Much data suggest that the binding of dynorphin-like peptides to kappa-opioid receptors (KORs) during the administration of and withdrawal from a variety of addictive drugs is aversive and serves to limit the reinforcing properties of those drugs and to enhance tolerance, withdrawal, and the probability of stress-induced relapse. In this study, we examined the role of KORs in mediating opioid withdrawal and its aversive consequences in rats. We found that selective blockade of KORs by i.p. administration of 20mg/kg nor-binaltorphimine (nor-BNI) 5h prior to naltrexone-precipitated withdrawal in morphine-dependent rats decreased feces excreted during a 30-min withdrawal session. More critically, this injection of nor-BNI decreased the subsequent conditioned place aversion (CPA) for the withdrawal chamber 2 days later. The subsequent finding that administration of nor-BNI 2h following withdrawal did not affect the CPA 2 days later suggested that nor-BNI reduced the CPA in the prior experiment because it reduced the aversive effects of withdrawal, not because it reduced the aversive/anxiogenic effects of the withdrawal chamber at the time of CPA testing. These data indicate that the binding of dynorphin-like peptides to KORs during opioid withdrawal serves to enhance withdrawal and its aversive consequences and suggest that selective KOR antagonists may be useful in reducing these aversive effects and consequent relapse.

Glutamate receptor antagonists can improve the symptoms of Parkinson’s disease (PD) and reduce l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in both animal models and humans, but usually produce intolerable side effects. Recent evidence suggests that upregulation of the major glutamate transporter, GLT-1, by the β-lactam antibiotic, ceftriaxone, can increase the removal of synaptic glutamate without producing noticeable side effects, and may provide an effective alternative to receptor antagonists for several neurodegenerative diseases.

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

We previously demonstrated that lesions of the nucleus accumbens (NAc) core enhanced locomotion and locomotor sensitization to repeated injections of nicotine in rats (Kelsey & Willmore, 2006). In this study, we compared the effects of separate lesions of the NAc core, NAc medial shell, and basolateral amygdala on context-specific locomotor sensitization to repeated injections of 0.4 mg/kg nicotine. Electrolytic lesions of the NAc core increased locomotion, and lesions of the core (but not the shell) and the basolateral amygdala enhanced context-specific locomotor sensitization by enhancing the development of sensitization in paired rats and decreasing expression in unpaired rats relative to sham-operated rats when challenged with an injection of 0.4 mg/kg nicotine in the locomotor chambers. These data are consistent with findings that the NAc core and the basolateral amygdala share a variety of behavioral functions and anatomical connections. The findings that lesions of these structures enhance context-specific locomotor sensitization while typically impairing other reward-related behaviors also indicate that the processes underlying locomotor sensitization and reward are not identical.

Acute injections of 8mg/kg of 3,4-dihydroxy-l-phenylalanine (l-DOPA) or 0.05mg/kg rimonabant equally improved contralateral forepaw stepping in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, and their combination improved stepping more than either drug alone. However, 0.05mg/kg rimonabant did not alter the changes in stepping produced by acute injections of a dyskinesic dose of 35mg/kg l-DOPA. Thus, not only is a cannabinoid antagonist monotherapeutic in this animal model of Parkinson's disease, but it also enhances the therapeutic effect of a moderate, but not a high, dose of l-DOPA.

RATIONALE:Cannabinoid, especially CB(1,) receptors have been implicated in the development and expression of a variety of behaviors produced by addictive drugs.OBJECTIVES:The intent was to determine if coadministration of the selective CB(1) receptor antagonist, rimonabant (SR141716A), would block the development or expression of locomotor sensitization to repeated injections of nicotine.MATERIALS AND METHODS:Male Long-Evans rats were injected with either 2 mg/kg rimonabant or its vehicle 30 min before an injection of 0.4 mg/kg nicotine or saline and immediately placed in activity chambers for 1 h on each of six sessions on alternating days. Before the two subsequent challenge sessions, all rats were injected with the vehicle and 0.4 mg/kg nicotine combination and then with the 2 mg/kg rimonabant and 0.4 mg/kg nicotine combination, respectively.RESULTS:Repeated injections of nicotine produced a progressive increase in locomotion that was blocked by coadministration of rimonabant. However, the subsequent nicotine challenge increased locomotion in both nicotine-pretreated groups equally more than in the saline-pretreated groups. Coadministration of rimonabant along with nicotine on the second challenge decreased the locomotion of the nicotine-pretreated rats to equal that of the saline-pretreated rats. Rimonabant had no effect on the saline-pretreated rats.CONCLUSION:These data suggest that rimonabant blocks the expression but not the development of locomotor sensitization to nicotine.

Given that adenosine A2A antagonists appear to be therapeutic in several animal models of Parkinson’s disease (PD), we examined the extent to which caffeine and selective A2A and A1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat.

Electrolytic lesions of the medial core of the nucleus accumbens (NAc) in male Long-Evans rats increased spontaneous locomotion, enhanced the locomotor stimulating effect of acute 5.0 mg/kg cocaine, enhanced the development and subsequent expression of locomotor sensitization produced by repeated injections of 0.4 mg/kg nicotine but not 7.5 mg/kg cocaine, and enhanced the expression of conditioned locomotion. Given that 6-hydroxydopamine lesions of the NAc typically have effects on locomotor-related processes that are opposite of those produced by electrolytic and excitotoxic lesions, these data are consistent with a hypothesis that the NAc output, especially from the core, inhibits a variety of such processes and that the DA input to the NAc enhances these processes by inhibiting this inhibitory output.

Many neural systems are undergoing marked development over adolescence, which may heighten an animal's vulnerability to stressors. One consequence may be altered sensitivity to drugs of abuse. We previously reported that social stressors in adolescence increased behavioral sensitization to nicotine in adulthood in female, but not male, rats. Here we examined whether social stressors in adolescence alter the functioning of the hypothalamic–pituitary–adrenal (HPA) axis by examining corticosterone release in response to restraint in adulthood. To further assess effects of social stressors on behavioral sensitivity to psychostimulants, we examined locomotor activity in response to nicotine and to amphetamine. In a second set of experiments, we investigated whether the same procedure of social stressors administered in adulthood produces effects similar to that observed when administered in adolescence. Rats underwent daily 1 h isolation followed by pairing with a new cage mate on either postnatal days 33–48 (pubertal stress: PS) or days 65–80 (adult stress: AS). Three weeks later rats tested for either: (a) corticosterone levels were measured in response to restraint, or (b) locomotor sensitization to nicotine (0.25 mg/kg; 5 days) followed by an amphetamine challenge (0.5 mg/kg) 24 h later. Effects of social stressors were evident only in females. PS females had increased locomotor activity to amphetamine compared to controls, and AS females had increased corticosterone release compared to controls. No effect of the social stressors was found in males at either age except for reduced weight gain during the stress procedure. Thus, females are more susceptible to the enduring effects of these moderate social stressors than are males. However, in terms of behavioral sensitivity to drugs of abuse, females may be more susceptible to stressors during adolescence than adulthood, although the reverse appears to be true for HPA function.

To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinson’s disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD.

A wide body of research has indicated that perinatal exposure to stressors alters the organism, notably by programming behavioral and neuroendocrine responses and sensitivity to drugs of abuse in adulthood. Recent evidence suggests that adolescence also may represent a sensitive period of brain development, and yet there has been little research on the long-lasting effects of stressors during this period. We investigated the effects of pubertal social stress (PS; daily 1-h isolation followed by pairing with a new cage mate on postnatal days 33–48) on locomotor sensitization to injections of nicotine and corticosterone response to restraint stress when the rats were adults (approximately 3 weeks after PS). There were no differences among the groups in locomotor activity to injections of saline. However, PS females had enhanced locomotor sensitization to repeated doses of nicotine compared to control (non-stressed; NS) females, whereas PS males and NS males did not differ. PS enhanced the corticosterone response to restraint in male rats previously sensitized to nicotine and decreased the corticosterone response in nonsensitized male rats. In contrast, PS females and NS females did not differ in plasma corticosterone levels in response to restraint stress, but NS females showed enhanced corticosterone release to restraint after sensitization to nicotine. Thus, during adolescence, social stressors can have long-lasting effects, and the effects appear to differ for males and females.

The dopamine D2 agonist bromocriptine has a long lasting, biphasic effect on locomotion, causing decreased activity during the first 60–90 min after the injection, followed by increased activity that peaks 90–180 min after the injection. In Experiment 1, repeated injections of 5.0 mg/kg bromocriptine produced rapid development of locomotor sensitization when rats were placed in activity chambers for 90 min immediately following each injection. Once sensitization had occurred, expression of sensitization was enhanced when the rats were tested for 90 min beginning 90 min after the injection. In contrast, when rats were placed in the activity chambers for 90 min after spending the first 90 min following each injection of bromocriptine in their home cage, the onset of locomotor sensitization was delayed and expression of sensitization was reduced. In Experiment 2, this inhibition of sensitization did not occur when rats spent the first 90 min following each injection of bromocriptine in a cage that was identical to their home cage, but was not their home cage. Thus, spending the first 90 min after the injection of bromocriptine in the home cage somehow inhibits the development of locomotor sensitization during the subsequent 90 min of each session. These data are consistent with other data indicating that repeated injections of drugs in the home cage often fail to produce the locomotor sensitization that is observed when these injections occur in novel cages.

RATIONALE AND OBJECTIVES:We attempted to determine if the effects of the glutamate NMDA receptor blocker dizocilpine (MK-801) on nicotine locomotor sensitization were due to a blockade of the development of sensitization or to state-dependency.METHODS AND RESULTS:In experiment 1, repeated co-administration of a high dose of dizocilpine (0.25 mg/kg) along with 0.4 mg/kg nicotine enhanced locomotion, failed to alter the development of locomotor sensitization to nicotine, but completely blocked the subsequent expression of sensitization to a challenge injection of nicotine alone. However, repeated injections of this dose of dizocilpine alone produced locomotion and sensitization that was equivalent to that produced by the dizocilpine/nicotine combination. In four separate replications in experiments 2 and 3, co-administration of a low dose of dizocilpine (0.075 mg/kg), which did not produce sensitization to itself, blocked both the development of nicotine sensitization and its subsequent expression in response to a challenge injection of nicotine. Moreover, this repeated dizocilpine/nicotine administration did not affect the subsequent development of sensitization to nicotine alone (experiment 3). Suggesting that these effects of dizocilpine may be confined to the development of sensitization, challenge injections of dizocilpine failed to block the capacity to express previously nicotine-sensitized locomotion (experiment 2).CONCLUSIONS:Co-administration of a low dose of dizocilpine can block the development of locomotor sensitization to repeated injections of nicotine without producing state-dependency. Thus, NMDA receptor activation appears to be critical for the development, but not the subsequent expression, of nicotine locomotor sensitization.

Phosphate wie (II), (V) und (VII), Lactone (IX) und Arabinofuranosederivate (X) werden, wie im Formelschema skizziert.

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

s of the First Congress of the Behavioral Pharmacology Society and the European Behavioural Pharmacology Society: PDF Only

Rationale: The mesolimbic dopamine (DA) system appears to play a major role in the locomotor activating and sensitizing effects of several addictive drugs. However, less is known about the neural structures that may modulate this system. Objective: We examined the effects of medial septal lesions on the locomotor activating and sensitizing effects of amphetamine in between-subjects (experiment 1) and within-subjects (experiment 2) experiments. Results: Repeated injections of 0.6 mg/kg (experiment 1) or 1.0 mg/kg (experiment 2) amphetamine over six sessions produced more locomotion in the lesioned rats than in the sham-operated controls. This repeated exposure to amphetamine subsequently increased the locomotor response to 0.2 mg/kg (experiment 2) and 0.4 mg/kg (both experiments) amphetamine in the lesioned rats, such that these sensitized, lesioned rats moved more in response to these doses than unsensitized, lesioned rats and sensitized controls did. Both experiments also indicated that this prior sensitization enhanced the locomotor response to 0.4 mg/kg amphetamine more in the lesioned rats than in the control rats when compared with the response produced by saline following sensitization or by the same dose of amphetamine prior to sensitization. In contrast, prior exposure to amphetamine decreased the locomotor response to 4.0 mg/kg amphetamine in the lesioned rats (experiment 1). Conclusions: Although medial septal lesions occasionally enhance locomotor responses to moderate doses of amphetamine prior to sensitization, a main effect of these lesions is to further enhance the effects of locomotor sensitization to amphetamine. Implications for drug addiction are discussed.

Long-term adrenalectomy (ADX) causes loss of spatial memory and of dentate gyrus cells. These effects are prevented by chronic replacement of corticosterone (CORT). The effects of acute replacement 3 months after ADX in rats classified as ADX or incomplete ADX (INC) on the basis of saline intake, weight, and plasma CORT levels were investigated. ADX rats swam longer and farther to find a platform in a spatial water-maze task (Exp. 1) and were impaired on a nonspatial object-recognition task (Exp. 2) compared with INC and SHAM rats. In both experiments, ADX decreased the size of the dentate gyrus, and replacement with CORT either 5 or 10 days prior to and during testing restored the performance of ADX rats without affecting the size of the dentate. CORT did not affect INC and SHAM rats. Thus, the adverse effects of ADX on memory may not be due to damage in the dentate, and the effects of CORT replacement may operate outside the hippocampus.

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal.

The role of associative factors in the effect of 15 min/day of restraint stress on morphine-induced behavioral sensitization was examined. Male rats were initially given seven systemic (10 µg/kg, IP) or intraventral tegmental area (VTA, 5 mg/side) injections of morphine, and were exposed to restraint, either just prior to drug injection (Paired-Stress) or 24 h after injection (Unpaired-Stress), or to no restraint (Control). In subsequent tests for behavioral sensitization to low doses of morphine (0.75 or 3.0mg/kg, IP), animals in the Paired-Stress condition were more active than animals in the Unpaired-Stress or Control conditions. These results indicate that temporal and possibly associative factors may contribute to stress-induced changes in sensitization to the behavioral activating effects of opioids.