raclopride and Body-Weight

Previous positron emission tomography (PET) studies have provided evidence that the psychological expectation of certain drugs combined to the placebo administration may lead to subjectively experienced placebo effects, which, in turn, are associated with dopamine (DA) release in the brain. Our recent study indicated that blind intravenous (i.v.) glucose induces DA release in male subjects. In the present study, we examined if the mere expectation of glucose (i.v. placebo) could similarly release DA in the basal ganglia. [(11)C]raclopride PET was performed for 12 lean [mean body mass index (BMI) = 22 kg/m(2)] and 12 overweight (mean BMI = 33 kg/m(2)) healthy subjects (12 men and 12 women). Each subject was imaged twice in a counter-balanced setting, after blind i.v. placebo and after open i.v. placebo. DA D2 receptor binding potentials (BP) were estimated. The results of the present study show that i.v. placebo administration with glucose expectation induces bilateral BP reduction in the ventral striatum in the male group, suggesting DA release. The stimulus did not induce dopaminergic placebo effect in the overweight or the lean group (males and females combined). Voxel-based analysis also suggested regionally selective BP increases in the dorsal striatum in the male subjects, whereas women showed no significant changes in BPs. The results support previously reported gender differences in the DA function after a pharmacological challenge (e.g., amphetamine and glucose). Also, they suggest that the DA release in the ventral striatum mediates placebo responses in the context of glucose expectation.

Topics: Adult; Basal Ganglia; Body Weight; Carbon Radioisotopes; Dopamine; Dopamine Antagonists; Feeding Behavior; Female; Glucose; Humans; Injections, Intravenous; Male; Overweight; Perception; Placebos; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Reward; Sex Characteristics

Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed.

Topics: Animals; Anxiety; Benzazepines; Body Weight; Brain; Carbon Isotopes; Central Nervous System Stimulants; Cognition; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Exploratory Behavior; Male; Methamphetamine; Psychomotor Performance; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Recognition, Psychology; Signal Transduction; Spiperone

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.

Topics: Animals; Baclofen; Behavior, Animal; Benzazepines; Benzodiazepines; Body Weight; Bulimia; Disease Models, Animal; Eating; Feeding Behavior; Female; Idazoxan; Lisdexamfetamine Dimesylate; Naltrexone; Olanzapine; Prazosin; Prodrugs; Raclopride; Rats; Rats, Wistar; Rolipram

Spinocerebellar ataxia 17 (SCA17) is an autosomal-dominant, late-onset neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat in the TATA-box-binding protein (TBP). To further investigate this devastating disease, we sought to create a first transgenic rat model for SCA17 that carries a full human cDNA fragment of the TBP gene with 64 CAA/CAG repeats (TBPQ64). In line with previous observations in mouse models for SCA17, TBPQ64 rats show a severe neurological phenotype including ataxia, impairment of postural reflexes, and hyperactivity in early stages followed by reduced activity, loss of body weight, and early death. Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum. Degeneration of Purkinje, basket, and stellate cells, changes in the morphology of the dendrites, nuclear TBP-positive immunoreactivity, and axonal torpedos were readily found by light and electron microscopy. While some of these changes are well recapitulated in existing mouse models for SCA17, we provide evidence that some crucial characteristics of SCA17 are better mirrored in TBPQ64 rats. Thus, this SCA17 model represents a valuable tool to pursue experimentation and therapeutic approaches that may be difficult or impossible to perform with SCA17 transgenic mice. We show for the first time positron emission tomography (PET) and diffusion tensor imaging (DTI) data of a SCA animal model that replicate recent PET studies in human SCA17 patients. Our results also confirm that DTI are potentially useful correlates of neuropathological changes in TBPQ64 rats and raise hope that DTI imaging could provide a biomarker for SCA17 patients.

Topics: Animals; Anxiety; Body Weight; Brain; Diffusion Tensor Imaging; Disease Models, Animal; Electronic Data Processing; Female; Genotype; Humans; Male; Maze Learning; Motor Activity; Neurologic Examination; Positron-Emission Tomography; Psychomotor Performance; Raclopride; Rats; Rats, Transgenic; Rotarod Performance Test; Severity of Illness Index; Spinocerebellar Ataxias; TATA-Box Binding Protein; Trinucleotide Repeat Expansion; Tubulin

Deficits in dopamine D2/D3 receptor (D2R/D3R) binding availability using PET imaging have been reported in obese humans and rodents. Similar deficits have been reported in cocaine-addicts and cocaine-exposed primates. We found that D2R/D3R binding availability negatively correlated with measures of body weight at the time of scan (ventral striatum), at 1 (ventral striatum) and 2 months (dorsal and ventral striatum) post scan in rats. Cocaine preference was negatively correlated with D2R/D3R binding availability 2 months (ventral striatum) post scan. Our findings suggest that inherent deficits in striatal D2R/D3R signaling are related to obesity and drug addiction susceptibility and that ventral and dorsal striatum serve dissociable roles in maintaining weight gain and cocaine preference. Measuring D2R/D3R binding availability provides a way for assessing susceptibility to weight gain and cocaine abuse in rodents and given the translational nature of PET imaging, potentially primates and humans.

Topics: Administration, Oral; Animals; Body Weight; Cocaine; Corpus Striatum; Food Preferences; Male; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Dopamine

The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.

Topics: Amphetamine; Analysis of Variance; Animals; Blood Glucose; Body Weight; Brain; Brain Mapping; Corpus Striatum; Diabetes Mellitus, Experimental; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Drug Administration Schedule; Drug Interactions; Enzyme Inhibitors; Hypoglycemic Agents; Image Processing, Computer-Assisted; Insulin; Magnetic Resonance Imaging; Male; MAP Kinase Signaling System; Oxygen; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

Chronic overeating of obesogenic diets can lead to obesity, reduced dopamine signaling, and increased consumption of added sugars to compensate for blunted reward. However, the specific role of diet composition yet remains unknown. To study this, Sprague-Dawley male rats were fed a high-energy diet with high fat and low carbohydrate content (HFHE), a fat-sugar combination high-energy diet (FCHE), or standard chow for 24 weeks. We found that both high-energy diets produced substantial body weight gain compared to chow-fed controls. To investigate dopamine control of short (2-h) intake of palatable sucrose or fructose solutions, rats were pretreated peripherally (IP) with equimolar doses (0-600 nmol/kg) of the dopamine D1 (SCH23390) and D2 (raclopride) subtype-specific receptor antagonists. The results showed an overall increase in the efficacy of D1 and D2 receptor antagonists on suppression of intake in obese rats compared to lean rats, with effects differing based on diets and test solutions. Specifically, SCH23390 potently reduced both sucrose and fructose intake in all groups; however, lower doses were more effective in HFHE rats. In contrast, raclopride was most effective at reducing fructose intake in the obese FCHE rats. Thus, it appears that obesity due to the consumption of combinations of dietary fat and sugar rather than extra calories from dietary fat alone may result in reduced D2 receptor signaling. Furthermore, such deficits seem to preferentially affect the control of fructose intake. These findings demonstrate for the first time a plausible interaction between diet composition and dopamine control of carbohydrate intake in diet-induced obese rats. It also provides additional evidence that sucrose and fructose intake is regulated differentially by the dopamine system.

Topics: Adiposity; Animals; Body Weight; Dietary Fats; Dopamine; Dopamine Antagonists; Eating; Energy Intake; Fructose; Male; Obesity; Raclopride; Rats; Rats, Sprague-Dawley; Sucrose

Nutritional status can impact dopamine systems in a manner that might be important to understanding possible common neurobiological mechanisms that mediate abnormal compulsive food (e.g., obesity) and drug taking. Limiting food intake, for example, can increase sensitivity to the behavioral effects of indirect-acting dopamine receptor agonists. Much less is known regarding possible diet-induced changes in sensitivity to direct-acting dopamine receptor drugs. The present study investigated the effects of a high fat diet and of food restriction on sensitivity of rats to the behavioral effects of a direct-acting dopamine receptor agonist and a dopamine receptor antagonist. Free access to high fat chow increased sensitivity to quinpirole-induced yawning without changing sensitivity to raclopride-induced catalepsy or quinpirole-induced hypothermia. Food restriction (10 g/day) decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy without affecting sensitivity to quinpirole-induced hypothermia. Free access to a standard chow restored sensitivity to the behavioral effects of both drugs in rats that were previously food-restricted but not in rats that previously ate a high fat diet. These data confirm that food restriction can decrease sensitivity to behavioral effects of direct-acting dopamine receptor drugs, they provide evidence (i.e., no change in hypothermic effects) indicating that these changes are not due to pharmacokinetic mechanisms, and they provide initial evidence showing enhanced sensitivity to behavioral effects of dopamine receptor drugs in rats eating a high fat diet. These changes in sensitivity of dopamine systems could be relevant to understanding the impact of nutrition on therapeutic and recreational drug use.

Topics: Animals; Behavior, Animal; Body Weight; Caloric Restriction; Catalepsy; Diet; Dietary Fats; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Yawning

The high co-morbidity of eating disorders and substance abuse suggests that nutritional status can impact vulnerability to drug abuse. These studies used rats to examine the effects of food restriction on dopamine clearance in striatum and on the behavioral effects of amphetamine (locomotion, conditioned place preference), the dopamine receptor agonist quinpirole (yawning), and the dopamine receptor antagonist raclopride (catalepsy). Amphetamine increased locomotion and produced conditioned place preference. Food restriction reduced dopamine clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction also decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy; normal sensitivity to both drugs was restored by free feeding. The same amphetamine treatment that normalized dopamine clearance, failed to restore normal sensitivity to quinpirole or raclopride, suggesting that in food-restricted rats the activity of dopamine transporters and dopamine receptors is differentially affected by pathways that are stimulated by amphetamine. These studies show that modest changes in nutritional status markedly alter dopamine neurotransmission and the behavioral effects of direct-acting dopamine receptor drugs (agonist and antagonist). These results underscore the potential importance of nutritional status (e.g., glucose and insulin) in modulating dopamine neurotransmission and in so doing they begin to establish a neurochemical link between the high co-morbidity of eating disorders and drug abuse.

Topics: Amphetamine; Animals; Behavior, Animal; Blood Glucose; Body Weight; Brain Chemistry; Caloric Restriction; Catalepsy; Conditioning, Operant; Diabetes Mellitus, Experimental; Dopamine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Male; Motor Activity; Nutritional Status; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Yawning

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.

Topics: Amphetamine; Animals; Behavior, Animal; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dopamine Agonists; Dopamine Antagonists; Insulin; Male; Quinpirole; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine; Streptozocin

Methylphenidate (MP) and amphetamine, which are the mainstay for the treatment of ADHD, have raised concerns because of their reinforcing effects and the fear that their chronic use during childhood or adolescence could induce changes in the brain that could facilitate drug abuse in adulthood.. Here we measured the effects of chronic treatment (8 months) with oral MP (1 or 2 mg/kg), which was initiated in periadolescent rats (postnatal day 30). Following this treatment, rats were tested on cocaine self-administration. In addition at 2 and 8 months of treatment we measured dopamine D2 receptor (D2R) availability in the striatum using [(11)C]raclopride microPET (microPET) imaging.. Animals treated for 8 months with 2 mg/kg of MP showed significantly reduced rates of cocaine self-administration at adulthood than vehicle treated rats. D2R availability in the striatum was significantly lower in rats after 2 months of treatment with MP (1 and 2 mg/kg) but significantly higher after 8 months of MP treatment than in the vehicle treated rats. In vehicle treated rats D2R availability decreased with age whereas it increased in rats treated with MP. Because low D2R levels in the striatum are associated with a propensity for self-administration of drugs both in laboratory animals and in humans, this effect could underlie the lower rates of cocaine self-administration observed in the rats given 8 months of treatment with MP.. Eight month treatment with oral MP beginning in adolescence decreased cocaine-self administration (1 mg/kg) during adulthood which could reflect the increases in D2R availability observed at this life stage since D2R increases are associated with reduced propensity for cocaine self administration. In contrast, two month treatment with MP started also at adolescence decreased D2R availability, which could raise concern that at this life stage short treatments could possibly increase vulnerability to drug abuse during adulthood. These findings indicate that MP effects on D2R expression in the striatum are sensitive not only to length of treatment but also to the developmental stage at which treatment is given. Future studies evaluating the effects of different lengths of treatment on drug self-administration are required to assess optimal duration of treatment regimes to minimize adverse effects on the propensity for drug self administration.

Topics: Animals; Body Weight; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Dopamine Antagonists; Dopamine Uptake Inhibitors; Magnetic Resonance Imaging; Male; Methylphenidate; Neostriatum; Positron-Emission Tomography; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Self Administration

CCK-1-receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats are hyperphagic and exhibit a greater preference for sucrose compared with lean controls [Long-Evans Tokushima Otsuka (LETO)]. To directly assess motivation to work for sucrose reward in this model of obesity and type 2 diabetes, we examined the operant performance of OLETF rats at nondiabetic and prediabetic stages (14 and 24 wk of age, respectively) on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. To evaluate the involvement of dopamine systems, the effects of the D1 receptor antagonist SCH23390 (100 and 200 nmol/kg ip) and the D2 receptor antagonist raclopride (200 and 400 nmol/kg ip), were also tested on PR responding for sucrose. Compared with age-matched LETO rats, 14-wk-old OLETF rats emitted more licks on the "active" empty spout operant on the FR-10 schedule of reinforcement to obtain 0.01 M and 0.3 M sucrose and completed higher ratio requirements on the PR schedule to gain access to 0.3 M and 1.0 M sucrose. At 24 wk, this effect was limited to 1.0 M sucrose. Both antagonists were potent in reducing operant responding to 0.3 M sucrose in both strains at both ages, and there was no strain effect to SCH23390 at either age. OLETF rats, on the other hand, showed an increased sensitivity to the higher dose of raclopride, resulting in reduced responding to sucrose reinforcement at 24 wk. Taken together, these findings provide the first direct evidence for an increased motivation for sucrose reward in the OLETF rats and suggest altered D2 receptor regulation with the progression of obesity and prediabetes.

Topics: Aging; Animals; Benzazepines; Body Weight; Conditioning, Operant; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Food Preferences; Glucose Tolerance Test; Male; Prediabetic State; Psychomotor Performance; Raclopride; Rats; Rats, Inbred OLETF; Receptors, Dopamine D1; Reinforcement Schedule; Sucrose

Genetic selection for chickens of high (HGPS) and low (LGPS) group productivity and survivability, resulted in two distinct genetic lines characterized by differences in cannibalism, flightiness, and immunocompetence. Additionally, birds exhibited differences in behaviour and social stress coping strategy. HGPS birds have a superior stress coping strategy compared with birds of LGPS or Dekalb XL (DXL), a commercial strain. Line differences in stress response and behaviour could be due to selection-induced differences in expression of the dopaminergic system. The dopamine (D2) receptor, an integral part of the dopaminergic system, was hypothesized to be a key contributory factor of the stress response. We tested this hypothesis by injecting either a D2 antagonist (raclopride) or saline in the dominant individual in pair-housed birds for 10 days and examining stress coping ability. Results showed that dominant birds of all strains showed a reduced frequency of aggressive pecks on subordinates following raclopride injection. In contrast, subordinates paired with raclopride-injected birds increased pecking frequency. Two days after stopping injections, LGPS and DXL birds returned to pre-injection levels of aggressive threats, while HGPS birds maintained depressed frequency of threats. Strain differences in aggressive responsiveness coincided with increased epinephrine levels in raclopride treated LGPS birds relative to control LGPS birds, but not by HGPS and DXL birds. Our findings suggest a functional linkage between the genetic basis of stress coping ability and the dopamine regulation of aggressive responsiveness. The data further indicate that the sympathetic-adreno-medullary axis is directly involved in regulating both stress coping strategy and aggressiveness.

Topics: Aggression; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Chickens; Chromatography, High Pressure Liquid; Dominance-Subordination; Dopamine Antagonists; Epinephrine; Immobility Response, Tonic; Raclopride; Selection, Genetic; Stress, Psychological; Time Factors

To investigate efficacy of cystamine induced neuroprotection, we conducted PET imaging studies of cerebral glucose metabolism with [(18)F]FDG (2-deoxy-2-[(18)F]fluoro-d-glucose) and striatal dopamine D2 receptor function with [(11)C]raclopride in R6/2 transgenic Huntington mice. In the control mice, exponentially decreasing glucose utilization was observed in the striatum N(str) [SUV]=(41.75+/-11.80)(58,str)*exp(-(0.041+/-0.007)*t [days]); cortex N(cort) [SUV]=24.14+/-3.66)(58,cort)*exp(-(0.043+/-0.007)*t [days]); and cerebellum N(cer) [SUV]=(34.97+/-10.58)(58,cer)*exp(-(0.037+/-0.008)*t [days]) as a function of age starting at 58 days. Given that the underlying degeneration rate in the cystamine treated mice is similar to that observed in control animals, the protection coefficient (beta) calculated from the equation N(t)=N(58)*exp(-(1-beta)*k*t) was 0.133+/-0.035 for the striatum; 0.122+/-0.028 for the cortex and 0.224+/-00.042 for the cerebellum with a dose of 100 mg/kg. The 50 mg/kg cystamine dose provided significant protection only for the striatum and only minor protection was obtained using lower doses. Striatal binding potential of [(11)C]raclopride was 1.059+/-0.030 in the control mice, and enhanced in the cystamine treated animals in a dose dependent manner up to 1.245+/-0.063 using the 100 mg/kg dose. Histological analysis confirmed cystamine induced neuroprotection of striatal and cortical neurons and Nissl staining revealed that formation of cellular inclusions was reversed in a dose dependent manner. Cerebral imaging and histological evidence support the use of cystamine as a neuroprotective agent for Huntington's disease (HD) pathology.

Topics: Age Factors; Animals; Binding, Competitive; Body Weight; Brain; Brain Chemistry; Brain Mapping; Cerebral Cortex; Cystamine; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Fluorodeoxyglucose F18; Glucose; Huntington Disease; Image Processing, Computer-Assisted; Inclusion Bodies; Male; Mice; Mice, Transgenic; Motor Activity; Neuroprotective Agents; Peptides; Positron-Emission Tomography; Raclopride; Transglutaminases; Tritium

In drug addiction, a sensitization phenomenon has been postulated to play a critical role. The aim of our study was to evaluate whether sensitization occurs to the rewarding properties of methylphenidate, a psychostimulant drug known to possess abuse potential, as assessed with the biased conditioned place preference method in rats. In addition, since the brain dopaminergic system is considered to be important in drug-reward, the involvement of dopamine D1- and D2-receptors both in the rewarding properties of methylphenidate and in sensitization to these properties was assessed. Conditioning with methylphenidate at doses of 1.25 to 20 mg/kg increased preference for the paired environment, whereas a dose of 0.31 mg/kg was ineffective. However, following the 7-day sensitization treatment with methylphenidate (0.62-20 mg/kg), conditioning with a dose of 0.31 mg/kg resulted in an increased preference for the paired environment, i.e., the rewarding properties of methylphenidate appeared to be sensitized. Control experiments indicated that the enhancement of preference was not due to attenuation of sensitization treatment-induced withdrawal nor to tolerance to aversive properties of methylphenidate. When conditioned with methylphenidate, D1-antagonist SCH 23390 but not D2-antagonist raclopride prevented place preference. However, when coadministered with methylphenidate during the sensitization treatment, both SCH 23390 and raclopride prevented the development of sensitization. These data indicate that the rewarding properties of methylphenidate are sensitized by prior exposure to the drug and that both D1- and D2-receptors, the latter of which possibly more specifically, appear to be involved in the development of this sensitization.

Topics: Animals; Anxiety; Benzazepines; Body Weight; Central Nervous System Stimulants; Conditioning, Operant; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Eating; Male; Methylphenidate; Motor Activity; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Reward; Substance Withdrawal Syndrome; Taste

With the stated aim of scanning small regions of interest in mice, several high-resolution positron emission tomographic (PET) systems are presently under development. Some, however, have low sensitivity and require high doses of radioactivity to achieve count statistics adequate to reconstruct small volumes. Using in vivo dissociation constants for three carbon-11 labelled ligands previously measured in rat brain, the present paper utilises simple saturation kinetics to estimate the limits on radioactivity and specific activity, to minimise the degree of receptor occupancy and achieve maximal specific binding of the radioligand. The extent of the problem is exemplified by considering a high-affinity ligand (dissociation constant in vitro approximately 0.1 nM; in vivo approximately 5 nmol/kg i.v. injected dose), where routinely produced levels of specific activity ( approximately 100 MBq/nmol) would limit the activity injected into mice to approximately 0.1 MBq for a 1% receptor occupancy. If, as is feasible, the new generation of high resolution PET systems requires an injected activity >10 MBq, then a >100-fold increase in specific activity would be needed for tracer kinetics to hold. The paper highlights the need to consider realistically achievable goals if high-resolution PET is to be accepted as a viable methodology to acquire pharmacologically and physiologically accurate ligand-receptor binding data in mice.

Topics: Animals; Body Weight; Brain; Carbon Radioisotopes; Cocaine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Ligands; Mice; Piperazines; Pyridines; Raclopride; Radioactivity; Receptors, Dopamine; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Salicylamides; Serotonin Antagonists; Tomography, Emission-Computed

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT1A receptor agonist and 5-HT2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D2/D3 receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D2/D3 receptor-mediated transmission.

Topics: Animals; Antidepressive Agents, Second-Generation; Benzimidazoles; Body Weight; Conditioning, Operant; Dopamine Antagonists; Feeding Behavior; Male; Mice; Motor Activity; Quinpirole; Raclopride; Rats; Rats, Wistar; Salicylamides; Serotonin Agents; Stress, Psychological; Sucrose

Exposure to toluene (40-320 ppm; 4 weeks, 6 h/day, 5 days/week), followed by a postexposure period of 29-40 days, decreased the wet weight of the caudate-putamen and of the subcortical limbic area (maximal effect of 10% attained at 80 ppm toluene) of the male rat. Furthermore, toluene exposure decreased the IC50 values (significant effects attained at 80 ppm), the KH, the KL, and the RH% values of dopamine on [3H]raclopride-binding in the caudate-putamen. Toluene exposure did not significantly affect either the body weights, the wet weights of the whole brain, the serum prolactin levels, the KD or the Bmax values of [3H]raclopride-binding in the caudate-putamen and the subcortical limbic area, or the IC50 values of dopamine at [3H]raclopride-binding sites in the subcortical limbic area. Exposure to xylene or styrene (80 and 40 ppm, respectively; 4 weeks, 6 h/day, 5 days/week), followed by a postexposure period of 26-32 days, had no effect on the parameters described above (prolactin levels were not analyzed). The present study indicates that long-term exposure to low concentrations of toluene (> or = 80 ppm), but not xylene (80 ppm) or styrene (40 ppm), leads to persistent increases in the affinity of dopamine D2 agonist binding in the rat caudate-putamen.

Topics: Aging; Analysis of Variance; Animals; Binding, Competitive; Body Weight; Caudate Nucleus; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Organ Size; Prolactin; Putamen; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Salicylamides; Styrenes; Toluene; Xylenes

To investigate the role of dopaminergic activity at D2 receptors in the mediation of the positive reinforcing effect of sucrose on ingestion in preweanling rats, we tested the effects of the D2 antagonist, raclopride, on the intake of 10% sucrose of rats on postnatal days (PN) 7, 14, and 21. Intake was measured during independent ingestion tests in which pups licked sucrose from the floor of a beaker and during oral catheter tests in which sucrose was continuously infused through an anterior, sublingual, oral catheter. Rats were tested once to eliminate the possibility that repeated test experience would affect the response to raclopride. Pretreatment with raclopride resulted in decreased intake in independent ingestion (II) tests, but not in oral catheter (OC) tests on PN 7, 14, and 21. The inhibition of intake was not due to a generalized motor deficit because raclopride did not affect latency to eat, time-sampled activity scores, or latency to withdraw the hindlimb from a raised position. These results demonstrate that dopaminergic activity at D2 receptors is necessary for the positive reinforcing effect of sucrose that maintains ingestion in the II test but not in the OC test.

Topics: Animals; Body Weight; Depression, Chemical; Dopamine; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Eating; Female; Male; Motor Activity; Pregnancy; Raclopride; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Reward; Salicylamides; Sucrose

Rats were administered haloperidol, clozapine, raclopride, or no drug for either 28 days or 8 months and then withdrawn from drug treatment for 3 weeks. Oral movements were repeatedly recorded, both by a human observer and by a computerized video analysis system which determined mouth openings and closings, or computer-scored movelets (CSMs). Four weeks of neuroleptic administration produced no changes in CSMs in any drug-treated group. Long-term administration induced distinctively different patterns of oral activity in the three drug groups, both in number of CSMs and the form of these movements. The oral movements which developed in the haloperidol-treated rats fit a previously described syndrome of late-onset oral dyskinesias which increased upon drug withdrawal. The clozapine- and raclopride-treated rats did not show the increased oral movements seen in the haloperidol animals, but each exhibited uniquely different CSM characteristics compared to controls. The results from this rodent model imply that haloperidol, but not clozapine or raclopride, produces late-onset oral dyskinesias in rats that fit the pattern expected for tardive dyskinesia.

Topics: Animals; Behavior, Animal; Body Weight; Clozapine; Dibenzazepines; Disease Models, Animal; Drinking; Dyskinesia, Drug-Induced; Female; Fourier Analysis; Haloperidol; Raclopride; Rats; Rats, Inbred Strains; Salicylamides