Age-related emotionality is associated with cortical delta-opioid receptor dysfunction-dependent astrogliosis

Multiple changes occur in the aging brain, leading to age-related emotional disorders. A growing body of recent evidence suggests that the cortical delta-opioid receptor system plays a critical role in anxiety- and depressive-like behaviors in the rodent. In this study, we show that aging mice promoted anxiety-like behaviors as characterized by both the light-dark and elevated plus-maze tests, and they exhibit an increase in astrocytes in the cingulate cortex due to the dysfunction of cortical delta-opioid receptor systems. As well as aging mice, mice with a dysfunction of the delta-opioid receptor system induced by chronic treatment with the selective delta-opioid receptor antagonist naltrindole, revealed astrogliosis in the cingulate cortex, which was associated with anxiety. We also found that the microinjection of cultured astrocytes into the cingulate cortex of young mice enhanced the expression of anxiety-like behavior. Our results indicate that the aging process promotes astrogliosis in the cingulate cortex through the dysfunction of cortical delta-opioid receptors. This phenomenon may lead to emotional disorders including aggravated anxiety during normal aging.     

Facilitation of enkephalins-induced delta-opioid behavioral responses by chronic amisulpride treatment

The endogenous opioid system is known to have a great influence on the dopaminergic system. Conversely, blockade of the dopaminergic system in D2 receptor knock-out mice triggers an increase in enkephalin supporting the important physiological relationship between both systems. Therefore, the aim of this study was to investigate whether or not chronic treatment with the specific D2 antagonist amisulpride (20mg/kg, i.p., twice daily for 5 days) could lead to a facilitation of behavioral effects of enkephalins, protected from their enzymatic degradation by the dual inhibitor N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-l-phenylalanine benzyl ester (RB101) (5mg/kg, i.v.) in mice. RB101 induced an increase in locomotor activity, antidepressant-like effects in the forced swim test, and antinociceptive effects in the hot-plate test. Chronic treatment with amisulpride potentiated the action of RB101 and this effect seemed to be restricted to behavioral responses induced by opioids acting on delta-opioid receptors (locomotor activity and forced swim test). This was confirmed by the use of the selective delta-opioid receptor agonist, (+)-4-[alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80; 2.5mg/kg, i.p.), and antagonist, naltrindole (5mg/kg, i.p.). Considering the involvement of delta-opioid receptors in mood regulation, the interaction between amisulpride and RB101 could lead to a new therapeutic approach in the treatment of some mood disorders.     

Differential role of mu, delta and kappa opioid receptors in ethanol-mediated locomotor activation and ethanol intake in preweanling rats

The opioid system modulates ethanol intake and reinforcement in adult and preweanling rodents. While adult heterogeneous rats normally do not show ethanol-mediated locomotor stimulation, preweanling rats show it quite clearly. We recently observed that naloxone, a non-specific opioid antagonist, attenuated ethanol-induced locomotor activation in preweanling rats. In the present study we tested the role of specific opioid receptors (mu, delta and kappa) in ethanol-mediated locomotor stimulation and ethanol intake. In Experiment 1 13-day-old rats received naloxonazine (mu antagonist: 0, 7.5 or 15 mg/kg), naltrindole (delta antagonist: 0, 2 or 4 mg/kg) or nor-binaltorphimine (kappa antagonist: 0, 2, 4 or 8 mg/kg) before an intragastric administration of ethanol (0 or 2.5 g/kg), and subsequent locomotor activity assessment. In Experiment 2, the same opioid antagonists were administered on postnatal days 13 and 14 before consumption of ethanol (6%), saccharin (0.05%) or distilled water. In Experiment 1 only naloxonazine reduced ethanol-mediated locomotor stimulation. None of the opioid antagonists affected locomotor activity in water controls. In Experiment 2 naloxonazine and naltrindole suppressed ingestion of all the solutions tested. Similar to what has been reported in adult rodents, mu-opioid receptors seem to modulate ethanol-activating effects during early ontogeny. Hence, there seems to be a partial overlap of neurochemical mechanisms involved in the rewarding and stimulating effects of ethanol in preweanling rats. Mu-receptor antagonists reduced both ethanol-induced activity and ethanol intake, but it is unclear whether the latter effect is specific to ethanol or only a reflection of an effect on consummatory behavior generally, since mu and delta receptor antagonists also suppressed ingestion of water and sacccharin.     

Involvement of mu- and delta-opioid receptors in the antinociceptive effects induced by AMPA receptor antagonist in the spinal cord of rats

The present study was performed to explore the involvement of opioid receptors in the antinociception induced by a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist in rats. The hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation was assessed by hot plate test and the Randall Selitto Test. Intrathecal injection of 20 nmol of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) disodium, a competitive AMPA receptor antagonist, increased significantly the HWLs to both thermal and mechanical stimulation in rats. The increased HWLs induced by NBQX were dose-dependently attenuated by the opioid receptor antagonist naloxone, while naloxone itself had no marked influences on the HWL of rats. Furthermore, the increased HWLs induced by NBQX were inhibited by the mu-opioid antagonist beta-funaltrexamine (beta-FNA) or the delta-opioid antagonist naltrindole, but not by the kappa-opioid antagonist nor-binaltorphimine (nor-BNI). The results suggest that mu- and delta-opioid receptors, not kappa-opioid receptor, are involved in the antinociception induced by AMPA antagonist in the spinal cord of rats.     

Chronic naltrindole administration does not modify the inhibitory effect of morphine on vocalization responses in the tail electric stimulation test in rats

To address the existence of possible functional interactions between delta- and mu- receptors in relation to the affective component of pain, we have studied the effects of functional blockade of delta-receptors by a chronic treatment with naltrindole (1 mg/kg, 8 consecutive days) on antinociceptive responses to morphine (2 and 5 mg/kg) in the tail electric stimulation test, in adult male rats. The thresholds for the motor response (tail withdrawal), vocalization during stimulus and vocalization afterdischarge were assessed. These responses are considered to be integrated at spinal, medulla oblongata and diencephalon-rhinencephalon levels, respectively. The results show that the vocalization during stimulus and the vocalization afterdischarge were significantly affected by morphine in a dose dependent manner, the latter response being the most sensitive to the effects of the mu-opioid agonist. However, no significant effect was observed on motor responses at the doses used in this study. Chronic naltrindole treatment did not modify the inhibitory effect of morphine on the vocalization responses. Since the vocalization afterdischarge is related to the affective component of pain, the data suggest that the delta-opioid receptor is not involved in the supraspinal mechanisms at which these responses are organized and that there is not a mu-delta interaction in the modulation of the affective responses to noxious electrical stimulation.     

Role of dopamine D(1) receptors for kappa-opioid-mediated locomotor activity and antinociception during the preweanling period: a study using D(1) receptor knockout mice

kappa-Opioid receptor agonists both increase the locomotor activity of preweanling rats and induce antinociception. To determine whether dopamine (DA) D(1) receptors are necessary for either of these kappa-opioid-mediated effects we used D(1) (D(1A)) receptor knockout mice (i.e., D(1)-deficient mice). Heterozygous, wild-type, and D(1)-deficient mice (13 days old at testing) were injected with the kappa-opioid receptor agonist U-50,488 methanesulfonate (0.0, 0.2, 1. 0, 2.5, or 5.0 mg/kg, s.c.) and locomotor activity was measured for 60 min. In a separate experiment, tail-flick latencies of heterozygous, wild-type, and D(1)-deficient 13-day-old mice were assessed both before and after treatment with U-50,488 (0.0, 1.0, 2. 5, 5.0, or 10.0 mg/kg, s.c.). Results showed that lower doses of U-50,488 (0.2 and 1.0 mg/kg) increased the locomotor activity of 13-day-old mice regardless of genotype. Besides affecting locomotion, kappa-opioid receptor stimulation induced antinociception in preweanling mice, as U-50,488 caused a dose-dependent increase in the tail-flick latencies of heterozygous, wild-type, and D(1)-deficient mice. U-50,488's locomotor activating and analgesic effects did not differ according to genotype, thus suggesting that D(1) receptors are not necessary for kappa-opioid-mediated locomotor activity and antinociception during the preweanling period.     

Opposite conditioned place preference responses to endomorphin-1 and endomorphin-2 in the mouse

An unbiased conditioned place preference paradigm was used to evaluate the reward effect of selective endogenous mu-opioid ligands, endomorphin-1 and endomorphin-2, in male CD-1 mice. Pre- and post-conditioning free-movement were measured on day 1 and day 5, respectively. Conditioning sessions were conducted twice daily from day 2 through day 4 consisting of the alternate injection of conditioning drug or vehicle. Intracerebroventricular (i.c.v.) injection of endomorphin-1 (0.3-10 microg) induced place preference in a dose-dependent manner; whereas, endomorphin-2 (1-10 microg) dose-dependently induced place aversion. Both endomorphin-1-induced place preference and endomorphin-2-induced place aversion were blocked by pretreatment i.c.v. with mu-opioid receptor antagonist, beta-funaltrexamine. Selective delta-opioid receptor antagonist, naltrindole, co-administered i.c.v. with endomorphin-1 or endomorphin-2 did not affect reward effect. However, endomorphin-2-induced place aversion, but not endomorphin-1-induced place preference, was blocked by the i.c.v.-administered selective kappa-opioid receptor antagonist, WIN 44,441-3. It is concluded that endomorphin-1 produces conditioned place preference, which is mediated by the stimulation of mu-, but not delta- or kappa-opioid receptors, while endomorphin-2 produces conditioned place aversion, which is mediated by the stimulation of mu- and kappa-, but not delta-opioid receptors.     

Age-dependent effects of κ-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate–putamen: an in vivo microdialysis study

κ-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate–putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because κ-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether κ-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 μg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying κ-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why κ-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.     

Delta-opioid receptor activation prevents appearance of irreversible damages of cardiomyocytes and exacerbates myocardial contractility dysfunction during ischemia and reperfusion

It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min reperfusion. This effect was completely abolished by pretreatment with a delta-antagonist naltrindole or a non-selective agonist naloxone. It was found that preactivation of cardiac delta-OR exacerbates reperfusion contractility dysfunction of the heart. This effect was also eliminated by opioid receptor antagonists. It is suggested that stimulation of cardiac delta-OR prevents irreversible cardiac cell damage but exacerbates contractility dysfunction during ischemia and reperfusion in vitro.     

Passive body heating improves sleep patterns in female patients with fibromyalgia

OBJECTIVE:

To assess the effect of passive body heating on the sleep patterns of patients with fibromyalgia.

METHODS:

Six menopausal women diagnosed with fibromyalgia according to the criteria determined by the American College of Rheumatology were included. All women underwent passive immersion in a warm bath at a temperature of 36±1°C for 15 sessions of 30 minutes each over a period of three weeks. Their sleep patterns were assessed by polysomnography at the following time-points: pre-intervention (baseline), the first day of the intervention (acute), the last day of the intervention (chronic), and three weeks after the end of the intervention (follow-up). Core body temperature was evaluated by a thermistor pill during the baseline, acute, chronic, and follow-up periods. The impact of this treatment on fibromyalgia was assessed via a specific questionnaire termed the Fibromyalgia Impact Questionnaire.

RESULTS:

Sleep latency, rapid eye movement sleep latency and slow wave sleep were significantly reduced in the chronic and acute conditions compared with baseline. Sleep efficiency was significantly increased during the chronic condition, and the awakening index was reduced at the chronic and follow-up time points relative to the baseline values. No significant differences were observed in total sleep time, time in sleep stages 1 or 2 or rapid eye movement sleep percentage. The core body temperature and Fibromyalgia Impact Questionnaire responses did not significantly change over the course of the study.

CONCLUSION:

Passive body heating had a positive effect on the sleep patterns of women with fibromyalgia.     

Social learning about ethanol in preweanling rats: role of endogenous opioids

The role of the endogenous opioid system in social learning about ethanol was examined in three experiments using preweanling rats. Experiment 1 showed that interactions with intoxicated siblings in the home cage on postnatal Days (PD) 12, 14, and 16 results in increased voluntary intake of ethanol when subjects are tested 24 hr after the final exposure. The results also suggested that the endogenous opioid system is not involved in acquisition. Administration of naloxone during social exposure to ethanol had no effect on later ethanol intake. Experiment 2 examined the effects of receptor‐selective antagonists administered prior to test. For subjects that had social exposure to ethanol, intake of ethanol was completely suppressed by either naloxone or the δ antagonist naltrindole. For ethanol‐naïve subjects, intake also was completely suppressed by naloxone. However, intake was partially blocked by naltrindole or the μ antagonist β‐FNA. Experiment 3 confirmed the differential involvement of μ and δ receptors in ethanol intake through a more comprehensive dose–response analysis of β‐FNA and naltrindole. Collectively, these data reveal that learning about ethanol from intoxicated conspecifics not only affects voluntary intake of ethanol but also alters the opioidergic response to ethanol consumption. © 2004 Wiley Periodicals, Inc. Dev Psychobiol 44: 132–139, 2004.     

Delta opioids reduce the neurotransmitter release probability by enhancing transient (KV4) K+-currents in corticostriatal synapses as evaluated by the paired pulse protocol

Field recordings were used to determine the influence of delta-opioid receptor activation on corticostriatal synaptic transmission. Application of the selective delta-opioid receptor agonist, [Tyr-D-Pen-Gly-Phe-D-Pen]-enkephalin (DPDPE, 1 microM), decreased the amplitude of the field-excitatory synaptic potential and at the same time increased the paired pulse ratio (PPR) suggesting a presynaptic site of action. This response reversed rapidly when DPDPE was washed and blocked by 1 nM of the selective delta-receptor antagonist naltrindole. Neither omega-conotoxin GVIA (1 microM) nor omega-agatoxin TK (400 nM), blockers of N- and P/Q-type Ca2+-channels, respectively, nor TEA (1 mM), blocker of some classes of K+-channels, occluded the effects of DPDPE. Instead, 1 mM 4-AP or 400 microM Ba2+ occluded completely the effects of DPDPE. Therefore, the results suggest that the modulation by delta opioids at corticostriatal terminals is mediated by transient (KV4) K+-conductances.     

Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia

Analgesic effects of delta opioid receptor (DOR) –selective agonists are enhanced during persistent inflammation and arthritis. Although the underlying mechanisms are still unknown, membrane density of DOR was shown to be increased 72 h after induction of inflammation, an effect abolished in mu opioid receptor (MOR) –knockout (KO) mice [Morinville A, Cahill CM, Kieffer B, Collier B, Beaudet A (2004b) Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain. Pain 109:266–273]. In this study, we demonstrated a crucial role of MOR in DOR-mediated antihyperalgesia. Intrathecal administration of the DOR selective agonist deltorphin II failed to induce antihyperalgesic effects in MOR-KO mice, whereas it dose-dependently reversed thermal hyperalgesia in wild-type mice. The antihyperalgesic effects of deltorphin II were blocked by naltrindole but not d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂ (CTOP) suggesting that this agonist was mainly acting through DOR. SNC80-induced antihyperalgesic effects in MOR-KO mice were also attenuated as compared with littermate controls. In contrast, kappa opioid receptor knockout did not affect deltorphin II–induced antihyperalgesia. As evaluated using mice lacking endogenous opioid peptides, the regulation of DOR’s effects was also independent of β-endorphin, enkephalins, or dynorphin opioids known to be released during persistent inflammation. We therefore conclude that DOR-mediated antihyperalgesia is dependent on MOR expression but that activation of MOR by endogenous opioids is probably not required.     

Daily running promotes spatial learning and memory in rats.

Previous studies on exercise have shown that physical activity improves learning and memory. Present study was performed to determine the effects of acute, chronic and continuous exercise with different periods on spatial learning and memory recorded as the latency and length of swim path in the Morris water maze testing in subsequent 8 days. Four rat groups were included as follows: (1) group C, controls which did not exercise; (2) group A, 30 days treadmill running before and 8 days during the Morris water maze testing period; (3) group B, 30 days exercise before the Morris water maze testing period only; (4) group D, 8 days exercise only during the Morris water maze testing period. The results showed that chronic (30 days) and continuous (during 8 days of Morris water maze testing days) treadmill training produced a significant enhancement in spatial learning and memory which was indicated by decreases in path length and latency to reach the platform in the Morris water maze test (p<0.05). The benefits in these tests were lost in 3 days, if the daily running session was abandoned. In group D with acute treadmill running (8 days exercise only) the difference between the group A disappeared in 1 week and benefit seemed to be obtained in comparison with the controls without running program. In conclusion the chronic and daily running exercises promoted learning and memory in Morris water maze, but the benefits were lost in few days without daily running sessions in adult rats.     

Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: evidence for opioid receptor modulation

In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic–pituitary–adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic–pituitary–adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) “binge” pattern cocaine administration (45mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic–pituitary–adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic “binge” cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic–pituitary–adrenal tolerance developed with chronic “binge” cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic–pituitary–adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.     

Behavioral changes in rats after acute, chronic and repeated administration of interleukin-1beta: relevance for affective disorders

BACKGROUND: Acute, peripheral and central administration of recombinant rat interleukin-1beta (IL-1beta) has been shown to decrease social exploration and locomotor activity and to induce alterations in brain biogenic amines in rats. The aims of this study were to examine whether acute, repeated and chronic administration of IL-1beta to rats may interfere with shuttle box escape learning, a model for anxiety- and depression-like behavior. METHODS: Sixty-four adult male viral-free Sprague-Dawley rats (200-300 g weight) housed in groups of four at 25 degrees C with a 12:12 light:dark cycle were used in the experiments. They were divided into 8 groups, i.e. 4 control and 4 experimental. The latter were divided into an acute group receiving a single intra-peritoneally (i.p.) challenge of IL-1beta (tested at the shuttle box 1 and 24 h later); a chronic group with daily i.p. injections of IL-1beta for 7 days (tested at the shuttle box 1 h later); and a group with repeated administration, i.e. one i.p. injection on the first day and a second challenge on the seventh day (tested at the shuttle box 1 h later). The control animals followed the same injecting and testing schedule but were treated i.p. with saline. RESULTS: The acute group treated with one IL-1beta challenge and tested 1 (P=0.001) and 24 h (P=0.002) later showed significant time elongations in the escape trials. The animals treated chronically with IL-1beta for seven consecutive days showed a significant increase in the latency at the escape trials (P=0.0001). Repeated administration of IL-1beta on the first day and a second on the seventh day did not significantly alter the time elongation in the escape trial. DISCUSSION: Acute and chronic administration of IL-1beta significantly increase the latency of escape to a foot shock, whereas repeated IL-1beta administration does not induce a sensitization of these behavioral responses.     

Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.     

Acute, but not chronic, exposure to d-cycloserine facilitates extinction and modulates spontaneous recovery of a conditioned taste aversion

D-cycloserine, the glutamate N-methyl-D-aspartate receptor partial agonist, has been reported to facilitate the extinction of learned fears acquired in both naturalistic and laboratory settings. The current study extended this literature by evaluating the ability of either chronic or acute administrations of DCS to modulate the extinction and spontaneous recovery of a conditioned taste aversion (CTA). Twenty-three hour fluid-deprived Sprague-Dawley rats acquired a strong CTA following 3 pairings of a conditioned stimulus (CS; 0.3% oral saccharin)+unconditioned stimulus [US; 81 mg/kg (i.p.) lithium chloride (LiCl)]. In separate groups of rats, we then employed 2 different extinction paradigms: (1) CS-only (CSO-EXT) in which saccharin was presented every-other day, or (2) Explicitly Unpaired (EU-EXT) in which both saccharin and LiCl were presented but on alternate days. Previous studies have indicated that the EU-EXT procedure speeds up the extinction process. Further, spontaneous recovery of a CTA emerges following CSO-EXT but the EU-EXT paradigm causes a suppression of spontaneous recovery. DCS (15 mg/kg, i.p.) was administered immediately after daily liquid presentations (saccharin or water, alternate days) during the extinction period. In an acute drug manipulation, DCS (15 mg/kg, i.p.) or saline control injections were administered for 4 days only. This was done during one of 3 different phases of extinction [i.e., static (2-5%), early dynamic (8-16%), or middle dynamic (20-40%) saccharin reacceptance]. Other animals assigned to the chronic DCS condition received daily DCS (15 mg/kg, i.p.) throughout extinction. Changes in saccharin drinking in these animals were compared to the data from rats that received no drug (saline controls). Once rats met our criterion for asymptotic extinction (90% reacceptance of the CS) they entered a 30-day latency period during which they received water for 1 h/day. The day after the completion of the latency period, a final opportunity to drink saccharin was provided (spontaneous recovery test). Saline-treated control rats that went through the EU-EXT procedure achieved asymptotic extinction more quickly than did the CSO-EXT rats and did not exhibit a spontaneous recovery of the CTA. Chronic DCS treatments did not significantly reduce the time to achieve asymptotic CTA extinction in rats exposed to either CSO or EU extinction methods. Further, animals treated with DCS throughout EU-EXT exhibited a spontaneous recovery of the CTA whereas the saline-treated, EU-EXT rats did not. Thus, chronic DCS treatment did not shorten the time to extinguish a CTA and this treatment eliminated the ability of EU-EXT to block spontaneous recovery of the CTA. Acute DCS treatments were more effective in reducing the time required to extinguish a CTA than were chronic drug treatments. Moreover, the timing of these acute DCS treatments affected spontaneous recovery of the CTA depending on the extinction method employed. Acute DCS administrations later in extinction were more effective in reducing spontaneous recovery than were early administrations if the rats went through the CSO-EXT procedure. However, late-in-extinction administrations of DCS facilitated spontaneous recovery of the CTA in rats that experienced the EU-EXT method. These data agree with other findings suggesting that DCS treatments are more effective when administered a limited number of times. Our data extend these findings to the CTA paradigm and further suggest that, depending on the extinction paradigm employed, acute exposure to DCS can speed up CTA extinction and reduce spontaneous recovery of the aversion. The timing of the acute DCS treatment during extinction is generally less important than its duration in predicting the rate of CTA extinction. However, the timing of acute DCS treatments during extinction and the method of extinction employed can interact to affect spontaneous recovery of a CTA.     

可卡因戒断对大鼠睡眠结构和脑电功率谱的影响

目的: 探索可卡因戒断对睡眠觉醒活动的影响。方法: 大鼠体内植入无线发射器,用药前、停药第1 d(急性)、8 d(亚急性)、14 d(亚慢性)记录自由活动大鼠脑电波24 h。结果: 停药第1 d睡眠觉醒周期上升(P<0.05)。停药第8 d夜晚和白天,非快动眼睡眠(NREM)增加(P<0.05),快动眼睡眠(REM)下降(P<0.01);停药第14 d,NREM睡眠夜晚显著增加(P<0.01)而白天仅略加强,白天和夜间REM睡眠均明显下降(P<0.01)。停药期间白天和夜间总睡眠无明显变化。整个实验期间,NREM、REM睡眠和觉醒状态的δ、θ 和α脑电功率谱均无显著变化。结论: 可卡因戒断所致睡眠障碍主要由于快、慢波睡眠间而非睡眠与觉醒间异动。急性戒断造成睡眠觉醒间转换异常,而睡眠结构失调则发生在亚急性和亚慢性戒断期间。