Stimulants Cocaine Research Articles

Cocaine stimulation of ovine fetal swallowing

Cocaine acts to block reuptake of neurotransmitters, resulting in elevated intra-synaptic norepinephrine levels. As monoaminergic systems may contribute to central regulation of swallowing motor activity as well as dipsogenic responses, and cocaine is known to alter fetal behavior, we examined the effect of intravenous cocaine on fetal swallowing. Six ovine fetuses (130 ± 1 days) were chronically prepared with esophageal electrodes and an esophageal flow probe. Following a 1-h control period, fetuses received an intravenous injection of 1.0 mg/kg cocaine over 30 s. Fetal blood samples were withdrawn at timed intervals and fetal swallowing activity was monitored for 180 min after the cocaine bolus. Basal fetal swallowing activity during the control period was 0.6 ± 0.1 swallows/min, with esophageal flow of 0.3 ± 0.1 ml/min. At 10 min following cocaine, fetal swallowing rate increased to 1.4 ± 0.4 swallows/min though esophageal flow did not change significantly (0.4 ± 0.2 ml/min). Swallowing rate then returned to basal levels. Fetal heart rate increased in response to cocaine injection (149 ± 14 to 174 ± 24 bts/min at 180 min) though there was no change in fetal mean blood pressure. These results demonstrate acute stimulation of fetal swallowing activity in response to intravenous cocaine injection. Together with previous reports, these data further illustrate the diversity of fetal behavioral effects in response to in utero cocaine exposure.

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.

Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine

The psychomotor stimulant cocaine is inactivated primarily by hydrolysis to benzoylecgonine, the major urinary metabolite of the drug. A non-specific carboxylesterase was purified from human liver that catalyzes the hydrolysis of the methyl ester group of cocaine to form benzoylecgonine. In the presence of ethanol, the enzyme also catalyzes the transesterification of cocaine producing the pharmacologically active metabolite cocaethylene (benzoylecgonine ethyl ester). The carboxylesterase obeys simple Michaelis-Menten kinetics with K m values of 116 μM for cocaine and 43 mM for ethanol. The enzymatic activity suggests that it may play an important role in regulating the detoxication of cocaine and in the formation of the active metabolite cocaethylene. Additionally, the enzyme catalyzes the formation of ethyloleate from oleic acid and ethanol. The carboxylesterase was purified from autopsy liver by gel filtration, chromatofocusing, ion-exchange, and hydrophobic interaction chromatography to purity by SDS-PAGE and agarose gel isoelectric focusing. The subunit molecular weight was determined to be 59,000 and the native molecular weight was estimated to be 170,000 from a calibrated gel filtration column, suggesting that the active enzyme is a trimer. The isoelectric point was approximately 5.8. Digestion of carbohydrate residues on the protein with an acetylglucosaminidase plus binding to several lectins indicates that the enzyme is glycosylated. The esterase was cleaved with two proteases, and the amino acid sequences from fourteen peptides were used to search GenBank. Two identical matches were found corresponding to carboxylesterase cDNAs from human liver and lung.

Conditioned cocaine induced hyperactivity: an association with increased medial prefrontal cortex serotonin

Two sets of contextual stimuli, only one of which was associated with drug treatment, were employed in a new paradigm to assess the conditioned effects of ten cocaine (20 mg/kg) treatments on motoric behavior. Two matched groups of Sprague-Dawley rats were sequentially placed into two similar but distinct test compartments. The drug treatment was administered immediately prior to placement into the second test compartment in one group (paired group) but 2 h later in the other group (unpaired group). Changes in the non drug behavioral baseline were assessed in the non drug compartment immediately prior to each drug treatment and provided the referent baseline for determining stimulus specificity of the observed behavioral effects in the drug compartment. Both groups had equivalent activity levels in the non-drug compartment. In the drug compartment, however, the paired group showed an overall cocaine stimulant effect expressed as a marked increase in distance traversed in the drug box. Additionally, the repeated cocaine treatment induced a conditioned drug effect as revealed by the higher level of motor activity in the paired compared to the unpaired treatment group exclusively in the drug compartment in two post-treatment non-drug tests for conditioning after 1-day and 21-day withdrawal and non-testing intervals. The biochemical assay results showed no significant group differences in DA and dopamine metabolites, DOPAC, HVA and 3-MT, in striatal, limbic or cortical tissue. No differences were observed either in NE or plasma corticosterone levels. Importantly, the analysis for serotonin revealed higher levels of 5-HT and 5-HIAA selectively in the prefrontal cortex. These results suggest a role for the prefrontal cortex in the mediation of conditioned stimulant effects of cocaine.

Differential temporal dynamics of serum and brain cocaine: Relationship to behavioral, neuroendocrine and neurochemical cocaine induced responses

Rats administered cocaine 10 mg/kg i.p. exhibited hyperlocomotion which occured within 5 min post injection. Subsequently, rats were injected with 10 mg/kg cocaine and brain and serum concentrations of cocaine were measured at 5, 10, and 20 min post injection. Within this time frame, cocaine concentration in limbic brain tissue was maximal at 5 min post injection and then declined substantially by 20 min post injection. In contrast, serum cocaine concentration increased from 5 to 20 min. post injection. Neurochemical effects of cocaine upon limbic dopamine turnover and plasma corticosterone had a time course similar to serum cocaine. Brain cocaine concentrations paralleled the locomotor stimulant cocaine response whereas cocaine neuroendocrine effects paralleled serum cocaine concentrations. These findings point to the importance of brain cocaine concentration ddeterminations in neurobehavioral studies of cocaine.

Antibody-Catalyzed Degradation of Cocaine

Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degradation of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine methyl ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.

Dextropropoxyphene addiction--a drug of primary abuse.

In order to establish a profile of the abuser of dextropropoxyphene (DPX) in our community, we reviewed all the records from the Detoxification Unit in the Mental Health Institute in Mexicali, Baja California, Mexico. A total of 209 records were reviewed, and 73 were included in our study. Those included had a diagnosis of DPX dependence according to DSM-III-R and no associated psychiatric pathology. Most of them were single, unemployed males, with a history of at least 4 years of continuous DPX abuse. They were consuming an average dose per day 3.5 times higher than the maximum therapeutic dose recommended. The onset of generalized seizures associated with the DPX abuse was confirmed in 53% of the cases. The drug most frequently abused along with DPX was a benzodiazepine (p < .01), followed by marijuana, heroin, alcohol, stimulants (cocaine and amphetamines), and inhalants; 17% of the cases were pure DPX abusers. DPX was the first opiate ever abused in 67% of the cases, 19% had abused heroin before DPX, and 14% started the use of both at the same time. The difference among these groups (p < .01) suggests DPX as an opiate of primary abuse and not as secondary to heroin dependence.

Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This form of classical conditioning is of considerable clinical relevance as intense craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. To understand better the neurobiology of cocaine-induced environment-specific conditioning, Fos expression was examined in the forebrain of rats exposed to an environment in which they had previously received cocaine. These results were compared to those observed following an acute injection of cocaine. Consistent with its stimulant actions, cocaine produced an increase in locomotion that was accompanied by an increase in Fos expression within specific limbic regions (cingulate cortex, claustrum, piriform cortex, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and amygdala) as well as the basal ganglia (dorsomedial striatum and nucleus accumbens). Exposure of rats to the cocaine-paired environment also produced an increase in locomotion, as compared to various control groups. In addition to this behavioral effect, conditioned subjects exhibited a significant increase in Fos expression within the cingulate cortex, claustrum, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and the amygdala, suggesting increased neuronal activity within these regions. In contrast to the dramatic effects observed within these structures, no conditional activation was observed within the piriform cortex, nucleus accumbens, or dorsal striatum, suggesting that these brain areas are not involved in the conditioned response. The present findings indicate that specific limbic regions exhibit increased neuronal activation during the presentation of cocaine-paired cues and may be involved in the formation of associations between cocaine's stimulant actions and the environment in which the drug administration occurred. Although the nucleus accumbens is necessary for the reinforcing and locomotor effects of cocaine, it does not exhibit a conditional Fos response, suggesting that different neural circuits are involved in the unconditioned and conditioned effects of cocaine.

General activity in baboons measured with a computerized, lightweight piezoelectric motion sensor: Effects of drugs

A small, 1-oz activity-monitoring device is described for measuring motor activity continuously for periods of up to 42 days. The monitor employs a piezoelectric sensor that detects extremely small accelerations induced by movements. The monitor can be placed on collars or harnesses (e.g., for rabbits, cats, dogs, nonhuman primates, etc.). The use of the monitor is described within numerous laboratories studying the behavioral pharmacology of drugs in individually caged laboratory baboons. Patterns of daily activity were reliably recorded over periods of several months, and reflected the normal activity patterns of animals. The activity monitor recorded reliable drug-induced changes in general activity that paralleled the known effects of the same drugs on learned behaviors. Low doses of the stimulants cocaine and d-amphetamine both increaed general activity. Marked reductions in general activity were observed following both the administration of Δ-9-tetrahydrocannabinol and an antihypertensive drug combination of diuretic and verapamil.

Conditioned sensitization to the psychomotor stimulant cocaine.

Conditioned sensitization to the psychomotor stimulant cocaine.

Potentiation of cocaine and d-amphetamine toxicity with caffeine.

The effect of caffeine when combined with cocaine or amphetamine was studied in rats. Animals were pretreated with intraperitoneal vehicle (normal saline [NS]) or caffeine 100 mg/kg, then challenged with intraperitoneal cocaine (0, 35, 50, 70, or 90 mg/kg) or intraperitoneal d-amphetamine (0, 15, 25, 35, or 42 mg/kg). Animal behavior, time to, and incidences of seizures and death were recorded. This dose of caffeine alone did not cause seizures or death. Caffeine pretreatment significantly increased the incidence of overt seizures induced by either cocaine or amphetamine. Caffeine increased the incidence of cocaine-induced death from 10% to 90% at the 70 mg/kg cocaine dose (P less than .01). Caffeine increased amphetamine-induced death from 0% to 80% at 15 mg/kg (P less than or equal to .01), 10% to 70% at 25 mg/kg (P less than or equal to .01), and 30% to 80% at 35 mg/kg (P less than or equal to .01). To investigate mechanisms, additional animals were pretreated with the adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

Magnesium alters the potency of cocaine and haloperidol on mouse aggression

Magnesium has been shown to have certain behavioral effects similar to the stimulants cocaine and amphetamine, particularly on mouse resident-intruder aggression. Consequently, it was hypothesized that magnesium should interact with the indirect agonist cocaine and the antagonist haloperidol to alter their potency in the mouse resident-intruder model. Acute and chronic drug effects were compared. Results demonstrate an enhancement of cocaine potency by 30 and 125 mg/kg MgCl2 and a lowering of cocaine potency by a 15% required-Mg2+ deficient diet as measured by shifts in the dose response to acutely administered cocaine. Following chronic 0.5 mg/kg cocaine for 15 days, a dose of 125 mg/kg acutely administered MgCl2 prevented the disruptive effects of chronic cocaine on mouse aggression. Acutely administered haloperidol was influenced by Mg2+ treatments in a manner opposite from the effects on cocaine, while the chronic effects of haloperidol were affected in the same manner by Mg2+ treatments as those shown for chronic cocaine. Several mechanisms are suggested to explain these interactions.

Standardization for determining image quality in thermal neutron radiographic testing : Yamagata, H.; Yoneda, K.; Fujine, S.; Kanda, K.; Katsurayama, K. Annual reports of the research reactor Institute Kyoto University, Vol. 19, pp. 116–123 (1986)

It is well established that cocaine stimulant effects are potentiated in a novel environment. The relationship between cocaine and novel stimuli, however, remains poorly understood. In this study, we examined the effects of different dose levels of cocaine (5.0, 10.0 and 20.0 mg/kg) administered to separate groups of rats (N = 10) on attentional behavior to a small novel object stimulus placed within a central zone (CZ) of a familiar open-field environment. This method has been used to assess attentional function in young animals, brain damaged animals and drug treated animals. In previous studies, we have shown that attention to a novel object stimulus can be quantified by an animal's contact time with the object. Following a series of pre-exposures to the test environment without the novel object, we found that cocaine in a brief 10 min test session with the novel object present produced a dose related decrease in mean contact time with the novel object. In contrast caffeine (5.0, 10.0 and 20.0 mg/kg), which induced a locomotor stimulant effect equivalent to cocaine, did not impair novel object contact time. Correlational analyses indicated absence of significant negative correlation coefficients of locomotor activity and contact time with the novel object. These considerations indicate that the observed cocaine impairment of attention to the novel stimulus is not attributable to hyperactivity per-se. Furthermore, cocaine, but not caffeine, induced a dose related decrease in the duration of spontaneous grooming. Thus, cocaine appears to diminish an animal's overall capability to maintain a behavioral process (i.e., investigate a novel object stimulus and/or engage in spontaneous bodily directed activity such as grooming). Altogether, the findings obtained in the present study indicate that cocaine impairs an animal's ability to sustain attention to stimuli and suggest a behavioral state analogous to an attention deficit disorder.

Drug Use by Tractor-Trailer Drivers

Blood or urine samples or both were obtained from 317 of 359 randomly selected tractor-trailer drivers asked to participate in a driver health survey conducted at a truck weighing station on Interstate 40 in Tennessee. Altogether, 29% of the drivers had evidence of alcohol, marijuana, cocaine, prescription or nonprescription stimulants, or some combination of these, in either blood or urine. Cannabinoids were found in 15% of the drivers' blood or urine; nonprescription stimulants such as phenylpropanolamine were found in 12%; prescription stimulants such as amphetamine were found in 5%; cocaine metabolites were found in 2%; and alcohol was found in less than 1%. These results provide the first objective information about the use of potentially abusive drugs by tractor-trailer drivers. The extent of driver impairment attributable to the observed drugs is uncertain because of the complex relationship between performance and drug concentrations.

Drug use in an alternative high school.

The drug involvement of students in an alternative high school is reported. Students include those transferred for behavior problems or dropouts returning to complete school. Drug use rates are exceptionally high, with significantly higher lifetime prevalence for nearly every drug. Current use of drugs is also very high, and 70 percent are in the two most serious adolescent drug use types; about a third are polydrug users, currently using at least two drugs with different psychoactive effects, and another third are stimulant users, taking marijuana, uppers, and/or cocaine. Only alcohol and marijuana were started earlier than other students–these students started both in early junior high. These extreme levels of involvement suggest further assessment of alternative schools and, if generalizability is confirmed, focusing of prevention and treatment programs on these high risk environments.

Trazodone-oral cocaine interactions

• Depression and dysphoria can follow the long-term use of cocaine. Little is known about the interaction of antidepressant drugs with cocaine and similar stimulants in humans. The physiologic and subjective effects of an oral 2-mg/kg dose of cocaine hydrochloride were measured in eight healthy cocaine-using men after pretreatment with a single, 100-mg oral dose of the triazolopyridine antidepressant trazodone hydrochloride or placebo in a double-blind study. The cocaineinduced effects of increased BP, increased pupil size, and decreased skin temperature were diminished by trazodone pretreatment. Trazodone alone did not alter plasma epinephrine or norepinephrine levels. An increase in plasma epinephrine levels after cocaine administration was not altered by trazodone pretreatment, but the increase in the norepinephrine level was larger. Trazodone alone produced mild sleepiness. Cocaine-induced euphoria was not altered by trazodone pretreatment, although feelings of tension and shakiness after cocaine administration were diminished.

Partial Prohibition of Non-Medical Drug Use: A Proposal

This article will examine partial prohibition of non-medically sanctioned use (“non-medical use”) of mind-altering drugs as a method of controlling and regulating non-medical use of these substances. Partial prohibition is a policy under which non-medical (1) simple possessions,1 and use, (2) importation, production and cultivation for personal use, and less certainly, (3) small gifts, and (4) even small sales, of mind-altering drugs would not be criminalized or prohibited.2 However, non-medical importation, production, and cultivation for the purpose of distribution; non-medical commercial distribution, and possibly all non-medical distribution; and operating a vehicle under the influence of a mind-altering drug, would be prohibited and criminalzied. Mind-altering drugs, as the term is used in this article, are the “controlled substances”:3 cocaine, amphetamines, and similar stimulants; barbiturates, non-barbiturate sedatives and hypnotics (for example, Quaalude), and minor tranquilizers such as Valium and Librium; strong hallucinogens such as LSD and PCP (“angel dust”); marihuana; and the opiate narcotics. It is the argument of this article that partial prohibition is a better method of control over most of “the controlled substances” than either the total prohibition of their non-medical distribution and use (prohibition of importation, production and cultivation regardless of their purposes, of distribution and of all possession) that prevails almost entirely today in this country, or than legalization of non-medical use of these drugs. Specifically, I view partial prohibition as the preferred method of control over all controlled substances other than marihuana ( i.e., heroin and other opiates, cocaine, amphetamines, and similar stimulants; barbiturates, non-barbiturate sedatives and hypnotics, and minor tranquilizers; and hallucinogens such as LSD and PCP). For marihuana, I see partial prohibition (which we are beginning to approach in “decriminalization” of possession and sometimes small gifts also) as better than total prohibition. But weighing the potential for harm of marihuana against the social costs of both total and partial prohibition, I submit that it would be preferable if marihuana were legalized or regulated.4 In addition, I propose that we institute carefully controlled experimental outpatient programs in which heroin addicts are lawfully maintained on heroin or injectable methadone.

Sensitization to cocaine stimulation in mice

Repeated administration of cocaine to B6AF1/J mice increased their running response to 20 mg/kg cocaine as much as four-fold over the response to the first injection. After four daily injections, the extent of the increase was proportional to the dose of cocaine that was used for pretreatment. Sensitization persisted for as long as 2 months after the last injection of cocaine. Cocaine-pretreated mice did not show an increased running response to either morphine or d-amphetamine. The response to cocaine was increased two-fold by treatment with morphine and three-fold by pretreatment with d-amphetamine. Pretreatment with either imipramine or reserpine did not produce sensitization to cocaine. There was no correlation between cocaine sensitization and whole-brain catecholamine levels. There were marked differences in both the running response to cocaine and the extent of cocaine sensitization betwee the parental strains, C57B1/6J and A/J. Experiments with recombinant-inbred lines, derived from C57B1/6By and BALB/cBy mice, suggest that the initial response to cocaine and the development of sensitization are controlled by different genetic determinants.

High affinity choline transport in guinea pig brain and the effect of norepinephrine.

Abstract—The influence of 1‐norepinephrine on the accumulation of [14C]choline by nuclei‐free homogenates and synaptosomes of guinea‐pig brain was studied. Kinetic analysis of choline accumulation by guinea‐pig brain resulted in both high and low affinity Michaelis constants. Norepinephrine stimulated the high affinity choline transport process but not the low and the magnitude of its stimulation in 3 different brain regions was correlated with the choline acetyltransferase activity of those regions. Depletion of norepinephrine from the brainstem by pretreatment with the catecholamine depleter alpha‐methyl‐para‐tyrosine significantly decreased the maximal velocity of choline transport. Both the alpha adrenergic receptor blocker phentolamine and the beta adrenergic receptor blocker propranalol inhibited norepinephrine induced stimulation of choline transport. Cocaine stimulated choline transport at low concentrations and pretreatment of animals with reserpine significantly antagonized cocaine's stimulation of choline transport. The results suggest that endogenous norepinephrine may modify the high affinity choline transport process in guinea‐pig brain.