Differential effects of morphine- and cocaine-induced nNOS immunoreactivity in the dentate gyrus of hippocampus of mice lacking mu-opioid receptors

This study investigated the expression of nNOS after repeated morphine or cocaine administration in order to determine if nNOS (neuronal nitric oxide synthase) is involved in the morphine- or cocaine-induced behavioral sensitization in mu-opioid receptor knockout (MOR(-/-)) mice. Higher numbers of nNOS-positive cells were observed in the dentate gyrus of the hippocampus (DG) of the wild-type (MOR(+/+)) mice repeatedly treated with either morphine or cocaine than in the saline treated MOR(+/+) mice (morphine, +122%; cocaine, +82%). Moreover, the MOR(-/-) mice also showed significantly higher morphine- or cocaine-induced nNOS expression levels in the DG than in the saline treated MOR(+/+) mice (morphine, +234%; cocaine, +54%). The MOR(-/-) mice showed a significantly higher morphine-induced nNOS expression level (+103%) or a lower cocaine-induced nNOS expression level (+38%) in the DG than in the morphine- or cocaine-treated MOR(+/+) mice. These results suggest that morphine and cocaine sensitization is differentially regulated by the mu-opioid receptors in MOR(-/-) mice via the nNOS systems in the DG.     

Dose-dependent cocaine place conditioning and D1 dopamine antagonist effects in male Japanese quail

The dopamine D1 receptor subtype has been implicated in drug reward processes in mammals. Two experiments investigated whether dose-dependent differences in cocaine conditioned place preference (CPP) would be obtained in an avian species and whether these cocaine effects were mediated by the dopamine D1 antagonist R(+/-)-SCH23390. In Experiment 1, male birds were given intraperitoneal injections of 1, 3, 10, or 30 mg/kg of cocaine hydrochloride, paired with a chamber that contained distinct visual cues. On alternate days, they received saline paired with a chamber containing different visual cues. A CPP test was given after four pairings of cocaine with the distinct chamber. In Experiment 2, 0.0025, 0.025, or 0.25 mg/kg of SCH 23390 or saline was administered 15 min prior to cocaine (3 mg/kg) and placement into the least preferred chamber. CPP was observed at 1, 3, and 10 mg/kg doses of cocaine but not at 30 mg/kg or saline. All doses of SCH 23390 attenuated cocaine-induced CPP. The findings suggest that cocaine administration results in a dose-dependent CPP, and that similar with mammals, it may be mediated by D1 receptors in an avian species. Thus, the avian species may be a beneficial comparative model for drug studies, especially those involving visual cue mechanisms of drug reward.     

Cocaine place conditioning increases pro-opiomelanocortin gene expression in rat hypothalamus

Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products in modulating cocaine reward and addiction-like behaviors in rodents. In this study, we investigated whether cocaine-induced conditioned place preference (CPP) alters POMC gene expression in the brain or pituitary of rats. Sprague-Dawley rats were conditioned with 4 injections of 0, 10 or 30 mg/kg cocaine (i.p.) over 8 days and tested 4 days after the last conditioning session. Another group received the same pattern of cocaine injections without conditioning. POMC mRNA levels in the hypothalamus (including arcuate nucleus), amygdala and anterior pituitary, as well as plasma ACTH and corticosterone levels were measured. Cocaine place conditioning at 10 and 30 mg/kg doses increased POMC mRNA levels in a dose-dependent manner in the hypothalamus, with no effect in the amygdala. Cocaine CPP had no effect on POMC mRNA levels in the anterior pituitary or on plasma ACTH or corticosterone levels. In rats that received cocaine at 30 mg/kg without conditioning, there was no such effect on hypothalamic POMC mRNA levels. Alteration of POMC gene expression in the hypothalamus is region-specific after cocaine place conditioning, and dose-dependent. The increased POMC gene expression in the hypothalamus suggests that it is involved in the reward/learning process of cocaine-induced conditioning.     

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. Our results, which reveal a decrease in the conditioned rewarding effects of threshold doses of cocaine, demonstrate that exposure to high doses of this drug can alter the reward system.     

Conditioned increases in behavioral activity and accumbens dopamine levels produced by intravenous cocaine

In vivo microdialysis, behavioral activity assessments, and a conditioned place preference (CPP) test were used to investigate dopaminergic correlates of cocaine-conditioned behaviors. Over 12 days, rats were given either intravenous cocaine (4.2 mg/kg) or saline (6 cocaine and 6 saline infusions) daily in distinctively different environments. The following day, rats were tested in the cocaine- and saline-paired environments; 48 hr later, CPP was determined. The cocaine-associated environment elicited greater nucleus accumbens dopamine (NAcc DA) levels, hyperactivity, and place preference, though the emergence of DA increases was not in synchrony with peak behavioral activation. Although conditioned behavioral effects after repeated cocaine are well documented, direct evidence of increased NAcc DA in response to a cocaine-paired environment has not been previously reported. Discrepancies with previous work are attributed to a number of methodological differences.     

Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference

We have demonstrated previously that mice expressing a constitutive deletion of the kainate receptor subunit GluR5 (GluR5 KO) do not differ from wildtype (WT) littermates of a congenic C57BL/6 background with regard to both the development of morphine physical dependence as measured by naloxone-precipitated withdrawal signs and to morphine reward as revealed by the expression of conditioned place preference (CPP). However, unlike WT, GluR5 KO mice fail to develop antinociceptive tolerance following repeated systemic morphine administration. In this report, we examined the impact of GluR5 deletion on cocaine-mediated CPP and locomotor sensitization. Expression of CPP was evident in WT mice following repeated daily administration of 20 mg/kg (but not 10 mg/kg) i.p. cocaine. Interestingly, GluR5 KO mice exhibited enhanced cocaine preference as compared with WT mice at both 10 and 20 mg/kg doses. In addition, while GluR5 KO mice did not differ from WT with respect to baseline locomotor activity, mutant mice demonstrated increased locomotor hyperactivity versus WT mice after repeated injection of 15 mg/kg i.p. cocaine. Collectively, these data indicate that GluR5 appears to negatively modulate some psychostimulant and rewarding properties of cocaine, as demonstrated by heightened sensitization and salience in mutant mice.     

Conditioned facilitation of brain reward function after repeated cocaine administration

Cocaine lowers brain reward thresholds, reflecting increased brain reward function. The authors investigated whether, similar to acute cocaine administration, cocaine-predictive conditioned stimuli would lower intracranial self-stimulation (ICSS) thresholds. Rats received a saline injection for 5 days, a cocaine injection (10 mg/kg) for 20 consecutive days, then saline for 5 additional days. Thresholds were measured immediately before and 10 min after each injection. The initial 5 saline injections had no effect on thresholds, whereas cocaine significantly lowered thresholds for 20 days. There was no tolerance or sensitization to this effect of cocaine over days. During the last 5 days when cocaine administration was substituted with saline, rats demonstrated a conditioned lowering of thresholds during the 2nd daily ICSS session. These data demonstrate that cocaine-predictive conditioned stimuli induce a conditioned facilitation of brain reward function.     

Genetic and pharmacological manipulation of mu opioid receptors in mice reveals a differential effect on behavioral sensitization to cocaine

Cocaine-induced behavioral sensitization is a complex phenomenon involving a number of neuromodulator and neurotransmitter systems. To specifically investigate the role of the micro opioid receptor (MOR) in cocaine-induced behavioral sensitization in mice, both genetic and pharmacological approaches were undertaken. MOR-1 deficient mice of varying backgrounds (C57BL/6J, 129S6, F1 hybrid 129S6xC57BL/6J and 129S6xC57BL/6J) and wild-type C57BL/6J mice exposed continuously to naltrexone, an opioid receptor antagonist, received single daily injections of saline or cocaine for 10 days. All mice received a single cocaine challenge 7 days following the last saline or cocaine injection to test for the expression of sensitization. The locomotor-stimulating and sensitizing effects of cocaine observed in MOR-1 wild-type mice were absent in MOR-1 knockout mice maintained on the mixed 129S6xC57BL/6J background. In contrast, MOR-1 deficient mice developed on a C57BL/6J background showed an accentuated sensitivity to cocaine-induced locomotion. Cocaine's psychomotor activating effects were more pronounced in the MOR-1 C57BL/6J knockouts injected daily with cocaine than in the MOR-1 wild-type mice. Similar locomotor-stimulating and sensitizing effects were found in both F1 hybrid 129S6xC57BL/6J MOR-1 wild-type and MOR-1 knockout mice, while the 129S6 strain showed an overall indifference to cocaine. That is, both the locomotor-stimulating and sensitizing effects of cocaine were absent in both MOR-1 wild-type and MOR-1 knockout mice maintained on the 129S6 background. Lastly, the locomotor-stimulating and sensitizing effects of cocaine were attenuated in C57BL/6J wild-type mice exposed continuously to naltrexone. Collectively, these data support a role for opioidergic involvement in cocaine-influenced behavior in mice. Moreover, MORs appear to differentially modulate a sensitized response to cocaine in different strains of mice as delineated by MOR-1 gene deletion and pharmacological antagonism.     

The neuronal nitric oxide synthase (nNOS) gene contributes to the regulation of tyrosine hydroxylase (TH) by cocaine

Recently, we demonstrated that intact nitric oxide (NO) signaling is essential for the development of cocaine behavioral sensitization in adulthood [M.A. Balda, K.L. Anderson, Y. Itzhak, Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice, Psychopharmacology (Berl) 200 (2008) 509–519]. Given the requirement of dopamine (DA) transmission in cocaine-induced behavioral sensitization and the interactions between NO and DA systems, the present study investigated the role of the neuronal nitric oxide synthase (nNOS) gene and the effect of cocaine on the expression of tyrosine hydroxylase (TH)-immunoreactive (-ir) neurons. Adult (postnatal day 80) wild type (WT) and nNOS knockout (KO) mice received saline or a sensitizing regimen of cocaine (20 mg/kg) for 5 days. After 24 h, TH immunoreactivity was assessed in the ventral tegmental area (VTA) and the dorsal striatum (dST) using stereology and Western blotting, respectively. We report that (a) nNOS KO mice express lower levels of TH-ir neurons in the VTA compared to WT counterparts, (b) cocaine administration to WT mice significantly increased striatal TH expression, and (c) the same cocaine administration to nNOS KO mice significantly decreased striatal TH expression. Thus, the nitrergic system may contribute to cocaine-induced behavioral sensitization by regulating dopaminergic neurotransmission.     

Specific blockade of morphine- and cocaine-induced reinforcing effects in conditioned place preference by nitrous oxide in mice

Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, the following day mice were given saline. This sequence alternated during the next 4 days. Control animals received saline every day. The behavior of animals was evaluated on day 8. N(2)O did not induce CPP but impaired the acquisition of morphine-induced CPP and blocked the expression of cocaine- and morphine-induced CPP. The effects of the gas were long lasting and persist 4 days following the exposure. Moreover no behavioral modifications in tests usually used to investigated emotional state as compared with control mice were observed in animals exposed to N(2)O, ruling out an effect of this gas on attention, anxiety, depression, locomotion and anhedonia. These studies raise the possibility that N(2)O could have a clinical benefit in the management of morphine and cocaine addiction.     

Contrasting effects of mu opioid receptor and delta opioid receptor deletion upon the behavioral and neurochemical effects of cocaine

Conventional brain microdialysis was used to assess basal and cocaine-induced dopamine (DA) levels in the nucleus accumbens of wildtype (WT) C57BL/6J mice and mice with constitutive deletion of ether mu- or delta-opioid receptors (MOR or DOR knockout [KO], respectively). Locomotor activity was assessed in these same animals. Basal locomotor activity of DOR KO was elevated relative to MOR KO, but did not differ from that of WT mice. DOR mice, but not WT or MOR KO, exhibited a significant increase in activity in response to an injection of saline. The acute administration of cocaine produced a dose-related increase in locomotor activity in the three genotypes. The locomotor activating effects of a low dose (10 mg/kg) of cocaine were enhanced in DOR KO mice whereas the locomotor activating effects of both a low and higher (20 mg/kg) dose of cocaine were reduced in MOR KO animals. Microdialysis studies revealed no difference between genotypes in basal DA levels. Acute administration of cocaine, but not saline, increased DA levels in WT and KO animals. Paradoxically, however, the magnitude of this effect was smaller in DOR KO as compared with that in either WT or MOR KO. These data indicate that constitutive deletion of either MOR or DOR results in contrasting effects upon responsiveness to cocaine, which is consistent with the distinct phenotypes previously described for these mutants.     

Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice

The organic cation transporter-3 (OCT3) can transport monoamines, similar to neuronal monoamine transporters. Due to the lack of selective ligands, however, the functional role of OCT3 is still unknown. Thus, we investigated behavioral effects of antisense against OCT3 (AS) in mice. AS (0.075-0.25 microg/0.25 microl/h, for 7 days) dose-dependently decreased immobility time. Moreover, although neither AS (0.075 microg/0.25 microl/h, for 7 days) or imipramine (4 mg/kg, i.p.) were effective, imipramine (4 mg/kg, i.p.) significantly decreased immobility time in mice treated with AS (0.075 microg/0.25 microl/h, for 7 days). Additionally, AS (0.25 microg/0.25 microl/h, for 7 days) significantly increased locomotor activity induced by methamphetamine (1 mg/kg, s.c.), but did not affect spontaneous locomotor activity. These results suggest that OCT3 might become a novel molecular target to treat depression and other diseases related to monoaminergic neuronal systems.     

Biperiden (an M1 antagonist) reduces memory consolidation of cocaine-conditioned place preference

It is well-known that cocaine dependence is a public health issue, and several studies stress the need to look for new and more effective treatments. Although the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and projects to several forebrain structures, is known to be critically involved in the neurobiology of cocaine dependence, acetylcholine (ACh) has also been shown to play an important role in cocaine dependence via its action on this reward system. ACh is also important in the formation of hippocampal memory associated with appetitive behavior. Thus, the aim of this study was to evaluate the effect of biperiden, an ACh antagonist with high affinity for muscarinic M1 type receptors, on the acquisition of cocaine-conditioned place preference (CPP) in mice. The cocaine and biperiden were dissolved in sterile saline and were administered intraperitoneally at a dose of 10mg/kg. The conditioning regime was 8 days long, and the cholinergic antagonist was given immediately at the end of each conditioning session. The test for CPP occurred 24h after the last session. The results showed that animals treated with biperiden spent significantly less time in the cocaine-paired compartment than did the ones treated with saline. This finding represents a reduction in the consolidation of cocaine-induced CPP. One hypothesis that could explain this outcome focuses on the action of cholinergic antagonists on the consolidation of contextual memories. The amnesic effect of M1 antagonists on aversive tasks and on morphine CPP has been demonstrated when administered before the training or the conditioning session. The present study highlights the possibility of impairment in the acquisition of an appetitive memory, even when the cholinergic drug is administered after the conditioning session. This protocol also rejects the possibility of performance disturbance and suggests a possible pharmacological tool in the treatment of cocaine dependence.     

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

This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed two rats/cage with no toys (SI2) or with toys (SE2), or three/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cage mates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr³⁴-DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.     

Individual differences in cocaine-induced locomotor activity of male Sprague–Dawley rats are not explained by plasma corticosterone levels

Humans differ in their initial response to, and subsequent abuse of, addictive drugs like cocaine. Rodents also exhibit marked individual differences in responsiveness to cocaine. Previously, we classified male Sprague–Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively), based on their acute low-dose cocaine-induced locomotor activity, and found that with repeated drug exposure LCRs exhibit greater cocaine locomotor sensitization, reward and reinforcement than HCRs. Differential cocaine-induced increases in striatal dopamine help to explain the LCR/HCR phenotypes. Differential levels of stress and/or anxiety could also contribute but have not been explored. Here we measured open-field activity and plasma corticosterone levels both pre- and post-cocaine treatment in LCRs, HCRs, and saline-treated controls. The three groups did not differ in baseline locomotor activity or corticosterone levels. Importantly, LCR/HCR differences in corticosterone levels were also not observed following acute cocaine (10 mg/kg, i.p.), when cocaine induced approximately 3.5-fold greater locomotor activity in HCRs than LCRs. Additionally, there were no LCR/HCR differences in plasma corticosterone levels following 5 days of once-daily cocaine, during which time LCRs developed locomotor sensitization such that their cocaine-induced locomotor activity no longer differed from that of HCRs. Likewise, there were no group activity differences in any of four concentric zones within the open-field chamber. In summary, neither plasma corticosterone levels nor thigmotaxis-type anxiety appears to be a factor that contributes to the observed cocaine-induced LCR/HCR behavioral differences.     

Expression of cocaine sensitization: regulation by the medial prefrontal cortex.

Extracellular levels of dopamine are increased in response to systemic administration of cocaine in several brain areas including the nucleus accumbens and medial prefrontal cortex. While the cocaine-induced increase in extracellular dopamine levels in the nucleus accumbens is augmented after repeated daily cocaine, the response of extracellular dopamine levels in the medial prefrontal cortex is attenuated. Since dopamine in the medial prefrontal cortex has an inhibitory effect on nucleus accumbens dopamine levels and locomotor activity, the role of medial prefrontal cortex dopamine tolerance in the expression of sensitized locomotor behavior was further examined by injection of D-amphetamine sulfate into the prelimbic portion of the medial prefrontal cortex just prior to cocaine challenge in cocaine-sensitized rats. Male Sprague-Dawley rats were non-handled (naive) or injected with either saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) for five consecutive days. After a seven to 12 day withdrawal period, rats were microinjected with either saline or various doses of amphetamine into primarily the prelimbic region of the medial prefrontal cortex followed by systemic injection of saline or cocaine. In naive rats, intramedial prefrontal cortex amphetamine produced a trend toward decreased locomotor responding to cocaine challenge while no effect of amphetamine was evident in daily saline pretreated rats. Daily cocaine pretreated rats that received saline in the medial prefrontal cortex demonstrated a sensitized locomotor response compared to their daily saline pretreated counterparts. This sensitization was blocked by a low dose of amphetamine (0.175 microg/side) in the medial prefrontal cortex, an effect which disappeared in animals administered higher amphetamine doses. The results suggest that in rats sensitized to cocaine, decreased medial prefrontal cortex dopamine levels in response to cocaine challenge may contribute to behavioral sensitization. Furthermore, the data indicate the possibility that there is an optimal range at which medial prefrontal cortex amphetamine exerts maximal behavioral inhibition. These findings implicate a role for decreased cortical control in producing sensitized behavioral responding to cocaine.     

Local injection of a glutamate uptake inhibitor into the ventral tegmental area produces sensitization to the behavioural effects of d-amphetamine

Circumstantial evidence suggests that sensitization to the behavioral effects of d-amphetamine is mediated by increased glutamate levels in the ventral tegmental area. To test this directly, the present study examined whether increasing glutamate levels in the ventral tegmental area with a glutamate uptake inhibitor is sufficient, in the absence of d-amphetamine administration, to elicit sensitization to a subsequent d-amphetamine challenge. Rats were treated bilaterally once a day for 2 days with either intra-ventral tegmental area L-trans-pyrollidine-2,4-dicarboxylic acid (50 nmol), saline, L-trans-pyrollidine-2,4-dicarboxylic acid coadministered with the competitive N-methyl-d-aspartate antagonist (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid; CPP, 0.5 nmol), or CPP alone (0.5 nmol; all 1.0 microl/side). Following a 2 day withdrawal period, all rats were administered systemic d-amphetamine (1 mg/kg, i.p.). Repeated intra-ventral tegmental area injection of L-trans-pyrollidine-2,4-dicarboxylic acid sensitized animals to the behavioral effects of a systemic d-amphetamine challenge, an action which was blocked by co-administration of CPP. The results directly implicate ventral tegmental area glutamate in the process of sensitization to d-amphetamine. Furthermore, they demonstrate that inhibition of glutamate uptake produces the neuroadaptations necessary to induce sensitization, adding support to the contention that d-amphetamine sensitizes by modulating glutamate uptake.     

Contribution of the suprachiasmatic nucleus to day:night variation in cocaine-seeking behavior

Recent work has shown that time-of-day influences drug-seeking behavior. The present experiments tested the hypothesis that the master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) is required for generating day:night differences in drug-seeking behavior, specifically the acquisition, extinction, and reinstatement of cocaine-induced conditioned place preference (CPP). Sham and SCN-lesioned (SCNx) rats were trained for cocaine-induced CPP behavior at either ZT4 (Zeitgeber time 4, 4 h after lights-on) or ZT12 (lights-off). After being tested for side preference, rats were allowed to extinguish CPP. This was followed by cocaine-induced reinstatement with 5 mg/kg and 10 mg/kg of cocaine. SCNx animals exhibited no 24-h locomotor activity rhythm. Acquisition of CPP behavior did not vary with time-of-day, but was greater in SCNx animals. Sham rats tested at ZT12 took significantly longer to extinguish CPP behavior compared to ZT4, an effect completely abolished by SCN lesions. Cocaine-induced reinstatement of CPP did not vary with time of day in sham rats. However, SCNx animals tested at ZT4 trended towards greater reinstatement to the low dose of cocaine, and displayed significantly less reinstatement to the higher dose of cocaine than sham rats. Additionally, SCNx rats tested for reinstatement to the lower dose of cocaine displayed greater reinstatement at ZT4 than at ZT12. We conclude that: 1) acquisition of CPP behavior does not vary between the two times of day tested but is influenced tonically by the SCN, 2) extinction of cocaine CPP varies with time-of-day and this variation depends critically on the SCN, and 3) reinstatement of cocaine CPP does not vary between the two times of day tested. However, day:night differences in reinstatement are unmasked in animals lacking an SCN, suggesting the possibility that an extra-SCN oscillator is responsible for generating variation in this cocaine-seeking behavior.     

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.     

Cocaine sensitization in male quail: temporal, conditioning, and dose-dependent characteristics

Chronic cocaine administration typically results in increased locomotor activity, known as behavioral sensitization. Investigating the time course of locomotor activity across trials may provide a more detailed analysis of the temporal changes that might occur within sensitization. Prior research with rodents shows that the peak of locomotor activity shifts from acute to chronic drug administration. The purpose of the current experiment was to investigate acute versus chronic cocaine effects on locomotor activity in an avian species, Japanese quail, and to investigate whether this phenomenon is dose-dependent. Subjects received daily ip injections of saline or 5, 10, or 20 mg/kg cocaine for 20 days. Following each injection, birds were placed in standard locomotor activity chambers, and activity was recorded for 150 min. A cocaine challenge was given after a ten-day withdrawal period. Two retraining trials were given to re-establish cocaine responding prior to a saline challenge in the drug-paired environment. Results showed that repeated administration of the 10 mg/kg dose of cocaine enhanced activity across 120 min compared with acute administration. In contrast, repeated administration of the 20 mg/kg dose resulted in greater cocaine-induced activity for 60 min compared with acute administration. In addition, behavioral sensitization was shown to be dose-dependent and appeared to be due, at least in part, to conditioning.