Differential Effects Of Cocaine Research Articles

Differential Effects of Cocaine and Morphine on the Diurnal Regulation of the Mouse Nucleus Accumbens Proteome.

Substance use disorders are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based quantitative proteomics, along with a data-independent acquisition analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveal cocaine and morphine differentially alter diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between the phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome. The proteomics data in this study are available via ProteomeXchange with identifier PXD042043.

Cocaine treatment before pregnancy differentially affects the anxiety and brain glucose metabolism of lactating rats if performed during adulthood or adolescence

Cocaine exposure disrupts the maternal behavior of lactating rats, yet it is less known whether it alters the affective changes that accompany motherhood. As the long-term action of cocaine on anxiety varies according to the developmental stage of the individuals, this study aimed to compare the effect of a chronic treatment with cocaine to adult and adolescent non-pregnant females on their anxiety-like behavior and basal brain metabolic activity during lactation. Thus, adult and adolescent virgin rats were exposed to cocaine (0.0 or 15.0 mg/kg ip) during 10 days and were mated four days later. Anxiety behavior was evaluated on postpartum days 3–4 in the elevated plus maze test, and the basal brain glucose metabolism was determined on postpartum days 7–9 by means of [18F] fluorodeoxyglucose positron emission tomography. Cocaine treatment during adulthood increased the anxiety-like behavior of lactating females whereas its administration during adolescence decreased it. Also, the basal glucose metabolism of the medial prefrontal cortex differed between lactating females treated with cocaine during adulthood and adolescence. These differential effects of cocaine, according to the age at which the drug was administered, support the idea that the adolescent and adult brains have a distinct susceptibility to this drug, which leads to divergent long-term changes in the neural circuits that regulate anxiety during lactation.

Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats.

Roman high (RHA)- and low (RLA)-avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short- and long-term neuronal plasticity via activation of the extracellular signal-regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction.

Differential effects of cocaine on histone posttranslational modifications in identified populations of striatal neurons

Drugs of abuse, such as cocaine, induce changes in gene expression and epigenetic marks including alterations in histone posttranslational modifications in striatal neurons. These changes are thought to participate in physiological memory mechanisms and to be critical for long-term behavioral alterations. However, the striatum is composed of multiple cell types, including two distinct populations of medium-sized spiny neurons, and little is known concerning the cell-type specificity of epigenetic modifications. To address this question we used bacterial artificial chromosome transgenic mice, which express EGFP fused to the N-terminus of the large subunit ribosomal protein L10a driven by the D1 or D2 dopamine receptor (D1R, D2R) promoter, respectively. Fluorescence in nucleoli was used to sort nuclei from D1R- or D2R-expressing neurons and to quantify by flow cytometry the cocaine-induced changes in histone acetylation and methylation specifically in these two types of nuclei. The two populations of medium-sized spiny neurons displayed different patterns of histone modifications 15 min or 24 h after a single injection of cocaine or 24 h after seven daily injections. In particular, acetylation of histone 3 on Lys 14 and of histone 4 on Lys 5 and 12, and methylation of histone 3 on Lys 9 exhibited distinct and persistent changes in the two cell types. Our data provide insights into the differential epigenetic responses to cocaine in D1R- and D2R-positive neurons and their potential regulation, which may participate in the persistent effects of cocaine in these neurons. The method described should have general utility for studying nuclear modifications in different types of neuronal or nonneuronal cell types.

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.

One-trial behavioral sensitization in preweanling rats: differential effects of cocaine, methamphetamine, methylphenidate, and d-amphetamine

Preweanling rats exhibit robust one-trial cocaine-induced behavioral sensitization; however, it is uncertain whether other psychostimulants can also induce sensitization in young rats using the one-trial procedure. The purpose of this study was to determine whether methamphetamine, methylphenidate, and D: -amphetamine are capable of inducing one-trial locomotor sensitization in preweanling rats. In a series of four experiments, rats were pretreated with cocaine (30 mg/kg), methamphetamine (2-12 mg/kg), methylphenidate (5-20 mg/kg), or amphetamine (5 mg/kg) before being placed in a novel activity chamber or the home cage on PD 19. Rats were then challenged with the same psychostimulant (20 mg/kg cocaine, 1-8 mg/kg methamphetamine, 2.5-7.5 mg/kg methylphenidate, or 1-2 mg/kg amphetamine) on PD 21, with distance traveled being measured for 180 min. In a separate experiment, rats were pretreated with methamphetamine on PD 16-19 and challenged with methamphetamine on PD 21. Only cocaine, but not various dose combinations of other psychostimulants, was able to produce one-trial behavioral sensitization in preweanling rats. Context-dependent locomotor sensitization was also evident if rats were pretreated with methamphetamine on PD 16-19 and tested on PD 21. It is uncertain why only cocaine was able to induce one-trial locomotor sensitization in preweanling rats, but it is possible that: (a) the neural circuitry mediating sensitization differs according to psychostimulant, (b) cocaine is more readily associated with environmental contexts than other psychostimulants, or (c) affinity and pharmacokinetic factors may underlie cocaine's ability to induce one-trial behavioral sensitization in preweanling rats.

Differential effects of cocaine and MDMA self-administration on cortical serotonin transporter availability in monkeys

Cocaine self-administration alters brain dopaminergic and serotonergic function primarily in mesolimbic and prefrontal brain regions whereas 3,4-methylenedioxymethamphetamine (MDMA) self-administration predominately alters brain serotonergic function in a more widespread distribution across cortical regions. We previously reported that, compared to drug-naïve rhesus monkeys, self-administration of cocaine but not MDMA was associated with increased serotonin transporter (SERT) availability in two mesolimbic regions, the caudate nucleus and putamen, as measured by positron emission tomography (PET) using the SERT-specific ligand [ 11C]-3-amino-4(2-dimethylamino-methyl-phenylsulfanyl)-benzonitrile ([ 11C]DASB). The goal of the present study was to extend this comparison between cocaine and MDMA self-administration to SERT availability in cortical regions, which have been shown previously to be affected in human drug abusers and are associated with executive function. PET studies using [ 11C]DASB were conducted in adult male rhesus monkeys with a history of cocaine (mean intake = 742.6 mg/kg) or MDMA (mean intake = 121.0 mg/kg) self-administration, and drug-naïve controls ( n = 4/group). Regions of interest were drawn for several cortical (prefrontal, temporal, parietal, occipital and midcingulate) and subcortical (thalamus, amygdala and hippocampus) areas. Cortical SERT availability was significantly higher in monkeys with a cocaine self-administration history compared to controls whereas MDMA self-administration resulted in lower levels of SERT availability. These data extend our previous findings indicating that cocaine and MDMA self-administration differentially alter SERT availability in subcortical and cortical regions, which may have implications for development of treatment drugs.

Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats

This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed two rats/cage with no toys (SI2) or with toys (SE2), or three/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cage mates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr 34-DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.

Schedule-induced polydipsia alters cocaine-but not ethanol-induced suppression of saccharin consumption

Under traditional water-deprived conditions, both LiCl and morphine produce comparable suppression of saccharin consumption after repeated pairings. However, under conditions of spaced food deliveries (i.e., schedule-induced polydipsia; SIP), morphine produces a significantly weaker suppression than LiCl. The differential responses have been attributed to an increase in the rewarding effects of drugs of abuse (such as morphine) that masked the expression of the aversive effects, a masking not evident with LiCl which has no reported rewarding effects. The present study extended this characterization to two additional drugs of abuse; cocaine and ethanol. Following schedule-induced saccharin consumption, female Sprague–Dawley rats were given injections of LiCl, cocaine, ethanol (at doses comparably effective in conditioning taste aversions under water deprivation) or distilled water vehicle. Although cocaine and ethanol both suppressed SIP, only cocaine produced a significantly delayed suppression relative to LiCl. The differential effects of cocaine (and morphine), but not ethanol, may be a function of the different reward profiles of these drugs. Given the differential ability of drugs of abuse to suppress consumption under conditions of spaced feedings, the SIP procedure may be a useful baseline to assess the rewarding effects of such drugs. Further, given the differential results with cocaine and ethanol, the relative rewarding effects of drugs may be differentially indexed in this preparation, as well.

Differential effects of cocaine and ketamine on time estimation: Implications for neurobiological models of interval timing

The present experiment examined the effects of cocaine (0.0 and 15 mg/kg, i.p.) and ketamine (0.0, 10.0 and 15 mg/kg, i.p.) on timing behavior using a 12-s differential reinforcement of low rates (DRL) procedure and a 2- vs. 8-s bisection procedure in rats. DRL (time production) and bisection (time perception) procedures are sensitive to effects of dopaminergic drugs and provide an assessment of the accuracy and precision of interval timing as well as the subject's level of impulsivity. When administered to rats trained on either the DRL or the bisection procedure, cocaine shifted the psychophysical functions leftward relative to control conditions. In contrast, ketamine produced no change in the temporal control of behavior on either procedure. These differential effects of cocaine and ketamine are consistent with previous reports suggesting that dopamine levels in the dorsal striatum, but not in prefrontal cortex, ventral striatum or hippocampal regions, are crucial for the regulation of the speed of an internal clock.

The effect of cocaine on the expression of motor activity and conditioned place preference in high and low alcohol-preferring Wistar rats

Outbred rats show significant variability in their propensity to consume alcohol. These experiments were designed to examine the effect of cocaine on the expression of motor activation or place preference in outbred Wistar rats that consumed either high or low quantities of alcohol. These rats were exposed to a 2-bottle limited access procedure and dichotomized into 2 groups, high (mean 0.91 g/kg/h) and low alcohol consumption (0.36 g/kg/h), and then exposed to repeated daily cocaine, 10 or 20 mg/kg, or saline injections. The low alcohol-consuming rats showed a significant increase in motor behavior to a cocaine challenge across both doses of cocaine, which did not differ from each other. The high alcohol-consuming rats showed a significant increase in motor behavior only at the high dose of cocaine. In Experiment 2 both high and low alcohol-consuming rats were exposed to a conditioned place preference procedure using cocaine 10 mg/kg. High alcohol-consuming rats showed a significant place preference to the cocaine-paired side while low consuming rats did not. The differential effects of cocaine on motor activating behavior and reward obtained in these experiments suggest that those factors determining whether an outbred Wistar rat will consume high or low amounts of alcohol are related, in part, to differential sensitivity of those neural systems underlying the effects of those drugs.

Stimulants, Sex, and Gender

This article examines the differential effects of cocaine and methamphetamine (MA) on sexual drive, performance, and pleasure among men and women. Based on a self-report questionnaire, we examine cocaine (n = 56) and MA (n = 52) users' associations between substance use and sex. Overall, the cocaine group endorsed primarily negative associations between drug use and sex, whereas MA users reported strong positive associations. Female cocaine users were least likely to endorse positive associations, whereas female MA users were the least likely to endorse negative associations. The question: “How does drug use affect sexual behavior?” cannot be answered without first specifying the drug and the gender of the user. Better information on this topic could greatly enhance the efforts of clinicians providing treatment services to drug using populations.

Ventral striatal anatomy of locomotor activity induced by cocaine, D-amphetamine, dopamine and D 1/D 2 agonists

The ventral striatum appears to play a critical role in mediating motoric effects (i.e. ambulatory activity and rearing) of psychostimulants such as cocaine. We evaluated whether sub-regions of the ventral striatum play differential roles in locomotion and rearing induced by various dopaminergic drugs. Injections of D-amphetamine and dopamine stimulated locomotion and rearing with a similar potency at each of the sub-regions: the core, medial shell or medial tubercle. However, injections of mixtures of the D 1- and D 2-type agonists SKF 38393 and quinpirole or cocaine into the medial olfactory tubercle or the medial shell of the nucleus accumbens induced marked locomotion and rearing, while these injections into the core induced little or no locomotion or rearing. Furthermore, cocaine injections into the lateral or posterior tubercle produced marginal locomotion and rearing, while cocaine injections into regions just dorsal to these tubercle sites, the lateral portion of the shell or the ventral pallidum, did not produce any stimulating effect. We conclude that dopaminergic compounds induce vigorous locomotion and rearing in both core and shell; the relative roles of the core and shell differ depending on chemical compounds. Similar to the nucleus accumbens, the olfactory tubercle, particularly the medial portion, also mediates these behaviors induced by dopaminergic compounds. The medial ventral striatum (i.e. the medial tubercle and medial shell) plays a more important role in cocaine-induced locomotion and rearing than the lateral ventral striatum (i.e. the core, lateral shell and lateral tubercle). Moreover, the differential effects of cocaine between the medial and lateral portions of the shell on locomotion and rearing suggest more than two functional units (the core vs. the shell) within the accumbens.

Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3,4-methylenedioxymethamphetamine (“ecstasy”)

Background: Psychomotor stimulant drugs can produce long-lasting changes in neurochemistry and behavior after multiple doses. In particular, neuroadaptations within corticolimbic brain structures that mediate incentive learning and motivated behavior have been demonstrated after chronic exposure to cocaine, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). As stimulus–reward learning is likely relevant to addictive behavior (i.e., augmented conditioned reward and stimulus control of behavior), we have investigated whether prior repeated administration of psychomotor stimulant drugs of abuse, including cocaine, d-amphetamine, or MDMA, would affect the acquisition of Pavlovian approach behavior. Methods: Water-deprived rats were tested for the acquisition of Pavlovian approach behavior after 5 days treatment with cocaine (15–20 mg/kg once or twice daily), d-amphetamine (2.5 mg/kg once or twice daily), or MDMA (2.5 mg/kg twice daily) followed by a 7-day, drug-free period. Results: Prior repeated treatment with cocaine or d-amphetamine produced a significant enhancement of acquisition of Pavlovian approach behavior, indicating accelerated stimulus–reward learning, whereas MDMA administration produced increased inappropriate responding, indicating impulsivity. Abnormal drug-induced approach behavior was found to persist throughout the testing period. Conclusions: These studies demonstrate that psychomotor stimulant-induced sensitization can produce long-term alterations in stimulus–reward learning and impulse control that may contribute to the compulsive drug taking that typifies addiction.

Differential effects of cocaine on local cerebral glucose utilization in the mouse and in the rat

The aim of the study was to determine whether cocaine causes a different pattern of functional changes in the rat as compared to the mouse. The [ 14C]2-deoxyglucose method, for measuring local cerebral metabolic rates for glucose, was carried out in Sprague–Dawley rats and in two strains of mice, C57BL/6 and DBA/2, following a single intravenous administration of cocaine. Cocaine, according to previous reports, increased glucose utilization in the nucleus accumbens of the rat, while the drug decreased metabolic rates in most of brain areas of both strains of mice. The post-hoc analysis, however, suggests that the pattern of metabolic changes differ in the two strains. In particular, the effect on the shell of the nucleus accumbens was present in the C57, but not in the DBA mice. As the C57 mice are more likely than DBA to initiate cocaine self-administration, the effect on the nucleus accumbens support the role of the mesolimbic pathway in mediating the motivational properties of psychostimulants.

Differential effects of cocaine on the positive inotropic effect of noradrenaline mediated by α 1- and β-adrenoceptors in failing human myocardium

Electrically driven (1 Hz) ventricular trabeculae from explanted failing human myocardium were indirectly examined for the localization of the α 1-adrenoceptor population and the β-adrenoceptor population in relation to sympathetic nerve endings. We examined the influence of neuronal uptake blockade by cocaine upon the horizontal position of the concentration–response curves for the inotropic effects exerted by noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. Cocaine shifted the concentration–response curve for α 1-adrenoceptor stimulation, but not that for β-adrenoceptor stimulation, to lower concentrations of noradrenaline in a parallel manner. The concentration–response curve for combined adrenoceptor stimulation was shifted by cocaine to lower concentrations of noradrenaline in a nonparallel manner. In explanted allograft heart, cocaine had no effect upon the position of the concentration–response curve to α 1-adrenoceptor stimulation. The data indicate that in the explanted native hearts the α 1-adrenoceptor population is located close to or within the synaptic cleft, while the β-adrenoceptor population remaining in the failing myocardium is located more distantly to the neuronal release sites.

Differential effects of cocaine and methamphetamine on neurotensin/neuromedin N and preprotachykinin messenger RNA expression in unique regions of the striatum

This study employed in situ hybridization to directly compare the effects of cocaine and methamphetamine on neurotensin/neuromedin N and preprotachykinin messenger RNAs in distinct striatal regions. Male, Sprague–Dawley rats received a single administration of 15 mg/kg methamphetamine (s.c.) or 30 mg/kg cocaine (i.p.) and were killed 30 min or 3 h later. Methamphetamine and cocaine produced significant increases in preprotachykinin messenger RNA in the striatum after 3 h, but often in different subregions. Both drugs produced similar effects on preprotachykinin messenger RNA in the rostral striatum. However, methamphetamine produced significant increases in all regions of the caudal striatum, whereas cocaine-induced preprotachykinin messenger RNA expression was limited to dorsal regions of this striatal area. Methamphetamine also produced a significant increase in preprotachykinin messenger RNA in the caudal striatum after 30 min, whereas cocaine had no significant effect on preprotachykinin messenger RNA at this early time-point. The pattern of changes in neurotensin/neuromedin N messenger RNA caused by methamphetamine and cocaine after 3 h was even more distinct. Cocaine produced significant increases in neurotensin/neuromedin N messenger RNA in all regions of the rostral striatum, whereas methamphetamine had no effect in these areas. Furthermore, in more caudal sections, cocaine predominantly affected neurotensin/neuromedin N expression in dorsal aspects of the striatum, whereas methamphetamine significantly increased neurotensin/neuromedin N messenger RNA in all regions. There was much less effect of either drug on neuropeptide expression in the nucleus accumbens. The only significant effect was an increase in neurotensin/neuromedin N messenger RNA in the core region 3 h after methamphetamine administration. These results indicate that methamphetamine and cocaine increase preprotachykinin and neurotensin/neuromedin N messenger RNAs in distinct regions of the striatum. The ability of methamphetamine and cocaine to alter neuropeptide messenger RNA expression in unique regions of the striatum may be important for the long-term effects of these drugs, such as sensitization, since the striatum is not homogeneous in its connections and function.

Dexamethasone suppression of the effects of cocaine on adrenocortical secretion in Lewis and fischer rats

There is evidence to suggest that cocaine acts centrally to enhance adrenocortical secretory activity and this effect may be associated with the reinforcing properties of this drug. Lewis (LEW) and Fischer (F344) rats are inbred strains which differ in their responses to the reinforcing effects of cocaine. Previous findings from this laboratory have demonstrated differences in the hypothalamic-pituitary-adrenocortical (HPA) responses to cocaine between these strains. To determine whether strain differences in glucocorticoid responsiveness play a role in the differential effects of cocaine on plasma corticosterone (CS) secretion in these strains, experiments were designed to suppress the HPA response to cocaine in these two rat strains. HPA activity was attenuated by central administration of the glucocorticoid agonist dexamethasone (DEX) using osmotic minipumps. A constant infusion of artificial cerebrospinal fluid or DEX (50, 100 or 500 ng/h) was delivered into the lateral ventricle of LEW and F344 rats. Four days later, the rats were challenged with cocaine HCl (0, 20 and 40 mg/kg, i.p.), and the plasma CS response 15 min later was quantified. Cocaine-induced alterations in circulating plasma CS were reduced in a dose-related manner by centrally administered DEX in both strains. Significant strain differences in the effects of DEX on the plasma CS response to cocaine were observed, suggesting that LEW rats were more sensitive to DEX suppression of HPA activity than F344 rats. DEX also produced dose-related effects on body weight in both strains and decreased adrenal weight at the highest dose in F344 rats. Blood collected on the final day of the experiment demonstrated that central infusions of DEX decreased plasma ACTH concentrations in both strains compared to control rats. These studies indicate that central administration of DEX produces a feedback inhibition of cocaine-induced glucocorticoid release and that LEW rats are more sensitive to DEX suppression than F344 rats.

Differential effects of cocaine, alcohol, and nicotine dependence on olfactory evoked potentials

Olfactory evoked potentials (OEP) were elicited by odorous and nonodorous stimuli in 50 adult subjects: 26 subjects with histories of either cocaine ( n = 19) or alcohol ( n = 7) dependence, 10 with histories of nicotine but no other drug dependence, 2 with clinical anosmia of peripheral origin, and 12 subjects without drug or olfactory disorders. The presentation of nonodorous stimuli (i.e. a nasal air puff) did not elicit OEP component amplitude and latency differences among the groups. However, the presentation of odorous stimuli elicited a significantly smaller P1 component in the cocaine-dependent and alcohol-dependent groups than in the normal control and nicotine-dependent groups. The P1 amplitude deficit in the cocaine-dependent group is consistent with case report data associating cocaine use with lesions of the peripheral and/or central olfactory apparatus.

Differential potentiation of L-tryptophan-induced head-twitch response in mice by cocaine and sertraline

Using selective monoamine uptake blockers and appropriate selective monoamine receptor antagonists, we have previously shown that cocaine enhances the frequency of 5-HT 2A receptor-mediated 5-hydroxytryptophan (5-HTP)-induced head-twitch response (HTR) in mice via inhibition of serotonin uptake. Concomitantly, cocaine prevented the maximal producible HTR frequency via simultaneous indirect stimulation of the inhibitory presynaptic 5-HT 1A and postsynaptic α 2 receptors. In the present study, we have investigated the effects of cocaine and the selective 5-HT (sertraline), norepinephrine (nisoxetine) and dopamine (GBR 12935) uptake inhibitors on the L-tryptophan-induced HTR in the presence of a nonselective monoamine oxidase inhibitor, tranylcypromine. We utilized two experimental protocols where cocaine or sertraline were administered either after (protocol 1) or prior to (protocol 2) L-tryptophan injection. Cocaine potentiated the ability of L-tryptophan to induce HTR to a greater extent in protocol 1, whereas sertraline induced a greater effect in protocol 2. However, in our earlier study cocaine (and also sertraline) up to 10 mg/kg produced a similar degree of potentiation in both experimental protocols on the 5-HTPinduced HTR. Furthermore, as in the latter study on the 5-HTP-induced HTR, in the present investigation nisoxetine potently attenuated whereas GBR 12935 did not modulate the induced HTR. The results show that the respective serotonergic and noradrenergic effects of cocaine also operate on the L-tryptophan-induced HTR. The differential effects of cocaine and sertraline in experimental protocols 1 and 2 on the L-tryptophan- versus 5-HTP-induced HTRs suggest that cocaine has additional effects on the conversion of L-tryptophan to 5-HT.