The neurosteroid dehydroepiandrosterone sulfate,but not androsterone,enhances the antidepressant effect of cocaine examined in the forced swim test — Possible role of serotonergic neurotransmission

One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5 mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.     

Augmentation of cocaine hyperactivity in rats by systemic ghrelin

The feeding-relevant pathway by which food deprivation (FD) augments cocaine action is unknown. Systemic administration of the 28 amino acid acylated peptide ghrelin (1-10 nmol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FD. The present experiment examined the impact of ghrelin or vehicle pretreatment on the locomotion and stereotypy induced by systemic cocaine hydrochloride. Male Sprague-Dawley rats were pretreated at -60 min with 0 or 5 nmol rat ghrelin (IP) and then injected (IP) at time 0 with 0, 2.5, 5.0, or 10.0 mg/kg cocaine. Locomotor activity was monitored over a 45-min post-cocaine period. Rats received the same ghrelin dose, but a different cocaine dose (in random order) on each of the four drug trials, with each drug trial separated by at least 2 days. Administration of 5 nmol ghrelin-0 mg/kg cocaine slightly increased locomotion relative to that of 0 nmol ghrelin-0 mg/kg cocaine. Cocaine increased locomotion as a function of dose in the 0 nmol ghrelin group, but the effect of cocaine was even greater when preceded by 5 nmol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, augments the acute effects of cocaine on locomotion in rats.     

Cocaine-induced closures of single batrachotoxin-activated Na+ channels in planar lipid bilayers

Batrachotoxin (BTX)-activated Na+ channels from rabbit skeletal muscle were incorporated into planar lipid bilayers. These channels appear to open most of the time at voltages greater than -60 mV. Local anesthetics, including QX-314, bupivacaine, and cocaine when applied internally, induce different durations of channel closures and can be characterized as "fast" (mean closed duration less than 10 ms at +50 mV), "intermediate" (approximately 80 ms), and "slow" (approximately 400 ms) blockers, respectively. The action of these local anesthetics on the Na+ channel is voltage dependent; larger depolarizations give rise to stronger binding interactions. Both the dose-response curve and the kinetics of the cocaine-induced closures indicate that there is a single class of cocaine-binding site. QX-314, though a quaternary-amine local anesthetic, apparently competes with the same binding site. External cocaine or bupivacaine application is almost as effective as internal application, whereas external QX-314 is ineffective. Interestingly, external Na+ ions reduce the cocaine binding affinity drastically, whereas internal Na+ ions have little effect. Both the cocaine association and dissociation rate constants are altered when external Na+ ion concentrations are raised. We conclude that (a) one cocaine molecule closes one BTX-activated Na+ channel in an all-or-none manner, (b) the binding affinity of cocaine is voltage sensitive, (c) this cocaine binding site can be reached by a hydrophilic pathway through internal surface and by a hydrophobic pathway through bilayer membrane, and (d) that this binding site interacts indirectly with the Na+ ions. A direct interaction between the receptor and Na+ ions seems minimal.     

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

Background

Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug''s consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit.

Methodology/Principal Findings

We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine.

Conclusions/Significance

Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus–nearly perfectly correlated with the infusion–likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

A cocaine insensitive chimeric insect serotonin transporter reveals domains critical for cocaine interaction.

Serotonin transporters are key target sites for clinical drugs and psychostimulants, such as fluoxetine and cocaine. Molecular cloning of a serotonin transporter from the central nervous system of the insect Manduca sexta enabled us to define domains that affect antagonist action, particularly cocaine. This insect serotonin transporter transiently expressed in CV-1 monkey kidney cells exhibits saturable, high affinity Na+ and Cl- dependent serotonin uptake, with estimated Km and Vmax values of 436 +/- 19 nm and 3.8 +/- 0.6 x 10-18 mol.cell.min-1, respectively. The Manduca high affinity Na+/Cl- dependent transporter shares 53% and 74% amino acid identity with the human and fruit fly serotonin transporters, respectively. However, in contrast to serotonin transporters from these two latter species, the Manduca transporter is inhibited poorly by fluoxetine (IC50 = 1.23 micro m) and cocaine (IC50 = 12.89 micro m). To delineate domains and residues that could play a role in cocaine interaction, the human serotonin transporter was mutated to incorporate unique amino acid substitutions, detected in the Manduca homologue. We identified a domain in extracellular loop 2 (amino acids 148-152), which, when inserted into the human transporter, results in decreased cocaine sensitivity of the latter (IC50 = 1.54 micro m). We also constructed a number of chimeras between the human and Manduca serotonin transporters (hSERT and MasSERT, respectively). The chimera, hSERT1-146/MasSERT106-587, which involved N-terminal swaps including transmembrane domains (TMDs) 1 and 2, was remarkably insensitive to cocaine (IC50 = 180 micro m) compared to the human (IC50 = 0.431 micro m) and Manduca serotonin transporters. The chimera MasSERT1-67/hSERT109-630, which involved only the TMD1 swap, showed greater sensitivity to cocaine (IC50 = 0.225 micro m) than the human transporter. Both chimeras showed twofold higher serotonin transport affinity compared to human and Manduca serotonin transporters. Our results show TMD1 and TMD2 affect the apparent substrate transport and antagonist sensitivity by possibly providing unique conformations to the transporter. The availability of these chimeras facilitates elucidation of specific amino acids involved in interactions with cocaine.     

High doses of amphetamine augment, rather than disrupt, exocytotic dopamine release in the dorsal and ventral striatum of the anesthetized rat

High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata. An equivalent high dose of cocaine (40 mg/kg) was also examined for comparison to psychostimulants acting preferentially by DAT inhibition. Parameters describing exocytotic DA release and neuronal DA uptake were determined from dynamic DA signals evoked by mild electrical stimulation previously established to be reinforcing. High-sensitivity FSCV with nanomolar detection was used to monitor changes in the background voltammetric signal as an index of DA efflux. Both doses of AMPH and cocaine markedly elevated evoked DA levels over the entire 2-h time course in the dorsal and ventral striatum. These increases were mediated by augmented vesicular DA release and diminished DA uptake typically acting concurrently. AMPH, but not cocaine, induced a slow, DA-like rise in some baseline recordings. However, this effect was highly variable in amplitude and duration, modest, and generally not present at all. These data thus describe a mechanistically similar activation of action potential-dependent dopaminergic neurotransmission by AMPH and cocaine in vivo. Moreover, DA efflux appears to be a unique, but secondary, AMPH action.     

Viral Transduction of Cocaine Hydrolase in Brain Reward Centers

1. Site-directed mutagenesis of human plasma butyrylcholinesterase has led to novel hydrolases that rapidly destroy cocaine. We are investigating whether viral gene transfer of such enzymes might reduce addiction liability by blocking cocaine from its sites of action.2. As groundwork for a possible gene therapy, we previously studied adenoviral transduction of cocaine hydrolases in the rat. Systemically injected vectors raised plasma cocaine hydrolase activity greatly, reduced pressor responses to cocaine, and lowered cocaine's tissue burden.3. In the present study, to reduce cocaine's brain access still further, vectors were injected directly into the nucleus accumbens. Six days later, medium sized neurons gained dramatic butyrylcholinesterase activity. Species-selective immunohistochemistry proved that the transgene accounted for this activity.4. Since the transgene product is so efficient with cocaine as a substrate, it is now reasonable to begin testing gene therapy in rodent models of cocaine addiction.     

Differentiating the rapid actions of cocaine

The subjective effects of intravenous cocaine are felt almost immediately, and this immediacy plays an important part in the drug's rewarding impact. The primary rewarding effect of cocaine involves blockade of dopamine reuptake; however, the onset of this action is too late to account for the drug's initial effects. Recent studies suggest that cocaine-predictive cues--including peripheral interoceptive cues generated by cocaine itself--come to cause more direct and earlier reward signalling by activating excitatory inputs to the dopamine system. The conditioned activation of the dopamine system by cocaine-predictive cues offers a new target for potential addiction therapies.     

Some observations on cardiac automatism in certain animals

Certain aspects of the acetylcholine hypothesis of cardiac automaticity have been tested in vitro with spontaneously beating cardiac tissue from rabbits, rats, dams, and hagfish. The beat of atria from rabbits and rats may be depressed or excited by acetylcholine, depending upon the state of the tissue. Proguanil and cocaine inhibition of the beat in the rat may be antagonized by acetylcholine so that reversal of the depression occurs. The action of acetylcholine on the hearts of clams was found to be strictly inhibitory. Proguanil and cocaine, in contrast to their action on mammalian atria, exert a stimulatory effect on the heart of the molluscs studied. In fact, cocaine stimulated these hearts when they were inhibited by acetylcholine. Studies on the non-innervated hagfish heart revealed that this tissue is completely insensitive to the action of acetylcholine. Extracts prepared from beating hearts of this species will accelerate hypodynamic hearts of the hagfish as well as of the mussel. An extract of the neurogenic lobster heart was without effect on the hagfish heart. Proguanil was likewise ineffective in concentrations which produced inhibition and excitation in rat and clam hearts respectively. It was concluded that acetylcholine does not play a role in the myogenic automatism of all species, and that another mechanism is responsible is suggested on the basis of results obtained in the hagfish hearts.     

Autonomic actions of cocaine

The development of our knowledge of the physiological, pharmacological, and biochemical actions of cocaine has in essence occurred in parallel with the development of our knowledge about the function of the autonomic nervous system. Cocaine is a sympathomimetic compound with potent local anesthetic properties. The principal hypothesis accepted to date to explain the sympathomimetic effects of cocaine is that this drug inhibits neuronal monoamine neurotransmitter reuptake by binding to a transporter or uptake site thereby increasing the effective concentration of neurotransmitter at adrenergic receptor sites. Much of the available evidence for this hypothesis has come from studies utilizing in vitro or in situ techniques. There have been relatively fewer studies examining the impact of cocaine on the autonomic nervous system in the intact animal. In addition, few studies have examined the effects of cocaine on central autonomic function. Past studies concerning the mechanism of action of cocaine are reviewed and recent data addressing the cardiovascular, respiratory, and central autonomic effects of cocaine are discussed.     

Differential impact of cocaine on meal patterns in female and male rats

Female rats, relative to males, exhibit greater behavioral activation to cocaine and other psychostimulants, but the effect of sex and the estrous cycle in modulating the hypophagic action of cocaine has not been evaluated. Meal patterns were recorded in automated food hoppers during the first 3 h of the dark phase in adult female and male rats after administration of ascending cocaine doses (0, 7.5, and 15 mg/kg cocaine, i.p.) on successive trials. Cocaine produced a greater suppression of feeding as well as a reduction in meal number over a 3 h test period in female rats during estrus, relative to that noted during diestrus. In contrast, during the 180 min test period, male rats showed minimal hypophagic responses to 7.5 or 15 mg/kg cocaine. These results extend the range of behavioral perturbations induced by cocaine that are modulated by sex and by the estrous cycle and are consistent with the notion that estradiol may modulate the neurochemical actions of cocaine.     

The use of high pressure for separation and production of bioactive molecules

Due to its action on the forces governing inter- and intramolecular interactions, the application of high pressure to biopurification or bio-elaboration of a product are of interest. The two closely thermodynamically related parameters, pressure and temperature, render processes based on their action clean, as no chemical reagents have to be added (and thus further removed) when they are applied. The use of high pressure in the development of desorption methods for the purification of bioactive molecules, particularly in the immunoaffinity field, is reviewed and discussed. Also mentioned is the application of the pressure parameter during the synthesis of a bioreagent. Finally, integrated processes relative to the synthesis and purification of these compounds are proposed.     

Effects of nitric oxide synthesis inhibition with or without nitric oxide inhalation on responses to systemic cocaine administration in rats

The effects of N^ω-nitro-L-arginine methyl ester (L-NAME) i.v. and nitric oxide (NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats. Cocaine (4 mg/kg/min i.v.) produced seizures then isoelectric electrocephalographic (isoEEG) activity as well as an initial increase in systolic blood pressure and heart rate, then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME (2 mg/kg/min i.v.) for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8). Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation (80 ppm) did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular system (lower dose for arrhythmias and asystole), but does not affect the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.     

Inhalational administration of cocaine in sheep

A pipe for administration of inhaled cocaine and its pyrolytic products in laboratory animals was developed and tested. In-vitro trials showed 30.0 +/- 5.2% (mean +/- SE) recovery of cocaine in solvent. Five non-pregnant ewes were instrumented with tracheal T-tubes and vascular catheters. After surgical recovery, ewes received three doses of cocaine (free base) in a randomized fashion; 2 mg/kg and 4 mg/kg both by inhalation, and 2 mg/kg intravenously. Arterial blood samples were collected and assayed for cocaine and its major metabolites by high performance liquid chromatography. Blood pressure and heart rate were continuously recorded. Cocaine administered by inhalation was eliminated with a half-life of 1.6 +/- 0.5 min (mean +/- SE) compared to 3.4 +/- 0.9 following intravenous administration (p less than 0.03). Likewise, clearance values were greater following inhalation, 5532 +/- 1756 ml/min/kg, than following intravenous administration, 163 +/- 20.6 ml/min/kg (p less than 0.04). Both routes of administration led to significant elevations in blood pressure, 7.5% increase after smoking vs 20% increase after intravenous administration. No correlation was found between inhalational dose of cocaine and peak plasma cocaine concentration.     

High affinity stereospecific binding of [3H] cocaine in striatum and its relationship to the dopamine transporter

A high affinity (KD 35 nM) binding site for [3H]cocaine is detected in rat brain striatum present at 2-3 pmol/mg protein of synaptic membranes. This binding is displaced by cocaine analogues with the same rank order as their inhibition of [3H]dopamine ([3H]DA) uptake into striatal synaptosomes (r = 0.99), paralleling the order of their central stimulant activity. The potent DA uptake inhibitors nomifensine, mazindol, and benztropine are more potent inhibitors of this high affinity [3H]cocaine binding than desipramine and imipramine. Cathinone and amphetamine, which are more potent central stimulants than cocaine, displace the high affinity [3H]cocaine binding stereospecifically, but with lower potency (IC50 approximately equal to 1 microM) than does cocaine. It is suggested that the DA transporter in striatum is the putative "cocaine receptor." Binding of [3H]cocaine, measured in 10 mM Na2HPO4-0.32 M sucrose, pH 7.4 buffer, is inhibited by physiologic concentrations of Na+ and K+ and by biogenic amines. DA and Na+ reduce the affinity of the putative "cocaine receptor" for [3H]cocaine without changing the Bmax, suggesting that inhibition may be competitive. However, TRIS reduces [3H]cocaine binding noncompetitively while Na+ potentiates it in TRIS buffer. Binding of [3H]mazindol is inhibited competitively by cocaine. In phosphate-sucrose buffer, cocaine and mazindol are equally potent in inhibiting [3H]mazindol binding, but in TRIS-NaCl buffer cocaine has 10 times lower potency. It is suggested that the cocaine receptor in the striatum may be an allosteric protein with mazindol and cocaine binding to overlapping sites, while Na+ and DA are allosteric modulators, which stabilize a lower affinity state for cocaine.     

Synergism between cocaine and atropine at the caudal ventrolateral medulla of cats

We have previously reported that the anticholinergic properties of cocaine may be important in cocaine induced apneusis. We have studied the effects of the cholinergic muscarinic antagonist atropine (ATR) on cocaine induced apneusis at the caudal chemosensitive areas of the ventrolateral medulla oblongata (CVLM). Experiments were performed in urethane anesthetized and tracheotomized cats with the CVLM surgically exposed. Topical application of ATR (44 mM ) to the CVLM produced significant decrements in minute ventilation (V(E)) and mean arterial blood pressure (MABP) (P<0.05) but the effects on tidal volume (V(T)), respiratory frequency (f) and heart rate (HR) were not significant. Administration of cocaine (37 mM) to ATR pretreated animals increased the incidence of cocaine induced respiratory arrest to more than twofold greater than when cocaine was administered in the absence of pretreatment. The ATR pretreated animals that did not experience inspiratory arrest after cocaine were shown to exhibit significant decrements in f and V(E) as a consequence of prolonged inspiratory pauses. The reduction in MABP after cocaine in ATR pretreated animals was also significant. These results suggest that ATR enhances the central respiratory toxicity of cocaine by acting synergistically at CVLM chemosensitive sites.     

Inhibition of Succinate Dehydrogenase by Malonic Acid Produces an "Excitotoxic" Lesion in Rat Striatum

Abstract: Clinical and preclinical evidence supports a possible role for thyrotropin-releasing hormone (TRH) in cocaine action. However, the interaction between cocaine and TRH has not been directly examined. In the following report we describe a solution hybridization RNase protection assay that can sensitively detect mRNA for the TRH precursor, prepro-TRH (ppTRH). Using this assay, we examined ppTRH mRNA levels in rat brain regions implicated in cocaine reinforcement, including the nucleus accumbens, hypothalamus, amygdala, hippocampus, and thalamus. Acute cocaine treatment (15 mg/kg) resulted in significant decreases in ppTRH mRNA levels in the amygdala and hippocampus, but not in the hypothalamus, nucleus accumbens, or thalamus, 45 min postinjection. Chronic cocaine treatment (15 mg/kg twice daily for 14 days) resulted in marked regulation in all regions but the thalamus. Regulation was strongly dependent on the length of cocaine withdrawal and persisted up to 72 h postinjection in the amygdala. These studies support the hypothesis that TRH or other ppTRH-derived peptides are involved in cocaine action, especially in the extrahypothalamic regions of the amygdala and hippocampus.     

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.     

Cocaine withdrawal produces behavioral disruptions in rats

There is currently no laboratory or clinical evidence from animal or human studies documenting a withdrawal syndrome associated with cocaine dependence, although many users report that withdrawal disturbances are responsible for their repeated use of the drug. In the present study rats self-administered i.v. cocaine and a sweetened drinking solution. When cocaine access was terminated there was a marked suppression in operant behavior reinforced by the sweetened solution, and this withdrawal disruption was immediately reversed when cocaine was reinstated. There were no physical signs of withdrawal, and food intake increased when cocaine was withdrawn. The results suggest that sensitive behavioral tests reveal aspects of drug dependence that may account for persistent abuse.