mild but significant impairment in the diffusing capacity of the lung. These findings suggest that heavy, habitual crack smoking produces (1) respiratory tract injury manifested by acute respiratory symptoms and evidence of chronic airflow obstruction in large airways, and (2) an abnormality in diffusion of gas at the alveolar-capillary level. The mechanism of the diffusion defect is unknown but could reflect damage to the alveolar-capillary membrane. Further study of the magnitude, persistence, reversibility, mechanism and clinical significance of the abnormality in diffusing capacity is needed.     

l-Isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors

Background

We previously reported isolation of l-isocorypalmine (l-ICP), a mono-demethylated analog of l-tetrahydropalmatine (l-THP), from the plant Corydalis yanhusuo. Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice.

Methods

Receptor binding, cAMP and [³⁵S]GTPγS assays were used to examine pharmacological actions of l-ICP in vitro. Effects of l-ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of l-ICP in mouse serum.

Results

Among more than 40 targets screened, l-ICP and l-THP bound only to dopamine (DA) receptors. l-ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l-THP bound to only D1 and D5 receptors, with lower affinities than l-ICP. At 10 mg/kg (i.p.), l-ICP inhibited spontaneous locomotor activity for a shorter time than l-THP. Pretreatment with l-ICP reduced cocaine-induced locomotor hyperactivities. Administration of l-ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l-ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l-ICP itself did not cause preference or aversion. HPLC analysis showed that l-ICP was the main compound in mouse serum following i.p. injection of l-ICP.

Conclusions

l-ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.     

Classically conditioned motor effects do not occur with cocaine in an unbiased conditioned place preferences procedure

Classical conditioning and behavioural sensitisation of motor activity induced with cocaine (10mg/kg, i.p.) were examined using an unbiased two-compartment conditioned place preference (CPP) procedure. Habituation of the rats to the testing environment prior to training was varied (i.e. either the rats were habituated to the environment for three 30min sessions or they were not) in order to examine a possible influence of latent inhibition on conditioned locomotion or behavioural sensitisation. Furthermore, rats were either trained with an explicit CS+ (cocaine-paired compartment) and CS- (vehicle-paired compartment), or else they were trained with no barrier between the compartments (effectively a single-compartment procedure with no explicit CS-) in order to examine a possible influence of stimulus change (training rats while confined to one compartment, but testing with no barrier between compartments). On a drug-free test day with free access to both compartments, rats previously exposed to cocaine in one compartment (CS+) and vehicle in the second compartment (CS-) spent more time in the CS+ compartment (conditioned place preference). However, under no circumstance was the rate of motor activity higher in the CS+ compartment than in the CS- compartment, as would be expected if cocaine-induced motor activity was classically conditioned to contextual cues. Whether or not increased activity extinguished with repeated drug-free exposures to previously drug-paired contexts depended on habituation experience. In addition, both habituation and current access to compartments (free or restricted) determined the presence of post-extinction sensitisation to a challenge dose of cocaine (7.5mg/kg). Classical conditioning and non-associative sensitisation, independently or together, cannot account for this pattern of results.     

Electrophysiological basis of the reinforcing effects of cocaine

The meteoric rise in cocaine abuse over the past decade has led renewed interest in the mechanisms by which this drug produces it potent reinforcing effects. Animal studies have clearly implicated the mesoaccumbens and mesocortical dopamine (DA) neuronal systems as integral brain sites involved in mediating self-administration of cocaine. Biochemical studies have determined that the most reward-relevant action of cocaine within the brain is the inhibition of reuptake of synaptic DA which occurs as a result of cocaine binding to a site on the DA transporter. In this review, electrophysiological studies regarding the effects of cocaine on mesoaccumbens and mesocortical DA systems are presented and a comprehensive picture of how cocaine influences both individual neurons and total neurotransmission within these reward-relevant systems is offered. It is concluded that the powerful rewarding effects of cocaine may be related to its preferential actions at DA and serotonin nerve terminals within the nucleus accumbens and a relatively poor compensatory reduction of impulse generation in mesoaccumbens DA cells. The possibility that this hypothesis can be generalized to account for the rewarding effects of other drugs of abuse is also discussed.     

Perinatal cocaine exposure reduces myocardial norepinephrine transporter function in the neonatal rat

Norepinephrine transporter (NET) mediates the active removal of norepinephrine (NE) released from sympathetic nerve terminals via reuptake, and NET function and expression can be regulated by cocaine. NET expression and its regulation by cocaine in the developing sympathetic nervous system during early postnatal period, however, have not been examined. We quantified immunodetectable NET protein expression in the neonatal rat heart to examine the developmental pattern of myocardial NET during the first 2 weeks after birth. To assess sympathetic innervations, we simultaneously quantified the expression of myocardial tyrosine hydroxylase (TH). Timed pregnant rats received daily intragastric treatment with saline (CTL) or cocaine at 60 mg/kg (Coc) from Gestational Day 2 until parturition. After birth, nursing mothers continued to receive the same treatment. The expression of myocardial TH and NET in neonatal rats were then studied at 1 day (Postnatal Day 1, PD1), 7 days (PD7) or 14 days (PD14) of age. We observed a similar age-dependent increase in the expression for myocardial NET and TH during the first 2 weeks of postnatal life, in both CTL and Coc animals. While myocardial TH was significantly up-regulated following perinatal cocaine exposure, no significant change in immunodetectable myocardial NET protein was evident. To further examine whether NET function might be affected by perinatal cocaine exposure, we performed NE uptake in myocardial membranes from PD14 CTL and Coc rats. We found that NE uptake was reduced at PD14 in the cocaine-treated group. Our results indicate that myocardial NET and TH are both developmentally regulated. Furthermore, our results indicate that perinatal exposure to cocaine did not change NET protein expression but impaired myocardial NET function in the neonatal rat.     

Electrophysiologic effects of cocaine on the canine ventricle

To evaluate the electrophysiologic effects of cocaine on the ventricle, 12 conscious dogs were studied before and after a bolus and infusion of cocaine titrated to maximum tolerance or to an increase in the mean blood pressure by at least 15%. Plasma cocaine levels, blood pressure, and surface and intracardiac electrograms were recorded. Programmed electrical stimulation was performed from the right ventricle at drive cycle lengths of 400 and 350 ms with introduction of up to three extrastimuli. The right ventricular effective refractory period decreased by 10% (p less than or equal to 0.01) and the mean blood pressure increased by 19% (p less than or equal to 0.01). No sustained spontaneous or induced ventricular arrhythmias were recorded after cocaine administration. There were no significant changes in pacing threshold, intraventricular conduction, heart rate, QRS or QTc intervals. The cocaine dose infused was 2.1 +/- 1.0 mg/kg; cocaine plasma levels were 1969 +/- 959 ng/ml immediately after the bolus and 508 +/- 234 ng/ml at the end of the study. It is concluded that in a presumably normal canine heart and at the doses given that cocaine decreases right ventricular effective refractory period, does not change intraventricular conduction, and does not result in sustained spontaneous or induced ventricular arrhythmias.     

Irritability following abstinence from cocaine predicts euphoric effects of cocaine administration

This study evaluated the association between negative affective symptoms during initial abstinence and euphorigenic response to experimentally administered cocaine. Cocaine-dependent individuals achieved 5 days of abstinence in a hospital setting. Forty milligrams of cocaine was given intravenously on the fifth day of abstinence, and participants were asked to rate the subjective effects produced by the drug. The associations between irritability, self-reported depression, and the subjective "high" produced by cocaine were evaluated. Increased levels of irritability and depression both correlated positively and statistically significantly with heightened response to experimentally administered cocaine as indexed by self-reported subjective "high." The positive association between irritability and subjective "high" remained after controlling for self-reported depressive symptoms. The opponent process model predicts that increased levels of negative affect should be associated with diminished euphoric response to cocaine; however, the opposite was observed. If these findings are replicated in a larger sample, then it may be necessary to reconsider the applicability of the opponent process model to cocaine addiction in humans.     

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixed-ratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3mg/kg/infusion) and high (1.0mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.     

Periadolescent nicotine exposure reduces cocaine reward in adult mice.

Fully mature mice exposed to low levels of nicotine during periadolescence exhibited reductions in the rewarding and subjective effects of cocaine. These results provide converging validity that periadolescent nicotine exposure can permanently decrease a subject's sensitivity to the reinforcing effects of cocaine. These changes were noted long after exposure, suggesting that nicotine may have altered neural systems mediating drug reward. Since reductions in the rewarding value of abused drugs are associated with increased self-administration, periadolescent nicotine exposure might increase the risk for substance abuse problems. The study thus provides biological support that nicotine might serve a "gateway" function for substance abuse.     

Modulation of intravenous cocaine effects by chronic oral cocaine in humans

RATIONALE: Agonist therapies have proven effective for the treatment of substance dependence disorders; limited data is available on their feasibility for treating cocaine dependence. OBJECTIVES: This laboratory study was designed to test the safety and utility of employing an agonist substitution therapy for the treatment of cocaine dependence in humans. METHODS: Oral cocaine served as the agonist treatment and was administered chronically over a range of doses to volunteers with cocaine abuse histories (n=8). Oral capsules were administered daily under blind conditions (q.i.d.) during this 5-week inpatient study using a dose-rising sequence (0 mg 10 days: 25 mg 3 days, 50 mg 4 days, 100 mg 10 days, 0 mg 7 days). During each of these oral dosing periods, an i.v. cocaine challenge (0, 25, and 50 mg, 1 h apart) was administered at least once. Physiological, subjective and pharmacokinetic measures were collected before and after i.v. drug administration; additional measures were collected daily. RESULTS: Oral cocaine produced no subjective effects or signs of toxicity but produced dose-related physiological effects. Significant interactions between oral and i.v. cocaine were observed; cocaine (100 mg, p.o.) significantly decreased responses to the 25-mg but not the 50-mg dose of i.v. cocaine for heart rate, mydriasis, and some subjective measures. There was no evidence of significant additive effects, although heart rate responses to i.v. cocaine were exaggerated during the final wash-out period. CONCLUSIONS: These data indicate that treatment with a cocaine "agonist" - in this case oral cocaine - can modestly attenuate the subjective and physiological responses to cocaine in humans under conditions that are safely tolerated.     

Predictors of motor development in children prenatally exposed to cocaine

The current study examined the pattern of motor development across the first 18 months of life in infants with in utero exposure to cocaine to determine how prenatal drug effects and level of exposure relates to motor development. Motor development was examined at 1, 4, 12, and 18 months of age (corrected for prematurity). Infants were divided into cocaine exposed (n=392) and comparison (n=776) groups. Exposure status was determined by meconium assay and maternal self-report with alcohol, marijuana, tobacco, and opiates present in both groups. Motor skills were assessed at 1 month using the NICU Network Neurobehavioral Scale (NNNS), at 4 months using the posture and fine motor assessment of infants (PFMAI), at 12 months using the Bayley Scales of Infant Development-Second Edition (BSID-II), and at 18 months using the Peabody Developmental Motor Scales (PDMS). Examiners masked to exposure status performed all assessments. Motor scores were converted to standard (z) scores, and hierarchical linear modeling (HLM) was used to examine the change in motor skills from 1 to 18 months of age. Infants with exposure to cocaine showed low motor skills at their initial status of 1 month but displayed significant increases over time. Both higher and lower levels of tobacco use related to poorer motor performance on average. Heavy cocaine use related to poorer motor performance as compared to no use, but there were no effects of level of cocaine use on change in motor skills.     

Testosterone modulates the effects of ethanol on male mouse aggression

In a series of three experiments, we evaluated the degree to which the effects of acutely administered ethanol on aggressive behavior of male CFW mice toward a male intruder interact with, and depend on, androgen levels. In the first experiment, mice were tested at 15 min after 0, 0.1, 0.3, 1.0, 1.7, or 3.0 g/kg of ethanol PO. The highest dose (3.0 g/kg) significantly suppressed aggression by the male residents. In the second experiment, aggressive behavior was suppressed from 5 to 60 min after 3.0 g/kg ethanol administration PO. The third experiment evaluated the role of testosterone in these effects in another set of male mice that were castrated and then implanted with a 7.5-mm or 2.5-mm silastic capsule of testosterone (T) or a silastic capsule containing cholesterol as a control. The castrated mice with 2.5-mm T capsules or cholesterol capsules had lower baseline levels of aggression than intact mice or castrated males with 7.5-mm T capsules, but they demonstrated an alcohol dose-response pattern similar to that of the intact males. The castrated males with 7.5-mm T capsules had a different dose-response curve than the other males. Doses of 1.0 and 1.7 g/kg ethanol PO significantly enhanced aggression; 5.6 g/kg was required to suppress aggression. Ethanol effects on aggressive behavior did not require T or changes in T level, but T levels altered behavioral sensitivity to ethanol.