Repeated Cocaine Exposure Research Articles

Monoaminergic Regulation of Neuroendocrine Function and Its Modification by Cocaine

Neuroendocrine pharmacology represents a potentially valuable approach to the assessment of alterations in neuronal function in the brain of human cocaine abusers. Neuroendocrine effects of the monoamine uptake inhibitor cocaine have predominantly been examined in laboratory animals. These preclinical studies may help to identify the optimal challenge tests to be performed in clinical studies. In laboratory animals, acute administration of cocaine activates the hypothalamic-pituitary-adrenal axis, via actions on serotonergic and dopaminergic neurons in the brain. Cocaine also reduces prolactin secretion, probably by dopaminergic mechanisms, although the necessary studies to confirm this hypothesis have not been performed. Cocaine also reduces renin secretion, and increases vasopressin and luteinizing hormone secretion, by mechanisms which have not been clearly established. The adrenocorticotropin, corticosterone, prolactin, and renin responses to cocaine are generally unaltered by prior cocaine exposure, suggesting that tolerance or sensitization to the endocrine effects of cocaine does not occur. However, several studies have determined that prior cocaine exposure alters the serotonergic regulation of hormone secretion. Chronic cocaine exposure reduces some of the hormone responses to the serotonin (5-HT) releasers p -chloroamphetamine and d-fenfluramine, suggesting deficits in the functional status of serotonergic nerve terminals. Additionally, repeated cocaine exposure produces subsensitive 5-HT1A-mediated hormone responses, and supersensitive 5-HT2-mediated responses. Alterations in dopaminergic- or noradrenergic-mediated hormone responses have not been examined in animals chronically exposed to cocaine. Endocrine studies in human cocaine abusers have largely examined basal hormone levels or the hormone responses to cocaine. Strong conclusions from these studies are limited because (1) many neuronal and nonneuronal systems regulate secretion of each hormone, so that alterations in basal hormone levels cannot be attributed to only one neurotransmitter; and (2) hormone responses to cocaine cannot be examined in cocaine-naive subjects due to ethical considerations, making it impossible to determine whether the response in cocaine abusers is abnormal. It may be more beneficial for studies in cocaine abusers to examine the hormone responses to drugs that specifically affect monoaminergic neurons and compare the data with cocaine-naive individuals.

Selective reduction in dopamine turnover in the rat frontal cortex and hypothalamus during withdrawal from repeated cocaine exposure

The effects of 7 days repeated cocaine administration on the dynamics of dopamine release and metabolism in four rat brain regions (frontal cortex, hypothalamus, nucleus accumbens and striatum) were evaluated 1 week (long-term effects) after the final cocaine injection. 3-Methoxytyramine and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were respectively used to assess the dynamics of dopamine release and metabolism. Consistent with a previous report, cocaine withdrawal was associated with marked reductions in DOPAC rate of formation in the frontal cortex and hypothalamus but not in the nucleus accumbens or the striatum. Dopamine release as indicated by 3-methoxytyramine steady-state concentration and its rate of formation was normal in all four brain regions 1 week after repeated cocaine exposure. The ratios of 3-methoxytyramine rate of formation to that of DOPAC were calculated and found to be increased in the frontal cortex and hypothalamus suggesting dopamine reuptake inhibition, at least 1 week after cocaine withdrawal, continued to be depressed in these regions. It is concluded that repeated cocaine has no long-term effect on dopamine release but produces selective long-term reductions in dopamine turnover in frontal cortex and hypothalamus. Cocaine withdrawal is therefore better associated with changes in dopamine turnover than with its release.

Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT 1A agonist, 8-OH-DPAT

The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT 1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT 1A agonist. Male rats received cocaine (15 mg/kg, i.p.) or saline twice daily for 7 days. Forty-two hr after the final cocaine injection, the 5-HT releaser d-fenfluramine (0, 0.2, 0.6, 2, or 5 mg/kg, i.p.) or the 5-HT 1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 μg/kg, s.c.) were administered. Blood samples were then collected for analysis of plasma ACTH, prolactin, and renin concentrations. The ACTH responses to d-fenfluramine and 8-OH-DPAT were inhibited in cocaine pretreated rats. However, the prolactin responses to d-fenfluramine and 8-OH-DPAT were not significantly modified by cocaine exposure. Additionally, the renin response to d-fenfluramine was unaltered by repeated cocaine administration, while 8-OH-DPAT did not alter renin secretion in either pretreatment group. In contrast to published reports which show that cocaine exposure produces supersensitive 5-HT 2A and/or 5-HT 2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT 1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT 1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT 1A agonists may represent a valuable approach to deermine deficits in 5-HT function in human cocaine abusers.

Influence of repeated cocaine exposure on the endocrine and behavioral responses to stress in rats.

Previous studies have determined that chronic cocaine exposure inhibits the serotonergic stimulation of hormone secretion. The present experiments were conducted to determine whether the endocrine responses to stress could be a useful approach to assess the influence of cocaine exposure on neuronal function. Male rats received twice daily injections of cocaine (1-15 mg/kg, IP) for 7 days. Animals were subsequently exposed to different stressors, i.e. conditioned emotional stress utilizing a low (0.5 mA) or high (1.5 mA) intensity footshock during training, or to immobilization stress. Immediately after the stress procedures, blood samples were collected for radioimmunoassay of plasma corticosterone, prolactin, and renin concentrations. Repeated cocaine exposure attenuated the stress-induced elevations of corticosterone and prolactin secretion, and attenuated some of the behavioral effects of the low intensity conditioned emotional stress. When exposed to the high intensity conditioned emotional stress, cocaine did not alter the endocrine or behavioral effects of stress. Finally, repeated cocaine exposure modified the immobilization stress-induced elevation of renin secretion; low doses of cocaine (1 or 5 mg/kg) attenuated, while higher doses (10 mg/kg) potentiated the renin response to immobilization stress. Thus, the influence of repeated cocaine exposure on the endocrine and behavioral responses to stress appears to depend upon the type and intensity of the stressor. Compared with previous studies which found altered neuroendocrine responses to serotonin releasers and agonists following cocaine exposure, the hormonal responses to stress are less consistently modified by cocaine.

Effect of cocaine on the production of puberty-accelerating pheromone by male mice

This study examined whether chronic cocaine exposure could reduce reproductive fitness of adult male mice by interfering with their production of the puberty-accelerating pheromone, an androgen-dependent urinary pheromone that accelerates puberty in juvenile female mice. Administered at a high dose of 60 mg/kg body weight/day, cocaine caused mortality, body weight loss, and suppression of circulating testosterone during the first week of treatment. However, at 40 mg/kg/day, it resulted in little adverse effect of these parameters. Animals showed habituation to repeated cocaine exposure by regaining part of the lost weight and reelevating suppressed testosterone level at later stages of treatment. Urine samples collected from animals receiving 60 mg/kg cocaine daily for 2 weeks lost the puberty-accelerating effect. However, neither a 3-day treatment of the same dose nor a lower dose of 40 mg/kg reduced the effectiveness. The diminished effect of cocaine-treated male mouse urine might reflect lowered testosterone levels with a lag of 10 to 15 days, similar to that of castrated male mouse urine . These results indicate that cocaine has no direct effect on the production of priming pheromone, and its metabolites in the urine did not affect the response of juvenile females to the pheromone.

Individual Differences in Locomotor Activity Are Associated with Levels of Tyrosine Hydroxylase and Neurofilament Proteins in the Ventral Tegmental Area of Sprague-Dawley Rats

We have demonstrated previously that chronic morphine and cocaine treatments increase levels of tyrosine hydroxylase (TH), and decrease levels of neurofilament (NF) proteins, in the ventral tegmental area (VTA), a major dopaminergic brain reward region, of outbred Sprague-Dawley rats. We have also found inherent differences in levels of these proteins in the VTA of inbred rat strains that differ in their behavioral responses to opiates, cocaine, and other drugs of abuse, with the Lewis rat showing higher levels of TH and lower levels of NFs in the VTA compared to the Fischer 344 rat. Based on recent reports that individual differences in drug responses among outbred Sprague-Dawley rats are highly correlated with the animals' locomotor response to novelty, we determined in the present study whether such within-strain differences in locomotor behavior are also associated with differences in levels of TH and NFs in the VTA. Groups of 42 Sprague-Dawley rats were assessed for locomotor activity in a novel environment. The four animals from each group with the lowest locomotor responses (designated L rats), and the four with the highest locomotor responses (designated H rats), were analyzed for TH and NF immunoreactivity by immunoblotting procedures. It was found that the VTA of L rats exhibited higher levels of TH and lower levels of three major NF proteins, NF-200, NF-160, and NF-68, compared to the VTA of H rats. A tendency for similar L versus H differences in TH and NF levels were observed when groups of rats with the second lowest and second highest locomotor responses were compared; no differences were seen in groups whose locomotor responses were closer to the median. These biochemical differences between H and L rats showed regional specificity, with no significant differences seen in several other regions of brain or spinal cord studied. Differences were also observed between L and H rats in their locomotor responses to acute and repeated cocaine exposure. The possible relationship between the individual differences in TH and NFs and individual differences in locomotor activity and other drug-related behaviors is discussed.

Effects of prior cocaine exposure on subsequent neuronal responsiveness

In vivo electrophysiological experiments were conducted to examine the responses of single, spontaneously-active neostriatal neurons to repeated cocaine exposure. The second of two administrations in a 30 min interval, attenuated the magnitude and duration of cocaine-induced depression in discharge rate, and enhanced the same variables for cocaine-evoked excitation . These findings indicate that the responsiveness of striatal neurons to cocaine may vary predictably as a function of previous exposure.

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1–15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.

Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [ 3H]dopamine release

Locomotor activity and stereotypy induced by cocaine is increased or ‘sensititized’ after repeated cocaine administration. This behavioral sensitization may be mediated by a persistent increase in dopamine (DA) transmission in mesolimbic and nigrostriatal pathways. Since the female estrous cycle and ovarian steroid hormones appear to affect both cocaine sensitization and DA transmission, studies were undertaken to determine the effects of ovarian steroids on sensitization of the behavioral responses to repeated cocaine injections and any concomitant effects on striatal DA release. Young female adult rats were ovariectomized and 2 weeks later were implanted with chronic release forms of estradiol (E), progesterone (P), both (EP) or vehicle (V). Locomotor and stereotypic behavior were rated after an initial injection of either saline or cocaine (10 mg/kg, i.p.) and after the 8th daily injection of saline or cocaine. A significant increase in both locomotor and stereotypic behaviors was seen after first cocaine injection relative to saline-injected animals and this response was not affected by steroid treatment. Repeated injections of cocaine caused sensitization of the initial behavioral response to cocaine (i.e. an increase in stereotypic and locomotor behavior) and the degree of cocaine sensitization was greatest in group E. Steroid treatment did not affect behavior in saline-treated rats. When striatal [ 3H]DA release was measured in vitro 1 or 7 days after the last injection, amphetamine-stimulated release was greater in vehicle-treated rats 7 days after cocaine injections but not 1 day after injections. In contrast, release was enhanced in group E both 1 and 7 days after cocaine. Combined EP treatment or P treatment alone did not enhance either behavioral sensitization of cocaine or amphetamine-stimulated release. Collectively these data indicate that E enhances both behavioral sensitization to cocaine and amphetamine-stimulated striatal DA release supporting the hypothesis that DA release may be E-modulated, neurochemical substrate of the behavioral effects of repeated cocaine exposure.

Differential effects of daily administration of cocaine on hepatic and cerebral glutathione in mice

Twenty-four hours after acute administration of cocaine HCl (25 mg/kg, i.p.) to male C57BL/ 6ByJ mice, there was no hepatotoxicity as measured by plasma aspartate aminotransferase (AST) activity. In contrast, daily administration of cocaine (25 mg/kg, i.p.) for 14 days induced marked hepatotoxicity, as characterized by a greater than 400% increase in plasma AST activity when assayed 24 hr after the last injection. Concomitantly, the liver had increased levels of cysteine, γ-glutamylcysteine, glutathione, cysteinylglycine, glutamate, methionine, taurine, and aspartate. The effect appeared to be selective for compounds of the glutathione metabolic pathways, because repeated cocaine exposure did not affect other amino acids such as leucine, isoleucine, phenylalanine, serine, and valine. There was a positive correlation between the magnitude of the elevation of cysteine and the extent of liver damage. Daily cocaine administration did not affect striatal or frontal cortex glutathione. A final cocaine challenge (50 mg/kg, i.p.) did not affect either hepatic or cerebral glutathione metabolism. The increase in hepatic cysteine and glutathione upon daily cocaine administration is a potentially important compensatory mechanism against cocaine-induced hepatotoxicity.

In Vitro electrophysiology of dorsal raphe serotonergic neurons in subchronic cocaine-treated rats: Development of tolerance to acute cocaine administration

An in vitro, extracellular slice preparation was used to examine the effects of subchronic cocaine administration on serotonergic cell firing in the dorsal raphe. Male Sprague—Dawley rats were administered cocaine (30 mg/kg, ip) for 7 days prior to experimentation. Following a 24-h washout period, rats were decapitated and dorsal raphe nucleus slices (400 μm) obtained. Slices were superfused with ACSF containing 1 AM phenylephrine and 1 μ M 5-hydroxytryptamine (5-HT). Acute cocaine application was found to inhibit basal firing rates in both saline- and cocaine-pretreated rats. In addition, an apparent tolerance to acute cocaine application was found in animals subchronically treated with cocaine. Animals exposed to repeated cocaine exposure required an acute cocaine concentration of 5.46 ± 0.5 μ M ( N = 5) to inhibit cell basal firing rates by 50% versus concentrations of 2.43 ± 0.35 μ M ( N = 5) for saline controls. Concentrations of 20 μ M cocaine typically produced complete inhibition of firing in cocaine-pretreated animals, whereas 10 μ M cocaine produced complete cessation of firing in saline controls. Repeated perfusion with equal concentrations of cocaine produced dose-dependent inhibition of firing which remained consistent at each application, indicating no development of an acute tolerance effect. In addition, inhibition responses to acute applications of 5-HT showed no differences between treatment groups. Furthermore, there were no indications of a developed tolerance to 5-HT application. Finally, ligand binding studies using 8-OH-DPAT in hippocampal tissue indicate that there are no significant differences in either K d or B max between subchronically cocaine-treated or salinetreated animals. These results seem to indicate that the inhibitory effects of cocaine are not due to direct effects on the presynaptic autoreceptor but are indirectly produced due to cocaine's inhibition of the 5-HT reuptake system.

Cocaine tolerance: Interactions among random‐ratio and random‐interval reinforcement‐schedule parameters and repeated exposure to cocaine

AbstractFood‐deprived pigeons were trained to peck a key under either a three‐component multiple random‐ratio 5, random‐ratio 25, random‐ratio 125 schedule or a three‐component multiple random‐interval 10‐sec, random‐interval 30‐sec, random‐interval 125‐sec schedule of food presentation. Following determination of acute effects of cocaine (1.0‐13.0 mg/kg), are‐sponse‐rate‐reducing dose was given before each daily session. Once performance under conditions of daily administration had become stable, other doses occasionally were substituted for the usual daily dose so that dose effects could be assessed. Tolerance, i.e., a rightward shift in the dose‐effect curve was observed in all subjects. For subjects studied under the random‐ratio schedules, however, the robustness of the tolerance usually was related to the schedule‐parameter value; tolerance was great at lower random values. By contrast, subjects whose responding was maintained by random‐interval schedules were less likely to show tolerance that was schedule‐parameter dependent. The results also provide suggestive evidence that dose may be an important factor in determining effects of repeated cocaine exposure; repeated administration of larger doses may be less likely to result in tolerance than similar exposure to smaller doses.