Sex differences in cocaine-induced behavioral sensitization.

To further understand how sex differences affect the development and maintenance of sensitization, 48 adult Fischer rats (24 female and 24 male) received chronic administration (14 days) of cocaine (15 mg/kg, i.p.) or saline or a challenge dose (7 days after chronic cocaine administration). Sex differences were observed in the development and maintenance of cocaine-induced total locomotor, ambulatory and rearing activity. Although, overall cocaine administration increased stereotypic activity in both male and female rats, female rats had significantly higher stereotypic activity than male rats across the three behavioral test days (1, 7 and 14). Female rats had statistically significant higher benzoylecognine levels after acute cocaine administration than male rats. However, no differences between male and female rats in benzoylecognine plasma levels were observed after chronic and challenge doses of cocaine administration. Interestingly, after acute and challenge cocaine administration, corticosterone levels were significantly higher in female rats when compared to male rats. This study confirms previous reports that there are sex differences in the behavioral response to cocaine. Moreover, this study expands previous studies by demonstrating that sex differences occur in only certain aspects of cocaine-induced behavioral activation and the development and maintenance of cocaine-induced behavioral sensitization.     

Frequency of cocaine administration affects behavioral and endocrine responses in male and female Fischer rats.

Accumulating evidence has shown disparate behavioral responses to cocaine in male and female rats. To date, there is a lack of understanding of how cocaine administration frequency affects sexually dimorphic behavioral responses. In the present study we investigated the behavioral and endocrine responses to single (1 x 15 mg/kg) and "binge" (3 x 15 mg/kg) cocaine administration in male and female Fischer rats. Overall, females showed a more prolonged and robust behavioral response to both acute and "binge" pattern cocaine administration. Furthermore, sex-dependent behavioral topographies emerged during binge-pattern cocaine administration; female rearing activity increased across "binge" injections while ambulatory activity decreased. In contrast, male ambulatory and rearing behaviors remained constant across injections of "binge" cocaine. At the hormonal level, both single and "binge" pattern cocaine administration decreased testosterone levels in male rats. However, cocaine's modulation of testosterone levels was transient since testosterone levels were decreased by cocaine 30 min but not 3 hr following a single injection. In both male and female rats, "binge" cocaine increased plasma progesterone levels. However, acute cocaine administration increased progesterone levels transiently in only female rats. Our results show that pattern of administration affects both cocaine-stimulated behavioral and endocrine responses in male and female rats.     

Progesterone attenuates cocaine-induced responses

In this review, we summarize literature focused on how progesterone alters cocaine-induced psychomotor, reinforcement, and physiological responses. Clinical studies suggest that progesterone attenuates the subjective effects of cocaine. Similarly, preclinical studies have demonstrated that cocaine-induced reward and psychomotor responses are attenuated after progesterone administration. In rats progesterone also reduces the reinforcement effects of cocaine attenuates acquisition, escalation, reinstatement of cocaine self-administration, and cocaine-seeking behaviors. Progesterone also counteracts the facilitatory effects of estrogen on cocaine self-administration and psychomotor activation. These findings suggest that progesterone has a potential in clinical applications as a treatment for cocaine addiction. Constantly changing progesterone serum levels in female humans and rats affect the female's reinforcement responses to cocaine and may in part contribute to the known sex differences in cocaine responses.     

Estrogen-dependent alterations in D2/D3-induced G protein activation in cocaine-sensitized female rats

Estrogen potentiates behavioral sensitization to cocaine in the female rat by mechanisms that remain undetermined. In this study, functional receptor autoradiography was used to investigate estrogen modulation of D2/D3 receptor-induced G protein activation in components of the reward pathway of female rats treated acutely and repeatedly with cocaine. Rats were ovariectomized and given an empty (OVX group) or estradiol benzoate-filled (OVX-EB group) implant. After a week, animals received a daily saline or cocaine injection (15 mg/kg, i.p.) for 5 days, and again on day 13. Animals were killed, and brains were removed and cryosectioned. D2/D3-stimulated [35S]guanosine 5'-(gamma-thio) triphosphate (GTPgammaS) binding was assessed in the cingulate cortex area 2 (Cg2), striatum (STR), nucleus accumbens (NAc) and ventral tegmental area (VTA). OVX-EB rats showed more [35S]GTPgammaS binding in the Cg2 and lower binding in the VTA than OVX rats; in the VTA this effect was reversed by a single cocaine injection. Repeated cocaine administration had opposite effects in OVX and OVX-EB rats. [35S]GTPgammaS binding was decreased in the Cg2, NAc and STR of OVX-EB rats, and increased in OVX rats. The present results support the hypothesis that cocaine-induced changes in D2/D3 receptor activation are regulated by estrogen. These data suggest that changes in D2/D3 receptor function represent one mechanism by which estrogen regulates behavioral sensitization to cocaine.     

Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine

Both clinical and rodent studies show sexually dimorphic patterns in the behavioral response to cocaine in all phases of the addiction process (induction, maintenance, and relapse). Clinical and rodent studies also indicate that hormonal fluctuations during the menstrual/estrous cycle modulate cocaine-induced subjective effects in women and locomotor activity in female rats. Evidence suggests that gonadal hormones underlie these observed differences and could be the biological basis of sex-specific differences in cocaine addiction. To study the effects of gonadal hormones on cocaine-induced activity, two approaches have been used. First, studies have examined the role of endogenous hormones through gonadectomy (GDX) and side-by-side comparisons with intact rats. Second, the individual contributions of testosterone, progesterone, and estrogen have been determined by hormone replacement in GDX rats. In this review, we discuss gonadal hormones as the biological basis for the behavioral responses to cocaine, and the clinical implications of these findings.     

Differences in rat dorsal striatal NMDA and AMPA receptors following acute and repeated cocaine-induced locomotor activation

Sprague-Dawley rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity induced by an acute low dose of cocaine. Upon repeated cocaine exposure, LCRs display greater locomotor sensitization, reward, and reinforcement than HCRs. Altered glutamate receptor expression in the brain reward pathway has been linked to locomotor sensitization and addiction. To determine if such changes contribute to the differential development of locomotor sensitization, we examined protein levels of total, phosphorylated, and cell surface glutamate N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors (Rs) following acute or repeated cocaine (10 mg/kg, i.p.) in LCRs, HCRs and saline controls. Three areas involved in the development and expression of locomotor sensitization were investigated: the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (dSTR). Our results revealed differences only in the dSTR, where we found that after acute cocaine, GluN2B(Tyr-1472) phosphorylation was significantly greater in LCRs, compared to HCRs and controls. Additionally in dSTR, after repeated cocaine, we observed significant increases in total GluA1, phosphorylated GluA1(Ser-845), and cell surface GluA1 in all cocaine-treated animals vs. controls. The acute cocaine-induced increases in NMDARs in dSTR of LCRs may help to explain the more ready development of locomotor sensitization and susceptibility to addiction-like behaviors in rats that initially exhibit little or no cocaine-induced activation, whereas the AMPAR increases after repeated cocaine may relate to recruitment of more dorsal striatal circuits and maintenance of the marked cocaine-induced locomotor activation observed in all of the rats.     

Prenatal exposure of bupropion may enhance agitation, anxiety responses, and sensitivity to cocaine effects in adult mice

Major depression and dysthymia afflict a proportion of gravid and breast-feeding women. These women are frequently recommended on antidepressants to relieve their symptoms even if the drug effects on fetal growth and postnatal development are not completely known. In a previous study, we reported that prenatal bupropion exposure seemed to enhance the hedonic value of cocaine in adult mice. This study was undertaken to examine the dose-related effects for prenatal bupropion exposure on the stress susceptibility, cocaine-associated reinforcing property, and cocaine-induced behavioral sensitization in adult mice. Our results showed that various doses (ranging 12.5-50 mg/kg) of prenatal bupropion administration at the third trimester of pregnancy did not affect body weight of the adult mice. Bupropion administration at 50 mg/kg enhanced both ambulatory and rearing responses in the open field test. Moreover, bupropion administration (at 25 and 50 mg/kg) significantly decreased the numbers in open arm entry in the elevated plus maze test. Furthermore, prenatal bupropion treatment appeared to facilitate the cocaine-induced place preference in a sex-dependent manner. Finally, prenatal bupropion exposure (at 25 and 50 mg/kg) accelerated and elevated the development of cocaine-induced sensitization in locomotor activity. While the antidepressant and smoking-curbing effects of bupropion have been addressed in literature, we suggest that prenatal bupropion exposure could run a risk of enhancing individual's agitation, stress susceptibility and cocaine stimulating propensity in adulthood.     

Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.     

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine.

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7-8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by approximately 60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.     

Quantitative mapping of cocaine-induced ΔFosB expression in the striatum of male and female rats

ΔFosB plays a critical role in drug-induced long-term changes in the brain. In the current study, we evaluated locomotor activity in male and female rats treated with saline or cocaine for 2 weeks and quantitatively mapped ΔFosB expression in the dorsal striatum and nucleus accumbens of each animal by using an anti-FosB antibody that recognizes ΔFosB isoforms preferentially. Behavioral analysis showed that while there was little difference between males and females that sensitized to cocaine, nonsensitizing rats showed a large sex difference. Nonsensitizing males showed low behavioral activation in response to cocaine on the first day of treatment, and their activity remained low. In contrast, nonsensitizing females showed high activation on the first day of treatment and their activity remained high. Western blot and immunohistochemical analyses indicated that basal levels of ΔFosB were higher in the nucleus accumbens than the dorsal striatum, but that the effect of cocaine on ΔFosB was greater in the dorsal striatum. Immunostaining showed that the effect of cocaine in both the dorsal striatum and nucleus accumbens was primarily to increase the intensity of ΔFosB immunoreactivity in individual neurons, rather than to increase the number of cells that express ΔFosB. Detailed mapping of ΔFosB-labeled nuclei showed that basal ΔFosB levels were highest in the medial portion of the dorsal striatum and dorsomedial accumbens, particularly adjacent to the lateral ventricle, whereas the cocaine-induced increase in ΔFosB was most pronounced in the lateral dorsal striatum, where basal ΔFosB expression was lowest. Sex differences in ΔFosB expression were small and independent of cocaine treatment. We discuss implications of the sex difference in locomotor activation and regionally-specific ΔFosB induction by cocaine.     

Adrenalectomy reduces exploratory activity in the rat: a specific role of corticosterone

The effect of chronic adrenalectomy (10 days) and subsequent steroid hormone administration on exploratory activity in male rats was studied. Chronic adrenalectomy significantly decreased ambulatory and rearing activities, while grooming and defecation scores were not affected. Subcutaneous administration of corticosterone (30 μg/100 g body wt) 1 hr before the open-field test restored the decreased exploratory behavior of adrenalectomized rats toward the activity observed in sham-operated control animals. Neither dexamethasone or progesterone were effective. Administration of the synthetic glucocorticoid 1 hr prior to corticosterone substitution of the adrenalectomized rats even resulted in a complete prevention of the normalization of the behavioral response. The observed specific action of corticosterone on exploratory behavior corresponds to the stringent specificity of the neuronal hippocampal corticosterone receptor system.     

Drug-environment interaction: Context dependency of cocaine-induced behavioral sensitization

The effect of the environmental context in which rats received cocaine upon subsequent cocaine-induced hyperactivity and stereotypy was explored. “Cocaine test cage” animals were injected with cocaine in the test cage and then received saline upon leaving it 40 minutes later, while in the “saline test cage” group the injections, were in the reverse order. Thus, all animals had identical injections, handling, and environmental exposure, differing only in whether they received cocaine during or after their test cage experience. The cocaine test cage animals displayed increasing response (p < .001) to the 10 daily cocaine injections, i.e., behavioral sensitization. However, in contrast, the “saline-test cage” animals had significantly less cocaine-induced activation upon 2 of 3 challenges with cocaine and showed no significant evidence of behavioral sensitization even though they had received the same dose and number of previous cocaine injections in a different environment. Thus, this study reveals environment- specific drug effects and suggests that environmental context plays a role in the development and manifestation of behavioral sensitization to cocaine.     

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.     

Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking

Chronic cocaine administration reduces G protein signaling efficacy. Here, we report that the expression of AGS3, which binds to GialphaGDP and inhibits GDP dissociation, was upregulated in the prefrontal cortex (PFC) during late withdrawal from repeated cocaine administration. Increased AGS3 was mimicked in the PFC of drug-naive rats by microinjecting a peptide containing the Gialpha binding domain (GPR) of AGS3 fused to the cell permeability domain of HIV-Tat. Infusion of Tat-GPR mimicked the phenotype of chronic cocaine-treated rats by manifesting sensitized locomotor behavior and drug seeking and by increasing glutamate transmission in nucleus accumbens. By preventing cocaine withdrawal-induced AGS3 expression with antisense oligonucleotides, signaling through Gialpha was normalized, and both cocaine-induced relapse to drug seeking and locomotor sensitization were prevented. When antisense oligonucleotide infusion was discontinued, drug seeking and sensitization were restored. It is proposed that AGS3 gates the expression of cocaine-induced plasticity by regulating G protein signaling in the PFC.     

Dose-response and time-response relationships between progesterone and the display of patterns of receptive and proceptive behavior in the female rat

The relationship between administration of progesterone and the display of patterns of receptive (response to the male) and preceptive (female initiated) sexual behavior was examined in ovariectomized, estrogen-primed female rats in a “restrained male” test situation. It was found that the degree of receptivity and proceptivity displayed was directly proportional to progesterone dose and time from progesterone injection (up to 4.5 hr). Higher progesterone doses and longer period of time from progesterone injection (up to 4.5 hr) were both associated with shorter latencies to return to the male following intromission and ejaculation. Receptivity could be induced with estrogen alone but progesterone was required for the display of proceptivity and higher doses of progesterone were needed to effect increases in proceptivity relative to receptivity. Proceptive behavior also occurred in a narrower time range than did receptive behavior. Receptivity alone is characterized as the lowest degree, and receptivity plus proceptivity as the highest degree, of expression of the total behavior pattern of the estrous female rat. Receptivity and proceptivity together constitute a continuum of estrous responsiveness. Increasing the progesterone dose from 0 to 200 μg, and increasing the latency from progesterone injection from 0 to 4.5 hr, were associated with increasing degree of expression of the total behavioral continuum.     

Cocaine-induced sensitization correlates with testosterone in male Japanese quail but not with estradiol in female Japanese quail

Research has indicated that gonadal hormones may mediate behavioral and biological responses to cocaine. Estrogen, in particular, has been shown to increase behavioral responding to cocaine in female rats relative to male rats. The current study investigated the effect of cocaine on locomotor activity and hormonal correlates in male and female Japanese quail (Coturnix japonica). In Japanese quail, circulating hormone levels can be manipulated without surgical alterations via modifying the photoperiod. Male and female quail were housed on either 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21 days. Blood samples were taken prior to the beginning of the experiment and assays were performed to determine the levels of testosterone (T) and estradiol (E2). Quail were given injections of saline or cocaine (10 or 20 mg/kg) once a day for 10 days. Immediately after each injection, birds were placed in open field arenas and distance traveled was measured for 30 min. Results showed that male quail housed under long-light conditions exhibited cocaine-induced sensitization to 10 mg/kg cocaine which was correlated with the high levels of plasma T. Female quail housed under short-light conditions demonstrated sensitization to 10 mg/kg cocaine, but this was not correlated with the levels of plasma E2. The current findings suggest that cocaine-induced locomotor activity was associated with T in males but not with E2 in females.     

Pressor, tachycardic and behavioral excitatory responses in conscious rats following ICV administration of ACTH and CRF are blocked by naloxone pretreatment

Experiments were conducted to compare the blood pressure and heart rate responses of conscious rats given intracerebroventricular (ICV) injections of adrenocorticotropin (ACTH 1-24) and corticotropin releasing factor (CRF). Under sodium pentobarbital anaesthesia, rats were implanted with a stainless-steel cannula into the lateral cerebral ventricle and had their right femoral artery and vein cannulated. Upon recovery (24-48 hr later) conscious, unrestrained rats were given ICV injections (total volume 5 microliter by gravity flow) of sterile saline, ACTH (1-24) (0.85 and 1.7 nmoles) or CRF (0.55 and 1.1 nmoles) and blood pressure and heart rate were monitored over the next 2 hr (from the abdominal aorta via the femoral arterial catheter). Both ACTH and CRF caused mean arterial pressure (MAP) to increase, which was paralleled with increases in mean heart rate (MHR). Moreover, these elevations in MAP and MHR were temporally associated with excessive grooming (for ACTH) and locomotor activity (for CRF), which occurred before and lasted as long as MAP and MHR were enhanced. Intravenous (IV) pretreatment whereby naloxone was given 10 min before ICV administration of ACTH (1.7 nmoles) or CRF (1.1 nmoles), showed that naloxone blocked the behavioral, pressor and tachycardic effects of both ACTH and CRF. The results demonstrate that the pressor, tachycardic and locomotor effects evoked in conscious rats by ICV administration of ACTH or CRF are antagonized by naloxone and that their hemodynamic changes may, in part, be mediated by prior behavioral activation.     

Marker-assisted dissection of genetic influences on motor and neuroendocrine sensitization to cocaine in rats

This study investigated genetic influences on behavioral and neuroendocrine responses to cocaine sensitization. We used male and female rats of the inbred strains Lewis (LEW) and spontaneously hypertensive rats (SHR), which display genetic differences in stress-related responses. The influence of two quantitative trait loci (QTL; Ofil1 and Ofil2 on chromosomes 4 and 7), which modulate stress reactivity in rats, on the effects of cocaine was also investigated through the use of recombinant lines (derived from a LEW   ×   SHR intercross) selected by their genotype at Ofil1 and Ofil2 . Animals were given repeated cocaine or saline injections and tested for locomotion (induction of sensitization). Two weeks later, all animals were challenged with cocaine, and locomotion and corticosterone levels were measured (expression of sensitization). Results indicated that male SHR rats showed more behavioral sensitization than LEW rats, whereas no strain differences in sensitization were seen among females. When challenged with cocaine, LEW and SHR rats of both sexes pretreated with cocaine showed behavioral sensitization compared with saline pretreated animals; however, only LEW rats displayed an increase in the corticosterone levels. Ofil1 was found to influence the induction of sensitization in males and Ofil2 modulated the locomotor effect of cocaine in females. This study provides evidence of a genotype-dependent relationship between the induction and expression of cocaine sensitization, and between the behavioral and neuroendocrine responses induced by cocaine. Moreover, the Ofil1 and Ofil2 loci may contain one or more genes that control the behavioral effects of cocaine in rats.     

Critical role of endogenous corticotropin-releasing factor (CRF) in the mediation of the behavioral action of cocaine in rats.

The role of endogenous CRF in the locomotor hyperactivity induced by cocaine was investigated by using the immunoneutralization of endogenous CRF and an antagonist of CRF-receptors (alpha-helical CRF9-41: alpha h-CRF) in rats. Different dilutions of anti-CRF antibody (1:5, 1:20, but not 1:100) injected intracerebroventricularly (i.c.v.) 24 hours before the cocaine treatment blocked the expression of locomotor hyperactivity. Pretreatment with different doses (0.001, 0.01, 0.1, 1.0 micrograms i.c.v.) of alpha h-CRF inhibited the locomotor hyperactivity induced by cocaine dose-dependently. Neither the immunoneutralization nor the receptor blockade for CRF changed the hyperactivity induced by another locomotor stimulant caffeine. These results serve as indirect in vivo evidence of the selective role of endogenous CRF in the cocaine-induced behavioral alterations. The findings have implications as concerns the possible role of CRF in human psychopathological changes induced by cocaine.