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Rationale Excessive intake of rewards, such as food and drugs, often has explicit negative consequences, including the development of obesity and addiction, respectively. Thus, choosing not to pursue reward is the result of a cost/benefit decision, proper execution of which requires inhibition of behavior. An extensive body of preclinical and clinical evidence implicates dopamine in certain forms of inhibition of behavior, but it is not fully known how it contributes to behavioral inhibition under threat of explicit punishment. Objectives To assess the involvement of midbrain dopamine neurons and their corticostriatal output regions, the ventral striatum and prefrontal cortex, in control over behavior under threat of explicit (foot shock) punishment in rats. Methods We used a recently developed behavioral inhibition task, which assesses the ability of rats to exert behavioral restraint at the mere sight of food reward, under threat of foot shock punishment. Using in vivo fiber photometry, chemogenetics, c-Fos immunohistochemistry, and behavioral pharmacology, we investigated how dopamine neurons in the ventral tegmental area, as well as its output areas, the ventral striatum and prefrontal cortex, contribute to behavior in this task. Results Using this multidisciplinary approach, we found little evidence for a direct involvement of ascending midbrain dopamine neurons in inhibitory control over behavior under threat of punishment. For example, photometry recordings suggested that VTA DA neurons do not directly govern control over behavior in the task, as no differences were observed in neuronal population activity during successful versus unsuccessful behavioral control. In addition, chemogenetic and pharmacological manipulations of the mesocorticolimbic DA system had little or no effect on the animals’ ability to exert inhibitory control over behavior. Rather, the dopamine system appeared to have a role in the motivational components of reward pursuit. Conclusions Together, our data provide insight into the mesocorticolimbic mechanisms behind motivated behaviors by showing a modulatory role of dopamine in the expression of cost/benefit decisions. In contrast to our expectations, dopamine did not appear to directly mediate the type of behavioral control that is tested in our task.

Introduction Alcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system—a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients. Method In a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking. Results Treatment with OSU did not impair neuropsychological function in any of the cognitive domains investigated (all p > 0.1). In fact, OSU treatment did, compared to placebo, improve future planning ability (F(1,46) = 6.9; p = 0.012; Cohen’s d = 0.54), verbal divergent thinking (F(1,44) = 10.1; p = 0.003; d = 0.96), and response time for emotional recognition (F(1,47) = 6.7; p = 0.013; d = 0.44). Conclusion OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.

Preclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules. Memantine was administered daily for a week, either 1 h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15 days after treatment discontinuation. Treatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation. These results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.

RationaleParkinson’s disease (PD) impairs working memory (WM) - the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes.ObjectivesWe hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults.MethodsWe tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively.ResultsPD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards).ConclusionsThis suggests a non-dopaminergic deficit of maintenance capacity and manipulation accuracy in PD patients, and a potential “overdosing” of intact manipulation mechanisms in healthy older adults by levodopa.

There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively.We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist.Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1-0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects).d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter "improvement" attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol.These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.

RATIONALE: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1(+/−)) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1(+/−) on innate and MA-modulated reward sensitivity are not known. OBJECTIVES: We examined innate reward sensitivity and facilitation by MA in H1(+/−) mice via intracranial self-stimulation (ICSS). METHODS: We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5–4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. RESULTS: H1(+/−) mice displayed reduced normalized maximum response rates in response to MA. H1(+/−) females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. CONCLUSIONS: H1(+/−) mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1(+/−) females (lower normalized M50 values).

Anhedonia, a deficit in reward processing, is an endophenotype of several neuropsychiatric conditions. Despite its prevalence and debilitating effects, treatments for anhedonia are lacking, primarily because its underlying mechanisms are poorly understood. Dopamine (DA) has been implicated in anhedonia through its role in reward-related learning; glucocorticoid systems may also be involved in that anhedonia is often preceded by chronic stress. This study investigated DA and glucocorticoid systems in anhedonia using a rat version of the probabilistic reward task (PRT). Adult male Wistar rats were trained on the PRT and then tested following: (1) activation or inhibition of DA activity induced by amphetamine (AMPH) or pramipexole (PRAMI) injections, (2) chronic mild stress (CMS), or (3) glucocorticoid system activation (dexamethasone (DEX)) or inhibition (mifepristone (MIFE)). AMPH increased and PRAMI decreased response bias, pointing to enhanced and diminished reward responsiveness with DA agonism and antagonism, respectively. CMS reduced response bias but only in a subpopulation of rats. DEX also decreased response bias, suggesting that glucocorticoid processes contribute to anhedonia, although glucocorticoid inhibition (MIFE) had no effect. None of the manipulations altered the ability to detect and respond to reward-paired stimuli. These results confirm a role of DA in anhedonia and elucidate the contribution of the glucocorticoid system to this effect. In addition, chronic stress may interfere with normal DA functioning, leading to impaired reward-related learning in some animals. These findings may direct future treatment of anhedonia by targeting DA and glucocorticoid systems, as well as a possible interaction between the two.

Delay-discounting procedures involving choice between small immediate rewards and large delayed rewards are used to study impulsivity in rodents. Improving existing procedures may provide new insights into the neurobiological mechanisms underlying decision-making processes. To develop a novel delay-discounting procedure that adjusts the delay value within individual sessions based on the rat’s most recent choices. Compared to previously developed procedure, we required a more consistent demonstration of preference, five consecutive choices of the large or small reward, a criterion that is more likely to reflect deliberate choice by the animal, as opposed to two consecutive choices. In addition, delays were changed in steps of 5 s (rather than 1 s), because 5-s increments should be more easily discriminated and may produce a more distinct effect on choice. We characterized the procedure behaviorally by manipulating the duration of the session and the consecutive choice criterion, and we investigated the stability of the behavior upon interruption of training. We also characterized the procedure pharmacologically by investigating the effects of dopaminergic compounds. Our procedures allowed obtaining two complementary measures of delay discounting: (1) the percentage of choices of the delay option and (2) the mean adjusting delay, an index of the delay that animals choose more frequently. We found that our procedure rapidly establishes a baseline of choice behavior that remains stable over time and is highly sensitive to manipulations of the dopaminergic system. This procedure may provide a useful tool for investigating the neurobiology of inter-temporal choice and decision-making.

Modafinil is a wake-promoting drug with FDA approval for the treatment of excessive daytime sleepiness that has been prescribed for ADHD and recently assessed as a potential treatment for psychostimulant dependence. Previous research indicates that modafinil modestly increases locomotor activity and produces similar discriminative stimulus effects to psychostimulants in rodents, although the subjective effects of modafinil are reportedly distinct from those of cocaine or amphetamine in humans with a history of psychostimulant abuse.The current study employed drug discrimination procedures in rats to examine the pharmacological actions contributing to modafinil's discriminative stimulus functions.Eight male Sprague-Dawley rats were trained to discriminate intragastric administration of 256 mg/kg modafinil from vehicle (5% arabic gum) under a FR 20 schedule of food reinforcement. Substitution tests were conducted with various dopaminergic agents (d-amphetamine, cocaine, PNU-91356A, GBR 12909, methylphenidate) and nondopaminergic agents (nicotine, ethanol). Antagonist tests were conducted with the selective D1 antagonist, SCH 39166, and the nonselective D2 antagonist, haloperidol.Rats trained to discriminate modafinil displayed complete stimulus generalization to cocaine, methylphenidate, and GBR 12909 and the discrimination was completely blocked by both SCH 39166 and haloperidol. Evidence for significant partial substitution was obtained with d-amphetamine, PNU-91356A, and nicotine.Results strongly support the role of dopaminergic mechanisms in the discriminative stimulus functions of modafinil, although further evaluation regarding the contribution of other neurotransmitter systems to these effects should be continued. The findings are discussed in light of clinical research efforts with modafinil as a treatment for psychostimulant dependence.

Contemporary theories propose that latent inhibition (LI) is due to a process of interference with the context playing a key role as recovery cue. Physiological studies have demonstrated that LI is a process dependent on striatal dopamine. D2 dopamine receptors have been specifically associated with its expression, while D1 receptor has shown a limited function. However, to evaluate the role of dopamine receptors in LI, it is necessary to analyse their activity during recovery phase, where the mechanisms involved in interference processes are performed. The experiments studied the involvement of the dopaminergic system in the retrieval process of LI. We analysed the effect of the systemic administration of dopaminergic D1 (SCH-23390) and D2 (sulpiride) antagonist during the test phase on LI and on its contextual specificity. Animals were pre-exposed to saccharin solution and conditioned with a LiCl administration in conditioning phase. Dopaminergic antagonist drugs were administered during the test phase. Experiment 2 used the same context in all the phases. Experiment 3 used a new context during conditioning and test phase. The D2 antagonist increased the LI effect and, in turn, diminished the normally suppressant effect of the context shift on LI. The opposite effect was observed under the D1 antagonist administration. This drug disrupted LI and enhanced the effect that the context shift had on this cognitive process. D2 receptor had a relevant role on retrieval processes of pre-exposure learning, while D1 receptor was related with the contextual control of conditioning.

L-dopa, the main therapeutic for Parkinson’s disease (PD), has been shown to increase brain dopamine concentrations that are necessary for proper motor control; however, PD patients experience non-motor symptoms that are not improved or could be exacerbated by L-dopa. The purpose of this study is to determine the effects of L-dopa treatment on cognitive and affective behavioral responses of rats, as well as their corresponding monoamine brain concentrations. Rats were treated with L-dopa (6 mg/kg; twice daily) for 10 consecutive days. Sodium ascorbate (400 mg/kg) was co-administered with L-dopa to investigate the effects of antioxidant co-treatment on behavior and monoamine concentrations. Rats underwent cognitive and affective behavioral testing. Monoamine concentrations of several brain regions were analyzed. L-dopa treatment resulted in significant impairment in the performance in the Barnes maze and improvement in conditioned fear stress paradigms. Specifically, L-dopa caused an increase in latency to find the goal box during Barnes maze testing and increased freezing behavior in context-induced conditioned fear testing. Furthermore, the rats in the conditioned fear stress experiments showed corresponding depletions in serotonin (5-HT) and its metabolite, 5-HIAA, in the dorsal raphe nucleus (DRN) and the mPFC. The behavioral impairments as well as monoamine depletions were blocked by ascorbate co-treatment. Chronic L-dopa may contribute to non-motor symptoms related to spatial memory and fear. These effects may be attributable to a dysregulation of brain 5-HT caused by L-dopa treatment. The results presented here provide further rationale for investigating adjunctive therapeutics to L-dopa for PD, such as antioxidants.

Brain histaminergic system is involved in the regulation of the dopaminergic circuitry. The role of histamine H3 receptor (H3R) in behaviors linked to amphetamine addiction and other behaviors induced by dopaminergic compounds has remained unclear.Our aim was to study whether H3R antagonist JNJ-39220675 inhibits amphetamine-induced stimulation and reward. The effects of JNJ-39220675 on dopamine D2-like receptor (D2R-like) agonist quinpirole-induced behaviors were also investigated in order to clarify whether the possible effects of H3R antagonists are D2R-like dependent.The effects of JNJ-39220675 on amphetamine and quinpirole-induced behavioral responses in mice were studied assessing the locomotor activation after both acute and repeated administrations of amphetamine and quinpirole. The place conditioning paradigm was also used as a measure of reward or aversion.JNJ-39220675 inhibited amphetamine-induced stimulation acutely but not after repeated administrations. Amphetamine (2 mg/kg) induced conditioned place preference that was not affected by either of the tested doses of JNJ-39220675 (1 and 10 mg/kg). Quinpirole (0.5 mg/kg) induced conditioned place aversion to which the pretreatment by JNJ-39220675 (10 mg/kg) had no effect. In repeated administration, JNJ-39220675 did, however, inhibit quinpirole-induced tolerance to hypokinesia.Our results show that although H3R antagonists inhibit ethanol reward, they may not possess the same ability on psychostimulants, such as amphetamine. However, if H3R antagonists will become clinically available, it is of importance that these compounds potentiate neither the rewarding nor aversive effects of other drugs.

RATIONALE People often face decisions that pit self-interested behavior aimed at maximizing personal reward against normative behavior such as acting cooperatively, which benefits others. The threat of social sanctions for defying the fairness norm prevents people from behaving overly selfish. Thus, normative behavior is influenced by both seeking rewards and avoiding punishment. However, the neurochemical processes mediating the impact of these influences remain unknown. Several lines of evidence link the dopaminergic system to reward and punishment processing, respectively, but this evidence stems from studies in non-social contexts. OBJECTIVES The present study investigates dopaminergic drug effects on individuals' reward seeking and punishment avoidance in social interaction. METHODS Two-hundred one healthy male participants were randomly assigned to receive 300 mg of L-3,4-dihydroxyphenylalanine (L-DOPA) or a placebo before playing an economic bargaining game. This game involved two conditions, one in which unfair behavior could be punished and one in which unfair behavior could not be punished. RESULTS In the absence of punishment threats, L-DOPA administration led to more selfish behavior, likely mediated through an increase in reward seeking. In contrast, L-DOPA administration had no significant effect on behavior when faced with punishment threats. CONCLUSIONS The results of this study broaden the role of the dopaminergic system in reward seeking to human social interactions. We could show that even a single dose of a dopaminergic drug may bring selfish behavior to the fore, which in turn may shed new light on potential causal relationships between the dopaminergic system and norm abiding behaviors in certain clinical subpopulations.

Methamphetamine (METH) induces hyperthermia in warm and hypothermia in cool environments. Our first goal was to further study the role of ambient temperature in METH’s effect on core temperature in rats. Previously, these effects were primarily demonstrated in high doses; we extended this investigation to the low-dose range (1 mg/kg METH). Our second goal was to identify the role of the D2 receptor in METH’s effects in cool ambient temperatures. Rats received METH (saline, 1, 5, and 10 mg/kg), raclopride (saline, 0.3, 0.6, and 1.2 mg/kg), or a combination (all doses of raclopride combined with 10 mg/kg METH). Treatments occurred in ambient temperatures of 18, 24, or 30 °C. Consistent with prior research, 5 and 10 mg/kg METH caused hyperthermia or hypothermia in a dose- and ambient temperature-dependent manner (60 min after METH). In contrast, 1 mg/kg produced similar levels of hyperthermia at all ambient temperatures. These findings suggest that a threshold METH dose exists; below this dose, METH still changes core temperature, but CNS control over temperature regulation is left intact. In our experiments regarding D2 blockade, raclopride decreased METH-induced core temperature at 30 and 24 °C (60 min after METH), consistent with previous findings. We extended these findings by demonstrating that in a cool ambient temperature (18 °C), raclopride pretreatment also lowered the core temperature response to METH. Although the D2 receptor is known to mediate hypothermia, the combination of METH and D2 blockade suggests a complex mediation of the core temperature response, perhaps involving neurotransmitter interactions.

Most neuroactive drugs affect brain metabolism as well as systemic and cerebral blood flow, thus altering brain temperature. Although this aspect of drug action usually remains in the shadows, drug-induced alterations in brain temperature reflect their metabolic neural effects and affect neural activity and neural functions.Here, I review brain temperature changes induced by neuroactive drugs, which are used therapeutically (general anesthetics), as a research tool (dopamine agonists and antagonists), and self-administered to induce desired psychic effects (cocaine, methamphetamine, ecstasy). I consider the mechanisms underlying these temperature fluctuations and their influence on neural, physiological, and behavioral effects of these drugs.By interacting with neural mechanisms regulating metabolic activity and heat exchange between the brain and the rest of the body, neuroactive drugs either increase or decrease brain temperatures both within (35-39 °C) and exceeding the range of physiological fluctuations. These temperature effects differ drastically depending upon the environmental conditions and activity state during drug administration. This state-dependence is especially important for drugs of abuse that are usually taken by humans during psycho-physiological activation and in environments that prevent proper heat dissipation from the brain. Under these conditions, amphetamine-like stimulants induce pathological brain hyperthermia (40 °C) associated with leakage of the blood-brain barrier and structural abnormalities of brain cells.The knowledge on brain temperature fluctuations induced by neuroactive drugs provides new information to understand how they influence metabolic neural activity, why their effects depend upon the behavioral context of administration, and the mechanisms underlying adverse drug effects including neurotoxicity.

Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson’s disease (PD). These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on a cognitive function is determined by the baseline dopamine levels in brain regions mediating that function. We directly tested this prevalent hypothesis, evaluating the effects of levodopa on stimulus-reward learning in healthy young adults, who presumably have optimal baseline dopamine levels and dopamine regulation. Twenty-six healthy, young adults completed a probabilistic reversal learning task in a randomized, double-blind, placebo-controlled, crossover design. Participants completed one session on levodopa 100 mg/carbidopa 25 mg and another session on placebo. We found that levodopa impaired reversal learning relative to placebo. Further analyses revealed that levodopa impaired learning from both punishment and reward. Exogenous dopamine impairs stimulus-reward learning, independent of PD pathology and prior to sensitization through repeated exposure, in healthy adults with normal cognition and baseline dopamine function. Our findings support the dopamine overdose hypothesis and caution clinicians about detrimental effects of levodopa in all clinical populations (e.g., early PD, restless leg syndrome) regardless of baseline cognitive and dopaminergic system function.

Depression is a frequent non-motor symptom in Parkinson's disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity.To further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD).Twenty PD patients (n = 10 ndPD; n = 10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [(99m)Tc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off18).Mean BDI scores were higher in dPD (25.0 +/- 5.6) than in ndPD patients (8.0 +/- 1.9, p0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87 +/- 0.19 vs. ndDP 0.69 +/- 0.18, p = 0.02) and right putamen (dPD 0.37 +/- 0.07 vs. ndPD 0.28 +/- 0.13, p = 0.03) than in ndPD patients.Our results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression.

Amphetamine-induced sensitization is thought to involve dopamine D(1) receptors. Using mice lacking dopamine D(1) receptors (D (1) (-/-) ), we found that they exhibited blunted sensitization to low doses of amphetamine, while others using different treatment and testing regimens reported inconsistent results. We investigated whether experimental variables, alteration in gene expression or cholinergic input played a role in amphetamine-induced responses.D (1) (-/-) and wild-type (D (1) (+/+) ) mice pretreated with amphetamine (1 mg/kg, 3-7 days) or various doses of nicotine (chronically but intermittently) were challenged with amphetamine (0.7 and/or 1 mg/kg) after short and long abstinence periods. Expression of brain-derived neurotrophic factor (BDNF) and phosphorylated c-AMP response element binding protein (p-CREB) genes were measured under basal conditions and after acute or repeated amphetamine treatments.D (1) (-/-) mice failed to exhibit amphetamine-induced sensitization following short-term treatments and long abstinence periods, but expressed sensitization following prolonged amphetamine treatment or a shorter abstinence period. Basal expression of p-CREB (but not BDNF) was higher in D (1) (-/-) than D (1) (+/+) mice and was reduced after amphetamine treatment. Prolonged nicotine pretreatment augmented locomotor responses to amphetamine in both genotypes and restored sensitization in D (1) (-/-) mice.D(1) receptors were necessary for induction, but may not be necessary for expression of amphetamine-induced sensitization at low doses. The manifestation of amphetamine sensitization depended on the duration of treatment and length of the withdrawal period. Cholinergic-nicotinic stimulation restored amphetamine-induced sensitization in D (1) (-/-) mice. Enhanced basal expression of p-CREB in D (1) (-/-) mice may represent an adaptive mechanism related to lack of D(1) receptors.

Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model.Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic alpha-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects.Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the alpha-1 antagonist prazosin.BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia.

Levodopa-induced dyskinesia (LID) is an inevitable complication of the long-term treatment of Parkinson’s disease (PD) with levodopa. In a rat model of LID, we observed that animals of almost identical genetic but slightly different environmental backgrounds displayed a very different profile in terms of their development and severity of LID. We hypothesised that this heterogeneity can be attributed to different levels of anxiety in individual animals. We evaluated the basal anxiety level of rats in this study using the elevated plus maze (EPM), open field (OF) test, and plasma corticosterone level. These animals then received unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway after which they were primed to develop LID. Finally, we manipulated the anxiety level of these animals by citalopram treatment over a 9-week period before they were killed. Although we could not establish an association between the anxiety level of rats with either the onset or severity of LID, our results showed that citalopram was able to mediate a partial alleviation in LID after chronic treatment, and the extent of recovery was negatively correlated to the anxiety measures of individual animals. Furthermore, this citalopram-mediated LID recovery appeared to be independent of any changes in striatal cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and cyclin-dependent kinase 5 (Cdk5) system, in contrast to our previous studies with fetal ventral mesencephalon transplants. However, chronic citalopram treatment almost completely abolished the expression of serotonin receptor 1B (5HT1B) in the striatum in animals exhibiting LID recovery. These results indicate a novel association of serotonin receptors in the development of LID and contributes to the evidence that the serotonergic system may play an important role in such movements.

Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.

Drugs that modulate the effective level of dopamine (DA) in cortico-striatal circuits have been shown to alter the perception of time in the seconds-to-minutes range. How this relationship changes as a function of repeated experience with the reinforcement contingencies and the gradual adaptation of the underlying neural circuits remains unclear.The present study examined the clock-speed enhancing effects of methamphetamine (MAP 0.5 or 1.0 mg/kg, ip) in groups of rats that received different levels of baseline training (20, 60, or 120 sessions) on a 50-s peak-interval (PI) procedure before initial drug administration.A curvilinear relationship was observed such that rats that received either minimal or intermediate levels of training (or=60 sessions) displayed dose- x training-related horizontal leftward shifts in their timing functions, suggesting that the speed of the internal clock was increased. In contrast, rats that had received an extended level of training (or=120 sessions) did not show this "classic" DA agonist curve-shift effect, but instead displayed a dose-dependent disruption of temporal control after MAP administration. A transition from DA-sensitive to DA-insensitive mechanisms is proposed to account for the loss of control of clock speed, as timing behaviors associated with the PI procedure gradually become learned habits through the strengthening of DA-glutamate connections.

Stress is a common experience in drug abusers. Methamphetamine (METH) is an abused psychostimulant that damages dopamine and serotonin terminals through pro-oxidant mechanisms and glutamate-mediated excitotoxicity. Both METH and stress increase dopamine and glutamate release in the striatum. Since dopamine inhibits striatal glutamate release and METH depletes dopamine, stress-induced glutamate release may be disinhibited after METH exposure. We examined if repeated stress would worsen excitotoxic damage to the striatum after METH pretreatment. In vivo microdialysis was used to examine stress-induced striatal glutamate release in rats pre-exposed to METH (7.5 mg/kg × 4 injections) or saline. The effects on striatal DA, serotonin, DAT, SERT, and spectrin proteolysis produced by chronic restraint stress (CRS, 6 h/day for 21 days) in the presence or absence of corticosterone synthesis inhibition by metyrapone (50 mg/kg) beginning 7 days after METH were also examined. Stress-induced glutamate release was augmented in rats pre-exposed to METH. CRS 7 days after METH enhanced METH-induced DAT depletions from 23 to 44% in the nonstressed versus stressed rats, respectively. Striatal SERT and serotonin tissue content were decreased by 51 and 36%, respectively, in rats exposed to both METH and CRS but was unchanged by either treatment alone. Spectrin proteolysis was increased by 53% in rats treated with both METH and CRS but was unaffected by either treatment alone. Metyrapone blocked the effects of CRS on METH-induced depletions of SERT but not DAT. Exposure to chronic stress depleted striatal dopamine and serotonin terminal markers possibly through excitotoxic mechanisms in METH-treated rats.

Rationale Touchscreens are widely used to examine rodent cognition. Current paradigms require animals to view stimuli and nose poke at an appropriate touchscreen location. After responding, there is little screen interaction and, as infra-red touchscreens eliminate the need for physical contact, minimal somatosensory feedback. It is therefore unclear if touchscreens can support the vigorous, repetitive responding required in paradigms like progressive ratio (PR) for assessing motivation and effort-related choice (ERC) for assessing decision-making. Objectives This study aims to adapt and validate PR and ERC for the rodent touchscreen. Methods Male C57Bl/6 mice were trained until responding on PR stabilised. Amphetamine, sulpiride and raclopride were administered via the intraperitoneal route to modify performance. Mice were transferred to ERC and paradigm parameters adjusted to demonstrate behavioural modification. ERC reward preference was assessed by home cage choice analysis. Results PR performance stabilised within seven sessions. Amphetamine (1 mg/kg) increased and raclopride (0.3 mg/kg) decreased performance by 63 and 28 %, respectively, with a 20-min injection-test interval. Sulpiride (50 mg/kg) decreased performance by 19 % following a 40-min injection-test interval. Increasing ERC operant requirements shifted responding from the operant response-dependent preferred reward towards the freely available alternative. Conclusions Vigorous, repetitive responding is sustainable in touchscreen PR and ERC and task validation mirrors non-touchscreen versions. Thus, motivation and reward-related decision-making can be measured directly with touchscreens and can be evaluated prior to cognitive testing in the same apparatus to avoid confounding by motivational factors.

Instrumental responding was evaluated to determine whether mice lacking dopamine [dopamine-deficient mice (DD mice)] could learn to preferentially press a visually cued, active lever for food reward over an inactive lever.When DD mice were treated with 3,4-L: -dihydroxyphenalanine (L-dopa) to restore dopamine signaling systemically, they were able to learn to press the active lever as well as control mice, whereas mice lacking dopamine would not perform the task. Importantly, DD mice treated with caffeine (to stimulate locomotor and feeding behaviors) also failed to show preference for the active lever and were slower to retrieve rewards after making a reinforced operant response. Selective restoration of dopamine signaling to the nigrostriatal pathway of DD mice via viral-mediated gene transfer completely restored learning and performance of this simple instrumental task. Furthermore, the virally treated DD mice were willing to lever press as much as control mice for reward in progressive-ratio and high fixed-ratio schedules of reinforcement.These results suggest that the deficit in goal-directed behavior observed in mice without dopamine signaling is the result of decreased motivation to obtain reward, and that dopamine signaling in the dorsal striatum is sufficient to restore normal goal-directed behavior on a variety of operant responding tasks.

Rationale: Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D1 and D2 receptors and the nucleus accumbens (Acb) in this respect. Objective: The present experiments were designed to study the role of dopamine D1 and D2 receptors in the Acb in inhibitory response control. Methods: Rats were trained in a five-choice serial reaction time task and received bilateral infusions into the Acb core or shell of either SCH 23390 or eticlopride (representing selective dopamine D 1 and D2 receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined. Results: Eticlopride into either the Acb core or shell did not affect premature responding, a measure for inhibitory response control, but increased reaction time and errors of omission. In contrast, SCH 23390 into both regions reduced premature responding, slightly improved attentional performance in the core and increased errors of omission in the shell. Amphetamine robustly increased premature responding which was dose-dependently blocked by eticlopride in the Acb core and attenuated by eticlopride in the shell. In addition, amphetamine slightly decreased accuracy and reaction time, and these effects were inhibited by eticlopride in both regions. SCH 23390 infusion into the Acb core or shell did not alter amphetamine's effects. Conclusion: Our data provide evidence for the involvement of dopamine D1 and D2 receptors in the Acb core and shell in inhibitory response control and attentional performance.

The 5-HT(2C) receptor modulates mesolimbic dopamine (DA) function and the expression of DA-dependent behaviors, including stimulant-induced hyperactivity. The 5-HT(2C) receptor may also be involved in drug-induced locomotion that is 5-HT-dependent.This study investigated the effects of the 5-HT(2C) receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB242084) on hyperlocomotion induced by psychomotor stimulants with selective, or mixed, actions on serotonergic and/or dopaminergic systems.Male Sprague-Dawley rats were treated in the presence or absence of SB242084 with releasers/reuptake inhibitors of DA (amphetamine and methylphenidate), 5-HT (fenfluramine and citalopram), or both 5-HT and DA (MDMA and cocaine). In addition, the effects of SB242084 combined with nicotine, morphine, or the 5-HT(1A/1B) receptor agonist RU24969 were examined. Locomotor activity was recorded for 2 h.SB242084 potentiated hyperactivity induced by MDMA (2.5-5 mg/kg), amphetamine (0.5 mg/kg), fenfluramine (5 mg/kg), cocaine (10 mg/kg), and methylphenidate (5 mg/kg). SB242084 modestly potentiated nicotine-induced (0.2-0.4 mg/kg) and morphine-induced (2.5 mg/kg) hyperactivity. SB242084 failed to influence hyperactivity induced by RU24969 (0.5-1 mg/kg) or citalopram (10-20mg/kg).SB242084 potentiated the locomotor stimulant effects of both indirect DA and 5-HT agonists. This potentiation may reflect two distinct mechanisms. The first involves direct enhancement of DA activity as shown by potentiation of the effects of amphetamine and methylphenidate. The second mechanism reflects an unmasking of stimulatory 5-HT receptors activated by 5-HT releasers (possibly 5-HT(1B/2A)) through blockade of inhibitory 5-HT(2C) receptors. The failure of SB242084 to potentiate the effect of citalopram might reflect differences between changes in synaptic levels of 5-HT produced by release compared to reuptake inhibition.

Startle inhibition by lead stimuli (prepulse inhibition, "PPI"), and the disruption of this process by dopamine agonists and N-methyl-D: -aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by the norepinephrine alpha-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions between dopamine and norepinephrine substrates, was tested in a series of experiments with the alpha-2 agonist, clonidine, which is used clinically to treat Tourette Syndrome (TS).PPI was measured in male Sprague-Dawley rats after pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist apomorphine, or the NMDA antagonist, phencyclidine.PPI was disrupted by cirazoline; this effect was prevented by clonidine but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals.PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine's failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.

3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) are illicit drugs that are increasingly used in combination. The acute and long-term effects of MDMA/METH combinations are largely uncharacterised.The current study investigated the behavioural, thermal and neurotoxic effects of MDMA and METH when given alone or in combined low doses.Male rats received four injections, one every 2 h, of vehicle, MDMA (2.5 or 5 mg/kg per injection), METH (2.5 or 5 mg/kg per injection) or combined MDMA/METH (1.25+1.25 mg/kg per injection or 2+2 mg/kg per injection). Drugs were given at an ambient temperature of 28 degrees C to simulate hot nightclub conditions. Body temperature, locomotor activity and head-weaving were assessed during acute drug administration while social interaction, anxiety-related behavior on the emergence test and neurochemical parameters were assessed 4-7 weeks later.All treatments acutely increased locomotor activity, while pronounced head-weaving was seen with both MDMA/METH treatments and the higher dose METH treatment. Acute hyperthermia was greatest with the higher dose MDMA/METH treatment and was also seen with MDMA but not METH treatment. Several weeks after drug administration, both MDMA/METH groups, both METH groups and the higher dose MDMA group showed decreased social interaction relative to controls, while both MDMA/METH groups and the lower dose MDMA group showed increased anxiety-like behaviour on the emergence test. MDMA treatment caused 5-HT and 5-HIAA depletion in several brain regions, while METH treatment reduced dopamine in the prefrontal cortex. Combined MDMA/METH treatment caused 5-HT and 5-HIAA depletion in several brain regions and a unique depletion of dopamine and DOPAC in the striatum.These results suggest that MDMA and METH in combination may have greater adverse acute effects (head-weaving, body temperature) and long-term effects (decreased social interaction, increased emergence anxiety, dopamine depletion) than equivalent doses of either drug alone.

Previous work has shown that stimulation of GABAergic, opioid, or dopaminergic systems within the nucleus accumbens modulates food intake and food-seeking behavior. However, it is not known whether such stimulation mimics a motivational state of food deprivation that commonly enables animals to learn a new operant response to obtain food.In order to address this question, acquisition of lever pressing for food in hungry animals was compared with acquisition in non-food-deprived rats subjected to various nucleus accumbens drug treatments.All animals were given the opportunity to learn an instrumental response (a lever press) to obtain a food pellet. Prior to training, ad lib-fed rats were infused with the gamma-aminobutyric acid (GABA)A agonist muscimol (100 ng/0.5 microl per side) or the mu-opioid receptor agonist D-Ala2, N-me-Phe4, Gly-ol5-enkephalin (DAMGO, 0.25 microg/0.5 microl per side), or saline into the nucleus accumbens shell (AcbSh). The indirect dopamine agonist amphetamine (10 microg/0.5 microl per side) was infused into the AcbSh or nucleus accumbens core (AcbC) of ad lib-fed rats. An additional group was food deprived and infused with saline in the AcbSh. Chow and sugar pellet intake responses after drug treatments were also evaluated in free-feeding tests.Muscimol, DAMGO, or amphetamine did not facilitate acquisition of lever pressing for food, despite clearly increasing food intake in free-feeding tests. In contrast, food-deprived animals rapidly learned the task.These findings suggest that pharmacological stimulation of any of these neurochemical systems in isolation is insufficient to enable acquisition of a food-reinforced operant task. Thus, these selective processes, while likely involved in control of food intake and food-seeking behavior, appear unable to recapitulate the conditions necessary to mimic the state of negative energy balance.

Rationale. The illicit use of cocaine is a persistent health problem worldwide. Currently, there are no broadly effective pharmacotherapies to treat cocaine addiction. A prerequisite for development of useful anti-cocaine medications is an understanding of the pharmacological basis of cocaine's effects. The functional analysis of behavior in laboratory animals has allowed for the development of strategies identifying candidate medications to treat cocaine addiction. Objectives. This review summarizes the current status of dopaminergic compounds as cocaine pharmacotherapies in animal models of cocaine addiction. Results. Maintenance medications should share key subjective effects with cocaine, yet have limited abuse liability and side effects. However, maintenance medications often have reinforcing effects that could contribute to abuse potential and side effects that could deter patient compliance. Combined with cocaine, these drugs enhance cocaine's effects. Cocaine antagonists should block the effects of cocaine and have no cocaine-like effects or side effects on their own. However, the cocaine-modulating effects of candidate cocaine antagonists are often surmountable, and, on their own, these drugs produce severe motoric side effects. In contrast, dopamine (DA) partial agonists should exhibit reduced abuse potential relative to agonists, as well as less severe motoric effects relative to antagonists. Combined with cocaine, these drugs should antagonize cocaine's effects. Conclusions. DA partial agonists, in particular the D3-selective and the D1-like partial agonists, offer a more encouraging profile for novel anti-cocaine medications. Neither class of drug is self-administered, and side effects are often less severe and only observed at doses above those that antagonize the effects of cocaine.

Dopamine is involved in a variety of motor and non-motor information-processing operations. One way to determine its contribution to human information processing is to study reaction time (RT) performance after oral absorption of its precursor, levodopa, which increases its concentration in the nervous system.The purpose of the present study was to investigate the effect of a single dose of levodopa on information processing in healthy human subjects using the additive-factor method. After oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design), eight adults (aged 21-28 years, mean 25 years) performed a two-choice visual RT task. Signal intensity, stimulus-response mapping and foreperiod duration were manipulated.The effects of these three variables were found additive on RT, indicating that that three independent stages - namely, stimulus preprocessing, response selection and motor adjustment - were manipulated. Levodopa improved RT performance in a specific way: it interacted with signal intensity but its effect was additive with those of stimulus-response mapping and foreperiod duration.These results show that levodopa specifically affects the stimulus preprocessing stage, which suggests that the dopaminergic system plays a role in sensory processing, possibly by acting on the level of arousal.

Rationale: The role played by D1-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D1-like receptor antagonist, SCH 23390, and the D1A receptor knockout mouse (i.e. D1A-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D1-like receptors for amphetamine-induced behavioral sensitization. Objective: The purpose of the present study was to determine: (a) whether D1A-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D1A and D1B receptor subtypes, blocks development of amphetamine sensitization in wild-type and D1A-deficient mice. Methods: In the first experiment, adult wild-type and D1A-deficient mice were injected with amphetamine (0, 1, 2, 4, or 8 mg/kg, IP) for 7 consecutive days. In the second experiment, wild-type and D1A-deficient mice were pretreated with SCH 23390 (0, 0.15, or 0.5 mg/kg, IP) 30 min prior to being injected with amphetamine (0 or 8 mg/kg, IP). After each daily amphetamine injection, mice were placed in activity chambers where distance traveled (i.e. horizontal locomotor activity) was measured for 60 min. On the test days, which occurred after 3 or 17 drug abstinence days, mice were injected with 1 mg/kg amphetamine and locomotion was measured for 120 min. Results: Both wild-type and D1A-deficient mice exhibited amphetamine-induced locomotor sensitization. Pretreatment with 0.5 mg/kg SCH 23390 blocked the development of locomotor sensitization in wild-type mice, but did not alter the sensitized responding of D1A-deficient mice. Conclusions: It appears that D1-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D1A nor D1B receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D1A-deficient mice. A possible explanation for these conflicting results is that D1A-deficient mice may have a compensatory mechanism (not involving D1B receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D1A receptor.

Rationale:L-Dopa induces dyskinesias during the treatment of Parkinson's disease and also in primates with nigrostriatal lesions produced by MPTP, but it is claimed that L-dopa does not provoke dyskinesia in humans or monkeys with an intact or mildly damaged nigrostriatal system. Objectives: This study assessed the behavioural and pharmacokinetic effects of chronic oral administration of L-dopa plus carbidopa alone, or with co-administration of the peripheral COMT inhibitor entacapone, to normal macaque monkeys. Repeated high dose L-dopa administration was shown to induce marked dyskinesias in monkeys with an intact nigrostriatal system, and the threshold for dyskinesia expression was increased by peripheral catechol-O-methyltransferase inhibition with entacapone. Methods: Six groups of normal macaque monkeys (n=8 per group; Macaca fascicularis) were treated with L-dopa (20, 40 or 80 mg/kg) plus carbidopa (5, 10 or 20 mg/kg) with or without the catechol-O-methyltransferase inhibitor entacapone (20, 40 or 80 mg/kg), or with entacapone alone (80 mg/kg), by oral administration once daily for 13 weeks. Results: Eleven of 16 animals receiving high dose L-dopa (80 mg/kg plus carbidopa 20 mg/kg PO with or without entacapone 80 mg/kg PO for 13 weeks) gradually developed reproducible and idiosyncratic combinations of chorea, athetosis and dystonia maximal at 60–100 min after L-dopa administration, which progressively intensified over the course of the study. The dyskinesias observed were similar in type and distribution to L-dopa-induced dyskinesia observed in patients with Parkinson's disease and in MPTP-treated primates. The occurrence of dyskinesia correlated with plasma concentrations of L-dopa, with animals displaying the most severe dyskinesias having significantly higher plasma concentrations of L-dopa one hour after dosing than animals with mild or moderate dyskinesia or no dyskinesia. Co-administration of entacapone with L-dopa plus carbidopa significantly lowered peak plasma concentrations of L-dopa and this was reflected by a decrease in the severity of dyskinesias, with only one animal receiving entacapone and high dose L-dopa plus carbidopa showing severe dyskinesia, while four receiving high dose L-dopa plus carbidopa alone did so. Conclusions: These results show for the first time that chronic oral L-dopa administration can provoke dyskinesias in primates independently of nigrostriatal damage, and that this effect is dose related.

Rationale: The long-term neurochemical effects produced by the repeated administration of methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) are well documented; however, the functional consequences have not been clearly defined. Objective: The present study was designed to investigate whether rats treated with a monoamine-depleting regimen of MA or MDMA exhibit disturbances in locomotor activity during the diurnal and nocturnal cycles. Methods: Rats were treated with the vehicle or a monoamine-depleting regimen of MA or MDMA (10 mg/kg, IP, every 2 h for four injections on a single day). One week after drug treatment, the rats were placed in residential activity chambers and their locomotor activity was monitored for the next 7-day/night cycles. Results: MA-treated rats exhibited depletions of striatal dopamine and serotonin content of approximately 70%, whereas MDMA-treated rats showed depletions of striatal serotonin content of approximately 50%. Rats treated with MA demonstrated a significant reduction in diurnal, but not nocturnal, locomotor activity, whereas MDMA-treated rats exhibited significant reductions in both diurnal and nocturnal locomotor activity. Analysis of the difference in activity between the nocturnal and diurnal cycles revealed that MA-treated animals exhibited a significantly greater change in activity as compared to that observed in vehicle- and MDMA-treated rats. Conclusions: Although it is unknown whether the adaptations in locomotor activity observed in MA- and MDMA-treated rats are due to the loss of dopamine and/or serotonin, these data suggest that the administration of a monoamine-depleting regimen of MA or MDMA results in alterations in light-cycle-dependent locomotor activity.

Rationale: The ameliorative effects of levodopa (l-3,4-dihydroxy-phenylalanine) on the motor impairment in Parkinson’s disease patients is well established, but characterization of its effects on the associated cognitive deficits is still incomplete. Objective: The present study determined the effect of different doses of levodopa on performance on a test of working memory in MPTP-treated rhesus monkeys, an animal model of Parkinson’s disease. Methods: Four MPTP-treated monkeys and their age-matched controls with the same experimental history as the MPTP-treated monkeys were tested on a spatial delay response task. Each daily session consisted of five trials at each of seven randomly presented delays (0, 10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five different conditions. In the first condition, control and MPTP-treated animals performed the task without levodopa. In the second condition, both groups were tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in which the doses of levodopa were increased to 250 and 500 mg, respectively, only the MPTP-treated animals were tested. In the final condition, the MPTP-treated animals where retested without levodopa. Results: Significant improvement was observed at all doses tested (range 100–500 mg). Conclusions: Levodopa can ameliorate memory impairments in this parkinsonian model.