Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were 'pair-fed' with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.     

Electrolytic lesions of a discrete area within the nucleus accumbens shell attenuate the long-term expression, but not early phase, of sensitization to cocaine

Repeated exposure to cocaine leads to behavioral sensitization, which is the augmentation of the locomotor response to a subsequent exposure to the drug. The nucleus accumbens (NAc), a major termination site of dopaminergic neurons, is believed to be involved in behavioral sensitization and studies have demonstrated that the NAc shell can be split into five zones of analysis; the vertex, arch, cone, intermediate and ventrolateral zones [Todtenkopf MS, Stellar JR. Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine. Synapse 2000;38:261–70]. Several reports show cocaine-induced c-fos expression particularly in the intermediate zone after 14, but not 2, drug-free days following repeated cocaine administration, suggesting that this region may be involved in sensitization and particularly in the later phase of expression, versus the earlier phase of sensitization. Bilateral electrolytic lesions of the intermediate zone were made in two groups of rats, which were then repeatedly exposed to cocaine (15 mg/kg, twice/day for 5 days). One group was subsequently given a single cocaine challenge injection (15 mg/kg) after 14 drug-free days, while the other group was challenged after only 2 drug-free days. Two sham surgery groups in which an electrode was lowered but no current was passed served as controls. Results show that lesioned animals as well as sham controls exhibited behavioral sensitization to the drug. However, following a 14-day drug-free period, the lesioned animals showed significant reduction in sensitization, compared to sham controls. Together these findings suggest that the intermediate zone of the NAc shell is indeed involved in the expression phase of behavioral sensitization to cocaine.     

Effects of cocaine, nicotine, dizocipline and alcohol on mice locomotor activity: cocaine-alcohol cross-sensitization involves upregulation of striatal dopamine transporter binding sites

We investigated if repeated administration of cocaine, nicotine, dizocipline (MK-801) and alcohol yields behavioral cross-sensitization between these agents. Swiss Webster mice received in their home cage one of the following intraperitoneal (i. p.) injections for 5 consecutive days: (a) saline, (b) cocaine (20 mg/kg), (c) nicotine (0.5 mg/kg), (d) MK-801 (0.3 mg/kg) and (e) ethanol (2.0 g/kg). After a 10-day drug free period, each group (n=30) was divided into three subgroups (n=10) and received challenge injections of either cocaine, nicotine or MK-801. The horizontal and vertical movements of the mice were recorded in locomotor activity cages (test cage). Among the various drugs tested, only the cocaine and ethanol experienced mice developed sensitization to a challenge injection of cocaine; MK-801 pretreated mice showed a sensitized response only to a challenge injection of MK-801. In a second experiment, mice in their home cages received (a) saline, (b) cocaine (20 mg/kg) or (c) ethanol (2.0 g/kg) for 5 days, and challenged with an i.p. ethanol injection (2.0 g/kg) after a 10-day drug free period. Both, cocaine and ethanol experienced mice developed marked sensitization to ethanol challenge compared with the saline experienced mice. Assessment of the densities of striatal dopamine transporter (DAT) sites (by [3H]mazindol binding) 11 days after the extinction of repeated treatment with either cocaine or ethanol revealed a significant increase (71-108%) in the number of DAT binding sites. Thus, among the various psychostimulants investigated in the present study cross-sensitization between cocaine and ethanol was only observed. The behavioral sensitization we measured was primarily 'drug-dependent', rather than 'context-dependent', because animals were exposed to the test cage only once. The finding that cocaine- and ethanol-induced behavioral sensitization is associated with upregulation of striatal DAT binding sites supports the hypothesis that similar neural substrates are involved in the psychomotor/rewarding effects of cocaine and alcohol.     

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations.

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.     

A role for corticotropin-releasing factor in the long-term expression of behavioral sensitization to cocaine

Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.     

Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine

The present study investigates the age-dependent effects of prenatal cocaine exposure on changes in the neurochemical and functional status of brain serotonin neurons. Pregnant rats were administered either saline or (−)cocaine HCl (15 mg/kg, subcutaneously), twice daily from gestational days 13 through 20. Neurochemical changes in frontal cortex, hypothalamus, hippocampus, striatum and midbrain of prepubescent and adult offspring were determined by measuring: (1) the content of serotonin (5-HT) and its major metabolite 5-hydroxyindolacetic acid (5-HIAA), and (2) the ability of the serotonin releasing drug p-chloroamphetamine (PCA) to reduce brain serotonin levels. Brain catecholamine content was determined in progeny for comparative purposes. Prior to maturation, prenatal exposure to cocaine did not alter basal levels of brain 5-HT or 5-HIAA in any brain region examined. However, in adult progeny prenatally exposed to cocaine, basal 5-HT content was significantly reduced in the frontal cortex (−32%) and hippocampus (−40%), suggesting maturation-dependent effects of prenatal cocaine exposure on brain 5-HT neurons. Consistent with the maturational onset of changes in 5-HT, striatal dopamine was significantly reduced (−10%) by prenatal exposure to cocaine only in adult offspring. Reductions in 5-HT in most brain regions, produced by pharmacological challenge with p-chloroamphetamine (PCA), were comparable in prenatal saline versus cocaine offspring. One notable exception was the markedly greater reduction (−40%) in 5-HT in the midbrain of immature offspring prenatally exposed to cocaine, suggesting alterations in midbrain 5-HT neurons prior to maturation. Overall, these data demonstrate prenatal cocaine exposure produces region-specific changes in 5-HT neurons in offspring with some deficits occurring only following maturation.     

Unconditioned and conditioned factors contribute to the 'reinstatement' of cocaine place conditioning following extinction in C57BL/6 mice

Relapse to drug use following prolonged periods of abstinence results, in part, from the ability of contextual cues paired previously with self-administered drug to elicit drug craving and -seeking behavior. Given the popularity of the mouse for the genetic analysis of drug-induced behaviors, a place conditioning model of drug-seeking behavior was used to examine the ability of cocaine (COC) to reinstate extinguished conditioned reward in mice. In a series of experiments, COC place conditioning was produced in male C57BL/6 (B6) mice by four pairings of COC (15 or 25 mg/kg, IP) with the non-preferred compartment of a two-compartment place conditioning apparatus. Following a post-conditioning test (Post-Test), place conditioning was extinguished by repeated testing. The mice were then challenged with one of five COC doses (0, 5, 10, 15 or 25 mg/kg, IP) and allowed free access to both environments. Following extinction, COC injections reinstated place conditioning to 100% or greater, relative to the Post-Test. In a control experiment, mice received either COC or SAL paired with non-preferred compartment and were then challenged with either COC (15 mg/kg, IP) or SAL on the Post-Test. COC-conditioned, but not SAL-conditioned, mice exhibited place conditioning when tested in a COC-free state. Interestingly, COC injection on the Post-Test elicited an increase in approach behavior in both SAL- and COC-conditioned mice and this increase was equivalent to that produced by COC conditioning alone. No direct relationships were observed between the magnitude of place conditioning and either COC-induced or -conditioned locomotor hyperactivity in the non-preferred compartment. Thus, at least two independent processes appear to underlie the ability of a COC injection to elicit approach behavior towards the non-preferred compartment of a biased place conditioning apparatus in mice-reactivation of the conditioned incentive motivational properties of COC-paired cues and elicitation of unconditioned behavioral disinhibition. One or both of these processes sensitizes with the passage of time, increasing the propensity of B6 mice to approach non-preferred environments upon COC re-administration.     

Increased tyrosine hydroxylase immunoreactivity in the rat cortex following prenatal cocaine exposure.

Cocaine has been found to be a neurobehavioral teratogen in both animals and humans. In this study the effects of cocaine on the developing catecholamine systems were examined. Rats were treated gestationally with cocaine (40 mg/kg s.c.) or saline from gestational day 13 until parturition. On postnatal day 28, tyrosine hydroxylase immunocytochemistry was performed. Increases in catecholamine fiber densities were observed in the hippocampus, anterior cingulate cortex, and parietal cortex in cocaine-treated animals. These findings may explain some of the behavioral alterations seen following prenatal cocaine exposure.     

Prenatal cocaine administration stimulates fetal brain tyrosine hydroxylase activity

Functional effects of prenatal cocaine exposure may be mediated in part by changes in catecholaminergic development. The present study examined whether cocaine administration influenced fetal brain activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. Subcutaneous (s.c.) injection of pregnant rats with 40 mg/kg of cocaine HCl daily from gestational day (GD) 8 to GD20 resulted in an 8.7% stimulation of fetal whole-brain TH activity compared to controls. We then switched to a s.c. implantation procedure involving Silastic capsules filled with 80 mg of cocaine base dissolved in polyethylene glycol (PEG). Implantation of 2 such capsules on GD18 produced a 28% increase in fetal TH activity measured only 3 days later on GD21. Subsequent experiments demonstrated that GD14 implantation was equally effective in stimulating fetal TH activity on GD17, but that the enzyme was unaffected in the brains of the treated dams. When cocaine-containing capsules were implanted on GD18, removed on GD21, and the females were allowed to deliver normally, offspring TH activity was still elevated on postnatal day 10 but not later. Finally, the presence of cocaine implants from GD18 to GD21 had no influence on fetal brain neurotransmitter and metabolite concentrations, however, the treated dams exhibited significant reductions in dopamine (DA) and the serotonin metabolite, 5-hydroxyindoleacetic acid. We conclude that maternal cocaine implants rapidly but transiently stimulate TH activity in the fetal brain, and that such stimulation prevented the DA depletion observed in the dams.     

Evidence for an involvement of muscarinic cholinergic systems in the induction but not expression of behavioral sensitization to cocaine

The present study was designed to determine whether the muscarinic cholinergic antagonist scopolamine can prevent the expression and induction of sensitization to the locomotor-activating effects of cocaine. Rats received one daily injection of cocaine (20 mg/kg i.p.) for 5 days. Two days after withdrawal of pretreatment, rats were pretreated with scopolamine (3.0 mg/kg s.c.) or its vehicle and challenged 15 min later with either saline or cocaine (20–30 mg/kg i.p.). In a second set of experiments, scopolamine (3.0 mg/kg s.c.) or its vehicle was given in combination with either saline or cocaine (20 mg/kg i.p.) for 5 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on day 7. The effects of acute administration of acopolamine (3.0 mg/kg s.c.) on cocaine-induced locomotor activity were also assessed. Acute administration of scopolamine increased both distance traveled and time spent in stereotypy. When scopolamine was administered 15 min prior to an acute injection of cocaine, a significant increase in the behavioral response to cocaine was seen. Daily injections of cocaine for 5 days produced sensitized behavioral responses to a subsequent cocaine challenge. Acute administration of scopolamine to animals preexposed and sensitized to cocaine did not disrupt the expression of sensitization to the locomotor and stereotypic effects of cocaine. In contrast, when scopolamine was given in combination with cocaine for 5 days, sensitization to the locomotor-activating effects of cocaine was prevented. These results suggest an important role of cholinergic muscarinic systems in mediating sensitization to the locomotor-activating effects of cocaine, which occurred after the repeated context-independent administration of this agent. In contrast, the enhanced stereotypic effects in response to the repeated administration of cocaine seem to be independent of alterations in muscarinic cholinergic transmission. (This article is a US Govemernment work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Estrogen and opioids interact to modulate the locomotor response to cocaine in the female rat

Estrogen is known to modulate the behavioral response to cocaine; however the mechanisms by which this is accomplished is unknown. In this study we examine one possible candidate, the endogenous opioid system. Adult Sprague-Dawley rats were ovariectomized (OVX), half received Silastic implants with estradiol benzoate (OVX-EB), the other half received empty implants (OVX). After 1 week, spontaneous locomotor and stereotyped activity was measured for 60 min using an automated system. On day 2, locomotor activity was recorded for 30 min. Rats were injected with saline (SAL) or naloxone (NAL) (2 mg/kg, i.p.) and activity measured for the next 20 min. Each of these groups were further subdivided, one that received a saline injection (SAL) and another that received a cocaine injection (COC) (15 mg/kg, i.p.). Locomotor and stereotyped activities were recorded for 60 min. This resulted in the following injection groups: SAL-SAL, NAL-SAL, SAL-COC and NAL-COC. During habituation, OVX rats displayed an overall higher level of activity than OVX-EB rats. Similar to what is observed in males, naloxone significantly reduced locomotion and stereotyped behavior but only in OVX rats. Estrogen administration to OVX rats abolished the effect of naloxone. Surprisingly, when naloxone was administered prior to cocaine, an increase in cocaine-induced locomotor and stereotyped activity was observed, but only in OVX-EB rats. These results indicate that opioid modulation of cocaine-induced locomotor and stereotype activity in the female differs from that reported in the male. In addition in the female, the effect of opioids on cocaine-induced locomotor behavior is dependent on plasma levels of estrogen.     

Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens

We have previously observed that chronic cocaine administration increases levels of adenylyl cyclase and cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc). In the present work we directly examined the involvement of the cAMP system at the level of the NAc in cocaine-induced locomotor activity and sensitization. Groups of rats were pretreated on 3 consecutive days with cocaine (10 mg/kg, i.p.) concurrently with intraaccumbens infusion of saline, 8-bromo-cAMP (2 μg/side; a membrane permeant analogue of cAMP which activates PKA), or RP-CPT-cAMP (20 nmol/side; which inhibits PKA). In a separate experiment, control animals received local infusion of either 8-bromo-cAMP or saline plus i.p. saline. All animals were tested for locomotor activity on pretreatment days, and following an additional cocaine challenge on a subsequent day. Over pretreatment days, animals given 8-bromo-cAMP showed greater cocaine-induced activity, while animals given RP-CPT-cAMP tended to be less active, compared to saline infused animals. When subsequently challenged with cocaine, animals pretreated with intraaccumbens 8-bromo-cAMP showed greater locomotor activity during the last 30 min of the 60 min test session than animals pretreated with saline or RP-CRT-cAMP. No differences in locomotor activity were evident between the two control groups on pretreatment or challenge days. These data suggest that PKA activation at the level of the NAc may have a facilitative role with respect to acute and long-term stimulant-induced locomotor activity.     

5-HT(1A) and 5-HT(2A) serotonin receptor turnover in adult rat offspring prenatally exposed to cocaine

This study investigated the effects of prenatal exposure to cocaine on the intracellular kinetics (i.e. rate constant of receptor production and degradation) that govern the maintenance and regulation of cortical 5-HT(1A) and 5-HT(2A) receptor densities in offspring. Adult male rat offspring, prenatally exposed to saline or (-) cocaine (15 mg/kg, s.c., b.i.d, from gestational day 13 through 20), were injected with either vehicle or the irreversible receptor antagonist, EEDQ (10 mg/kg, s.c.), and sacrificed at various post-injection times to monitor the recovery of receptor densities in cerebral cortex. In both saline and cocaine exposed offspring, initial EEDQ-induced reductions (>80%) in 5-HT(1A) and 5-HT(2A) receptor densities were followed by a time-dependent repopulation that reached steady state ([B(max)](ss)) densities comparable to non-EEDQ treated controls by day 10 post-treatment. Calculation of 5-HT(1A) receptor kinetic parameters indicated that prenatal exposure to cocaine did not significantly alter: (1) the receptor production rate (saline: 0.809 fmol/mg protein/h; cocaine: 0.724 fmol/mg protein/h), (2) the receptor degradation rate constant (saline: 0.0063 h(-1); cocaine: 0.0062 h(-1)) or (3) the half-life (t(1/2)) of receptor repopulation (saline: 109.2 h; cocaine: 111.5 h). Similarly, 5-HT(2A) receptor rate constants for production (1. 550 fmol/mg protein/h) and degradation (0.0061 h(-1)) and consequently, t(1/2) (113.2 h), were not significantly altered by prenatal exposure to cocaine. These data suggest that within homogenates of cerebral cortex, prenatal exposure to cocaine did not alter the overall intracellular processes that underlie receptor production or degradation and determine steady state densities of 5-HT(1A) or 5-HT(2A) receptors.     

Prenatal cocaine and/or nicotine exposure produces depression and anxiety in aging rats

The adult use of cocaine and nicotine has been linked to depression and/or anxiety. Changes in emotional behavior were assessed using behavioral paradigms developed as animal analogs of psychiatric disorders in 12-14 month old Sprague-Dawley rats exposed daily on gestational days 8-20 to cocaine and nicotine, either alone or in combination. Results from the elevated plus maze (EPM), used to assess anxiety-related behaviors, indicated that offspring prenatally exposed to either high-dose cocaine (40 mg/kg/day) or high-dose nicotine (5.0 mg/kg/day) were less timid/more impulsive. Animals from these two groups spent the most time on the open arms, and had the highest percentage of entries into the open arms of the EPM. Combined in utero exposure to cocaine and nicotine nullified these effects. Cocaine challenge (20 mg/kg) did not interact with prenatal treatment, but increased activity on all arms of the EPM in all groups. Sucrose preference was used as a measure of anhedonia, a cardinal symptom of depressive illness. Reduced sucrose preference was seen only in the group of offspring prenatally exposed to high-dose cocaine (40 mg/kg) plus low-dose nicotine (2.5 mg/kg/day). Exposure to a water-deprivation stress normalized sucrose preference in this group, without altering preference or intake in the other prenatal treatment groups. Transient hyperactivity was seen in the offspring of dams treated with high-dose nicotine, an effect that was again reversed in combined drug groups. Traditional gender differences in activity levels and sucrose intake, that is, females greater than males, were still evident in this population of aging rats. These data indicate that prenatal exposure to cocaine and/or nicotine has long-term effects on emotional behavior. Combined drug exposure contributed to the development of depressive symptoms, but not anxiety-like behavior, in a dose-dependent manner. In contrast, exposure to high doses of either drug alone reduced cautionary behavior. Data from this line of research could provide insight into the pathogenesis of emotional disorders, especially during the aging process.     

Prenatal cocaine exposure decreases brain-derived neurotrophic factor proteins in the rat brain

The pregnant rats received daily sc injections of cocaine (30 mg/kg) or saline from the gestational day (GD) 7 to GD 20. At 1 week postnatal, all pups were killed and the hippocampus, cortex and striatum were dissected out. Levels of brain-derived neurotrophic factor (BDNF) under the basal condition and depolarization with high potassium (40 mM) were measured. The results showed that hippocampal BDNF levels under basal and depolarization conditions were all significantly lower in the pups prenatally exposed to cocaine than those exposed to saline. There were no significant differences in basal BDNF levels between the cocaine and saline groups in the cortex or striatum. However, the prenatally cocaine-treated pups showed significantly less BDNF release following high potassium depolarization than the saline-treated animals did in both these regions. The results support the suggestion that prenatal cocaine exposure decreases BDNF expression in the offspring.     

Stress‐induced sensitization to cocaine: actin cytoskeleton remodeling within mesocorticolimbic nuclei

This study investigated the consequence of repeated stress on actin cytoskeleton remodeling in the nucleus accumbens (NAc) and prefrontal cortex (Pfc), and the involvement of this remodeling in the expression of stress‐induced motor cross‐sensitization with cocaine. Wistar rats were restrained daily (2 h) for 7 days and, 3 weeks later, their NAc and Pfc were dissected 45 min after acute saline or cocaine (30 mg/kg i.p.). F‐actin, actin‐binding proteins (ABP) and GluR1 were quantified by Western blotting, and dendritic spines and postsynaptic density (PSD) size measured by electron microscopy. In the NAc from the stress plus cocaine group we observed a decrease in the phosphorylation of two ABPs, cofilin and cortactin, and an increase in the PSD size and the surface expression of GluR1, consistent with a more highly branched actin cytoskeleton. The Pfc also showed evidence of increased actin polymerization after stress as an increase was observed in Arp2, and in the number of spines. Inhibiting actin cycling and polymerization with latrunculin A into the NAc, but not the Pfc, inhibited the expression of cross‐sensitization to cocaine (15 mg/kg i.p.) and restored the expression of GluR1 to control levels. This study shows that a history of repeated stress alters the ability of a subsequent cocaine injection to modulate dendritic spine morphology, actin dynamics and GluR1 expression in the NAc. Furthermore, by regulating GluR1 expression in the NAc, elevated actin cycling contributes to the expression of cross‐sensitization between stress and cocaine, while stress‐induced changes in the Pfc were not associated with cross‐sensitization.     

Effects of CP 154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats

We examined the influence of CP 154,526, a selective antagonist of corticotropin-releasing factor (CRF)1 receptors, in the locomotor, sensitizing, discriminative stimulus and rewarding effects of cocaine, as well as on the cocaine-induced reinstatement of cocaine-seeking behavior in male Wistar rats. CP 154,526 in doses of 5, 10 and 20 mg/kg, which did not affect basal locomotor activity, dose-dependently reduced the hyperactivation evoked by cocaine. To assess the effects of CP 154,526 on the expression of cocaine sensitization, the rats were injected with either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) after pretreatment with saline or CP 154,526 on day 5 of withdrawal. The cocaine-induced hyperactivity in sensitized rats was reduced by CP 154,526 (10 and 20 mg/kg). In rats trained to discriminate cocaine (10 mg/kg) from saline, pretreatment with CP 154,526 (5-20 mg/kg) did not affect the cocaine (1.25-10 mg/kg)-induced discriminative stimulus effects. In a self-administration model, the rats were trained to self-administer cocaine (0.5 mg/kg/infusion) in the FR 5 schedule of reinforcement. Administration of CP 154,526 (10-20 mg/kg) did not alter the rewarding effects of cocaine, assessed as the number of active-lever presses and infusions; however, following a 10-day extinction phase, CP 154,526 (5-20 mg/kg) significantly decreased in a dose-dependent manner the cocaine (10 mg/kg) priming-induced reinstatement of cocaine-seeking behavior. The present study implies that CRF1 receptors control the expression of cocaine hyperactivation and sensitization as well as the cocaine-induced relapse behavior, but do not play any role in cocaine discrimination and self-administration. These findings may suggest that CRF1 receptor antagonists should be considered as possible medications in the treatment of cocaine addiction.     

Prenatal cocaine alters dopamine transporter binding in postnatal day 10 rat striatum

The effect of in utero cocaine exposure on the postnatal binding of the radiolabeled dopamine (DA) uptake inhibitor [₃H]GBR 12935 to the DA uptake complex was examined in male rats. One set of pregnant Sprague-Dawley rats was given subcutaneous (s.c.) injections of cocaine (40 mg/kg) or 0.9% saline from gestational day (GD) 8–21. Another set of animals received bilateral s.c. Silastic implants, each containing 60 mg cocaine base dissolved in polyethylene glycol (PEG) or PEG only, from GD 18-21. The density of[₃H]GBR 12935 binding to the DA transporter in striatum and mesencephalon was assessed by quantitative autoradiography on postnatal day (PND) 1, 10, 30, and 60. Both treatment methods resulted in a decrease of [₃H]GBR 12935 binding in dorsal lateral striatum of cocaine-exposed offspring on PND 10. There were no significant differences in [₃H]GBR 12935 binding between offspring of cocaine and vehicle-treated dams at any other time points examined. Thus, prenatal cocaine exposure by either daily injection from GD 8–21 or continuous infusion from GD 18–21 resulted in a transient decrease in DA transporter binding in the dorsal lateral striatum that was apparent on PND 10. © 1996 Wiley-Liss, Inc.     

Modulation of behavioral sensitization to cocaine by NAALADase inhibition

Sensitization to cocaine has been attributed to alterations in excitatory amino acid and dopamine neurotransmission in the mesolimbic system. The present study sought to determine whether inhibition of NAALADase, an enzyme that cleaves glutamate from the endogenous neuropeptide, N-acetyl-aspartyl-glutamate (NAAG), attenuates sensitization to the psychomotor stimulant effects of cocaine. Rats received daily injections of cocaine (20.0 mg/kg/day; i.p.) or saline for 5 days. Fifteen minutes prior to these injections they received an i.p. injection of the NAALADase inhibitor, 2-PMPA (50.0-100 mg/kg), or vehicle. Locomotor activity and stereotypy produced by a challenge dose of cocaine (15.0 mg/kg) were assessed 3 days later. Acute cocaine administration increased locomotor activity in control animals. In animals with a prior history of cocaine administration, the behavioral response to cocaine was significantly enhanced. In animals that had received 2-PMPA in combination with cocaine, the enhancement of cocaine-induced locomotor activity was attenuated. No alteration in cocaine-evoked activity was observed in animals that had received once daily injections of 2-PMPA, alone. Acute administration of 2-PMPA also did not modify saline-induced locomotor activity or activity produced by an acute cocaine challenge. These data demonstrate that NAALADase inhibition attenuates the development of sensitization to the locomotor-activating effects of cocaine. Furthermore, this action cannot be attributed to an antagonism of the acute effects of cocaine.