Electrolytic lesions of the nucleus accumbens core (but not the medial shell) and the basolateral amygdala enhance context-specific locomotor sensitization to nicotine in rats.

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.

The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat.

RATIONALE AND OBJECTIVES: 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. MATERIALS AND METHODS: Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill. RESULTS: The MFB lesions decreased contralateral stepping by 74-83%, and 8 mg/kg 3,4-dihydroxy-L-phenylalanine (L-DOPA) increased contralateral stepping by 25-26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GPE; 20-40 microg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A(2A) antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A(1) [corrected] antagonist 8-cyclopentyltheophylline (3-7 mg/kg) and A(1) agonist N(6)-cyclopentyladenosine (0.03-0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects. CONCLUSIONS: In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A2A, but not an A1, antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GPE are critical sites of therapeutic action.

Rimonabant blocks the expression but not the development of locomotor sensitization to nicotine in rats.

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.

The kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), decreases morphine withdrawal and the consequent conditioned place aversion in rats.

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.

Low doses of dizocilpine block the development and subsequent expression of locomotor sensitization to nicotine in rats.

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.

NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats.

RATIONALE AND OBJECTIVES: 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. METHODS: Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both front paws was measured separately as the paws were dragged backwards and laterally. The effects of i.p. injections of varying doses of L-dopa, the non-competitive NMDA receptor antagonist dizocilpine [(+)-MK-801], the competitive NMDA receptor antagonist CPP, and combinations of L-dopa and NMDA receptor antagonists were then examined on stepping in three separate groups of rats. RESULTS: The lesioned rats stepped less often with their contralateral paw than with their ipsilateral paw, and the magnitude of this stepping deficit was positively correlated with the amount of DA depletion in the ipsilateral dorsal striatum. L-dopa (1-25 mg/kg) dose dependently enhanced stepping with the contralateral paw, and 0.15-0.3 mg/kg dizocilpine and 1.5-6.25 mg/kg CPP enhanced stepping with the contralateral paw as much as did 8 mg/kg L-dopa. The combinations of L-dopa and each of the NMDA receptor antagonists did not significantly improve stepping more than either drug alone. Moreover, none of the drugs completely eliminated the stepping deficits, and high doses began to impair stepping with the ipsilateral paw by inducing turning. CONCLUSIONS: These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.

Prior experience with bromocriptine in the home cage attenuates locomotor sensitization in rats.

The dopamine D(2) 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.

The effects of the ß-lactam antibiotic, ceftriaxone, on forepaw stepping and L-DOPA-induced dyskinesia in a rodent model of Parkinson's disease.

RATIONALE: 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 ß-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. OBJECTIVES: We examined whether repeated i.p. injections of ceftriaxone would, like glutamate antagonists, reduce the deficits in contralateral forepaw stepping produced by unilateral injections of 6-OHDA into the medial forebrain bundle of rats and reduce LID (as measured by abnormal involuntary movements). METHODS AND RESULTS: In Experiment 1, daily injections of 100 mg/kg ceftriaxone improved contralateral forepaw stepping by 44%, and these therapeutic effects were still apparent 29 days following the cessation of treatment. In Experiment 2, daily injections of 50 mg/kg ceftriaxone were as effective as daily injections of 10 mg/kg L-DOPA in increasing contralateral forepaw stepping by 40%. These therapeutic effects of ceftriaxone were decreased by an injection of 10 mg/kg of the selective GLT-1 antagonist, dihydrokainate (DHK), and were still evident 69 days after the cessation of ceftriaxone injections. Furthermore, ceftriaxone did not produce dyskinesia by itself and reduced the development, but not the expression, of LID. CONCLUSIONS: These data suggest that ceftriaxone, by producing a long-term increase in GLT-1 function and increasing the removal of synaptic glutamate, may offer several advantages over L-DOPA as therapy for PD.

Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task.

RATIONALE: 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. OBJECTIVES: To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward. MATERIALS AND METHODS: Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays. RESULTS: Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine. CONCLUSIONS: The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.

Electrolytic lesions of the nucleus accumbens enhance locomotor sensitization to nicotine in rats.

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.

Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats.

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.

Stress during adolescence enhances locomotor sensitization to nicotine in adulthood in female, but not male, rats.

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.