Carbamazepine produces nonspecific effects on cocaine self-administration in rats.

Anecdotal evidence in humans suggest that carbamazepine suppresses cocaine-induced rush and craving. Such claims are unsupported in controlled trials using a placebo control. In the present study, rats were trained to self-administer i.v. cocaine in daily 2-hr sessions in which every tenth lever press delivered 1 mg/kg cocaine. After responding was stable, they were injected before each session with the vehicle for 2 days followed by carbamazepine for 2 days. At a 7 mg/kg dose, carbamazepine was without effect, whereas 15 mg/kg suppressed responding for cocaine only on the second (day 4) day of carbamazepine treatment. With 4 consecutive days of treatment, carbamazepine (15 mg/kg) reduced cocaine-maintained responding slightly, but significantly. In another group of animals trained to lever-press for food reinforcement, carbamazepine (15 mg/kg) also significantly decreased the rate of responding, suggesting that the suppression of responding was not specific to cocaine-reinforced behavior.     

Differential effects of central serotonin manipulation on hyperactive and stereotyped behaviour

The locomotor response following injection of dopamine into the nucleus accumbens was attenuated by the injection of 5HT and potentiated by the injection of methysergide into the same site. D-amphetamine-induced locomotor activity was also reduced by the intra-accumbens injection of 5HT. In contrast, apomorphine- induced stereotyped behaviour (sniffing, licking, biting, gnawing) was reduced by systematic administration of the putative 5HT receptor antagonists, cyproheptadine and metergoline. In addition the low intensity sniffing responses produced by a low dose of apomorphine were converted to high intensity biting, gnawing or licking by the putative 5HT receptor agonist, quipazine or the putative 5HT uptake blocker, ORG 6582. The selective induction of either hyperactive or stereotyped behaviour may therefore be influenced by the functional state of central serotonergic systems.     

Fluoxetine-induced attenuation of amphetamine self-administration in rats

Daily injections of fluoxetine (5.0 mg/kg i.p.) to rats trained to self-administer intravenous d-amphetamine produced marked decreases in drug intake on three successive days of treatment. After fluoxetine injections were stopped, the number of daily amphetamine self-injections was still significantly reduced for an additional 2 days. When trained amphetamine self-administration animals were placed in an apparatus which delivered i.v. saline with each lever press, increased self-injection is observed. Acute fluoxetine injection did not alter this response. However, if fluoxetine is given prior to amphetamine exposure for 1 day and animals are then tested for the saline response, lever pressing activity is significantly reduced. These data might suggest that 5-hydroxytryptaminergic neurons mediate some aversive or negative reinforcing property of amphetamine. If true, this finding could be exploited clinically in cases of human psychomotor stimulant addiction.     

Differential regulation of accumbal dopamine transmission in rats following cocaine, heroin and speedball self-administration

Cocaine/heroin combinations (speedball) exert synergistic neurochemical and behavioral effects that are thought to contribute to the increased abuse potential and subjective effects reported by polydrug users. In vivo fast-scan cyclic voltammetry was used to examine the effects of chronic intravenous self-administration (25 consecutive sessions) of cocaine (250 μg/inf), heroin (4.95 μg/inf) and speedball (250/4.95 μg/inf cocaine/heroin) on changes in electrically evoked dopamine (DA) efflux, maximal rate of DA uptake (V(max)) and the apparent affinity (K(m)) of the DA transporter in the nucleus accumbens. The increase in electrically evoked DA was comparable following cocaine and speedball injection; however, heroin did not increase evoked DA. DA transporter K(m) values were similarly elevated following cocaine and speedball, but unaffected by heroin. However, speedball self-administration significantly increased baseline V(max), while heroin and cocaine did not change baseline V(max), compared with the baseline V(max) values of drug-na?ve animals. Overall, elevated DA clearance is a likely consequence of synergistic elevations of nucleus accumbens extracellular DA concentrations by chronic speedball self-administration, as reported previously in microdialysis studies. The present results indicate neuroadaptive processes that are unique to cocaine/heroin combinations and cannot be readily explained by simple additivity of changes observed with cocaine and heroin alone.     

Differential long-term neuroadaptations of glutamate receptors in the basolateral and central amygdala after withdrawal from cocaine self-administration in rats

Humans and laboratory animals remain highly vulnerable to relapse to cocaine-seeking after prolonged periods of withdrawal from the drug. It has been hypothesized that this persistent cocaine relapse vulnerability involves drug-induced alterations in glutamatergic synapses within the mesolimbic dopamine reward system. Previous studies have shown that cocaine self-administration induces long-lasting neuroadaptations in glutamate neurons of the ventral tegmental area and nucleus accumbens. Here, we determined the effect of cocaine self-administration and subsequent withdrawal on glutamate receptor expression in the amygdala, a component of the mesolimbic dopamine system that is involved in cocaine seeking and craving induced by drug-associated cues. Rats were trained for 10 days to self-administer intravenous cocaine (6 h/day) or saline (a control condition) and were killed after one or 30 withdrawal days. Basolateral and central amygdala tissues were assayed for protein expression of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits (GluR1 and GluR2) and the NMDA receptor subunits (NR1, NR2A and NR2B). In the basolateral amygdala, GluR1 but not GluR2 levels were increased on days 1 and 30, NR2A levels were increased on day 1, and NR2B levels were decreased on day 30 of withdrawal from cocaine. In the central amygdala, GluR2 but not GluR1 levels were increased on days 1 and 30, NR1 levels were increased on day 30 and NR2A or NR2B levels were not altered after withdrawal from cocaine. These results indicate that cocaine self-administration and subsequent withdrawal induces long-lasting and differential neuroadaptations in basolateral and central amygdala glutamate receptors.     

Vasopressin neuropeptides and acquisition of heroin and cocaine self-administration in rats

The effect of the vasopressin neuropeptide des-glycinamide (Arg8)-vasopressin (DGAVP) on reducing the acquisition of intravenous heroin self-administration in rats was analyzed. When rats reduced in body weight were allowed to self-administer heroin for 1 h per day in the presence of a fixed time, non contingent food delivery schedule, it appeared that heroin intake was related in an orderly way to the unit dose of heroin delivered. DGAVP decreased heroin intake during days 4 and 5 of acquisition, especially when a high dose of heroin was delivered. DGAVP decreased heroin intake more effectively when rats were tested without the food delivery schedule and for 6 h instead of 1 h sessions per day. Structure activity relationship studies revealed that the peptide (pGlu4, Cyt6)AVP-(4-8) was the shortest active sequence mimicking the effect of DGAVP and that this peptide was somewhat more potent than DGAVP in this respect. The peptide (pGlu4,Cyt6)AVP-(4-9) increased the heroin intake of the rats. DGAVP and (pGlu4,Cyt6)-AVP-(4-8) also decreased cocaine intake of body weight reduced rats given the opportunity to self-administer cocaine intravenously in daily 6 h sessions. It is concluded that vasopressin neuropeptides may decrease the reinforcing efficacy of heroin and cocaine during acquisition of drug self-administration rather than interact with nutritional and environmental factors influencing drug taking behavior.     

The effects of oral micronized progesterone on smoked cocaine self-administration in women

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.     

高频电刺激伏隔核对可卡因成瘾大鼠自身给药行为学的影响

目的:研究可卡因诱导的大鼠自身给药行为,为临床治疗药物成瘾提供新的思路.方法:24只雄性大鼠随机分为对照组,假手术组和DBS高频电刺激组,每组8只.3组大鼠全部行右侧颈静脉长期置管术,假手术组和刺激组同时进行双侧伏隔核电极植入术,术后第7天起进行每天2小时的自身给药训练,训练程序为固定比率的FRI程序(即大鼠触碰鼻触一次可获得药物注射一次).每次注射后20s内为不应期,当大鼠连续3天触鼻频率最高值与最低值的差值小于均数标准差的1/4后,FRI模式下的大鼠自身给药训练成功.模型建立成功以后对DBS刺激组进行高频电刺激.结果:刺激组大鼠在高频电刺激15天触鼻频率与自身给药动练第15天触鼻频率相比明显减少(P＜0.01),而对照组和假手术组无明显统计学差异(P＞0.05);剌激组大鼠触鼻频率与假刺激组和对照组相比明显减少(P＜0.01).结论:脑深部高频电刺激可抑制可卡因成瘾大鼠对可卡因的依赖.     

Central cholinergic influence on self-administration of morphine and amphetamine

Atropine and methylatropine were tested in rats for an ability to alter the reinforcing action of intravenous morphine sulfate and d-amphetamine sulfate (60 μg/kg/injection). Atropine blocked the self-administration of morphine, but methylatropine did not. Similarly, atropine but not methylatropine prevented the establishment of a conditioned reinforcer based on passive intravenous infusions of morphine. Self-administration of d-amphetamine was enhanced by atropine but not by methylatropine. The results indicate that a central cholinergic system exerts an influence on the brain mechanisms which are affected by morphine or d-amphetamine to produce positive reinforcement.     

Sensitization enhances acquisition of cocaine self-administration in female rats: Estradiol further enhances cocaine intake after acquisition

Cocaine self-administration in rodents has been used widely as a preclinical model of cocaine use in humans. In laboratory animals, estradiol enhances behavioral sensitization to cocaine and the acquisition of cocaine self-administration in female rats. The rewarding effect of cocaine has been shown to be enhanced following behavioral sensitization in male rats. This experiment examined whether behavioral sensitization to cocaine would promote cocaine-taking behavior in female rats, and whether estradiol could further modulate cocaine-taking behavior in cocaine-sensitized rats. Ovariectomized female rats were pretreated with either cocaine or saline for 4 days per week for 3 weeks. Self-administration sessions started 2 weeks after the last dose of drug. Female Sprague-Dawley rats received either estradiol or oil 30 min prior to the start of each session and self-administration was carried out 5 days per week for 4 weeks. The dose of cocaine self-administered each week was as follows (in mg/kg/infusion): week 1, 0.1; week 2, 0.1; week 3, 0.15; and week 4, 0.4. The rats that received cocaine pretreatment took fewer days to acquire cocaine self-administration and took more cocaine than rats that received saline pretreatment. Estradiol enhanced cocaine intake during the last six self-administration sessions after acquisition but did not affect acquisition of self-administration at the lowest doses of cocaine used. In conclusion, cocaine sensitization promotes the acquisition of cocaine self-administration in female rats. Furthermore, prior cocaine experience is more powerful than estradiol at enhancing acquisition, while estradiol enhances intake of cocaine after acquisition of self-administration.     

Alterations in ionotropic glutamate receptor subunits during binge cocaine self-administration and withdrawal in rats

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in glutamatergic function in brain regions associated with reinforcement. Previous studies have examined ionotropic glutamate receptor (iGluR) subunit protein level changes following acute and chronic experimenter-administered cocaine or after withdrawal periods from experimenter-administered cocaine. To evaluate whether alterations in expression of iGluRs are associated with cocaine reinforcement, protein levels were assessed after binge (8 h/day, 15 days; 24-h access, days 16-21) cocaine self-administration and following 2 weeks of abstinence from this binge. Western blotting was used to compare levels of iGluR protein expression (NR1-3B, GluR1-7, KA2) in the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NAc), striatum and prefrontal cortex (PFC) of rats. iGluR subunits were altered in a time-dependent manner in all brain regions studied; however, selective alterations in certain iGluR subtypes appeared to be associated with binge cocaine self-administration and withdrawal in a region-specific manner. In the SN and VTA, alterations in iGluR protein levels compared with controls occurred only following binge access, whereas in the striatum and PFC, iGluR alterations occurred with binge access and following withdrawal. In the NAc, GluR2/3 levels were increased following withdrawal compared with binge access, and were the only changes observed in this region. Because subunit composition determines the functional properties of iGluRs, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine.     

Altered dopamine transporter function and phosphorylation following chronic cocaine self-administration and extinction in rats

Cocaine binds with the dopamine transporter (DAT), an effect that has been extensively implicated in its reinforcing effects. However, persisting adaptations in DAT regulation after cocaine self-administration have not been extensively investigated. Here, we determined the changes in molecular mechanisms of DAT regulation in the caudate-putamen (CPu) and nucleus accumbens (NAcc) of rats with a history of cocaine self-administration, followed by 3 weeks of withdrawal under extinction conditions (i.e., no cocaine available). DA uptake was significantly higher in the CPu of cocaine-experienced animals as compared to saline-yoked controls. DAT V_max was elevated in the CPu without changes in apparent affinity for DA. In spite of elevated CPu DAT activity, total and surface DAT density and DAT-PP2Ac (protein phosphatase 2A catalytic subunit) interaction remained unaltered, although p-Ser- DAT phosphorylation was elevated. In contrast to the CPu, there were no differences between cocaine and saline rats in the levels of DA uptake, DAT V_max and K_m values, total and surface DAT, p-Ser-DAT phosphorylation, or DAT-PP2Ac interactions in the NAcc. These results show that chronic cocaine self-administration leads to lasting, regionally specific alterations in striatal DA uptake and DAT-Ser phosphorylation. Such changes may be related to habitual patterns of cocaine-seeking observed during relapse.     

Circadian rhythms of house sparrows are phase-shifted by pharmacological manipulation of brain serotonin

Summary Fluoxetine, a specific serotonergic reuptake blocker and indirect agonist, and 5,6-dihydroxytryptamine, a serotonergic neurotoxin, affect the free-running locomotor rhythms of house sparrows,Passer domesticus. Both compounds caused phase-shifts in the circadian system that times locomotor activity of the birds. The magnitude and direction of the phase-shifts were dependent on the circadian phase of the drug administration, suggesting that serotonergic activity can modulate the circadian pacemaker of the house sparrow.Abbreviations 5HT serotonin, 5-hydroxytryptamine - 5,6-DHT 5,6-dihydroxytryptamine - DMI desmethylimipramine - SCN suprachiasmatic nuclei - CT circadian time - CAP compound action potential This paper is dedicated to Professor Colin S. Pittendrigh on the occasion of his 65th birthday     

Attempt at modification of the pharmacological and toxic effects of cocaine]

The increase in locomotor activity induced by cocaine (15 mg/kg, i.p.) in the mouse was antagonized by pretreatment with compounds which inhibited monoanimergic receptors such as phenoxybenzamine, chlorpromazine or methysergide. On the contrary, the lethal dose of cocaine in rats and mice was not reduced by these substances. These data suggest that monoamines are involved in mediating the motor activity of cocaine but not implicated in the toxic effect of the drug.     

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.     

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.     

Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats

Summary. Caffeine, the most widely consumed psychostimulant drug, acutely stimulates motor behaviour and enhances dopamine agonists actions whilst chronically it induces tolerance to either caffeine- or dopamine agonist-induced motor activating effects. The present study examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity. To this end, motor activation and rotational behaviour stimulated by either caffeine or D-amphetamine (0.5, 2 mg/kg), given 3 days after the last caffeine administration, were evaluated in neurologically intact and unilaterally 6-hydroxydopamine-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor and turning behaviour. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-hydroxydopamine-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects, rather than in tolerance, and induces neuroadaptive facilitatory changes in dopamine transmission.     

Impact of pubertal and adult estradiol treatments on cocaine self-administration

Estradiol is thought to play a critical role in the increased vulnerability to psychostimulant abuse in women. Sex differences in the ability of estradiol to influence cocaine self-administration in adult rats have been hypothesized to depend upon pubertal estradiol exposure. The current study investigated whether the presence of gonadal hormones during puberty affected cocaine self-administration behavior and its sensitivity to adult estradiol treatment in male and female Sprague–Dawley rats. Subjects were gonadectomized or SHAM-operated at postnatal day (PD) 22, and received either OIL or estradiol benzoate (EB) during the approximate time of puberty (PD27 to PD37). Adult rats were subsequently treated with either EB or OIL 30 min before cocaine self-administration (0.3 mg/kg/inf) in order to examine the effects of pubertal manipulations on the estradiol sensitivity of acquisition on a fixed ratio (FR) 1 schedule, total intake on a FR5 schedule and motivation on a progressive ratio schedule. Adult EB treatment only affected cocaine self-administration in females, which is consistent with previous research. Adult EB treatment enhanced acquisition in all females irrespective of puberty manipulations. All females, except those treated with EB during puberty, displayed increased cocaine intake following adult EB treatment. Adult EB treatment only enhanced motivation in females that were intact during puberty, whereas those treated with EB during puberty showed reduced motivation. Therefore, the sensitivities of different self-administration behaviors to adult estradiol treatment are organized independently in females, with pubertal estradiol exerting a greater influence over motivational processes, and negligible effects on learning/acquisition.     

Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.