Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine

Recent data indicate that cocaine locomotor responses may be influenced by dopamine (DA) neurotransmission and adenosine neuromodulation involving the A2A receptor (A2AR). Male Wistar rats were injected with MSX-3 (1-25 mg/kg; an antagonist of A2AR), CGS 21680 (0.05-0.2 mg/kg; an agonist of A2AR), SCH 23390 (0.125-0.25 mg/kg; an antagonist of DA D1/5R), raclopride (0.1-0.8 mg/kg; an antagonist of DA D2/3R), nafadotride (0.2-0.4 mg/kg; an antagonist of DA D3R) or 7-OH-PIPAT (0.01-1 mg/kg; an agonist of DA D3R) to verify the hypothesis that adenosine A2AR and DA receptors and their antagonistic interactions may control locomotor and sensitizing effects of cocaine. In well-habituated animals, MSX-3 (5 mg/kg) increased, while raclopride (0.4-0.8 mg/kg) decreased basal locomotor activation; the other drugs were inactive. The locomotor hyperactivation induced by acute cocaine (10 mg/kg) was enhanced by MSX-3 (5-25 mg/kg) or nafadotride (0.4 mg/kg), while CGS 21680 (0.2 mg/kg), SCH 23390 (0.25 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (0.1 mg/kg) decreased this effect of cocaine. Given during the development of sensitization (in combination with 5-daily cocaine, 10 mg/kg, injections), MSX-3 (5-25 mg/kg) increased, but CGS 21680 (0.2 mg/kg) and raclopride (0.8 mg/kg) reduced the locomotor response to a cocaine challenge dose (10 mg/kg) on day 10. When injected acutely with a cocaine challenge dose (on day 10), CGS 21680 (0.2 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (1 mg/kg) reduced, while MSX-3 (5 mg/kg) or nafadotride (0.4 mg/kg) enhanced the expression of cocaine sensitization. The present results show that adenosine A2ARs and DA D3Rs exert inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, while DA D2Rs had an opposing role in such effects. Pharmacological stimulation of adenosine A2ARs protected against both the development and expression of cocaine sensitization, which may offer a therapeutic potential of A2AR agonists in the treatment of cocaine dependence. The results suggest an antagonistic role of A2ARs in D2R-mediated cocaine actions based at least in part on the existence of A2A/D2 heteromeric receptor complexes.     

The effects of cocaine on multivariate locomotor behavior and defecation

The present study utilized a multifactorial open-field analysis (Digiscan activity) to assess behavioral changes induced by various doses of cocaine known to stimulate locomotion. The measures that were implemented included ambulation, rearing, stereotypic behavior, rotational movements and changes in defecation levels. Thirty-two male Sprague-Dawley rats were habituated to Digiscan-16 Animal Activity Monitors (Omnitech Electronics, Columbus, OH) before being injected with 0.0, 10, 20 or 30 mg/kg cocaine. Rats were kept on a reversed light/dark schedule and tested in the middle of the dark cycle. It was found that cocaine consistently increased activity measures; most prominently affecting the rotational and ambulatory indices. Interestingly, this 'activity print' appeared to be dose-dependent and specific to cocaine. Open-field defecation levels were compared to home-cage levels as an additional behavioral correlate. Defecation decreased under all doses of cocaine as compared to control levels (saline injection). This result is attributed to cocaine's weakly sympathomimetic effect.     

Intra-accumbens pertussis toxin sensitizes rats to the locomotor activating effects of a single cocaine challenge

Drugs of abuse share common neurochemical signaling substrates, many of which are components of the cAMP cascade. Interestingly, a number of these substrates have been linked to drug-influenced behaviors. This study sought to understand the role of one signaling substrate, inhibitory G-proteins, in a drug-induced phenomenon known as behavioral sensitization. Specifically, we used pertussis toxin (PTX) as a tool to investigate the relationship between cocaine-induced alterations in cAMP signaling and behavior. Vehicle (1 micro l/side) or PTX (0.15 or 0.25 micro g/1 micro l/side) was bilaterally infused into the nucleus accumbens of rats. Locomotor activity was assessed on days 7, 14 and 21 post-infusion. Intra-accumbal PTX produced a dose-dependent increase in locomotor activity. On day 21 following behavioral monitoring for 1 h, rats were acutely challenged with cocaine (15 mg/kg, i.p.) and behavioral data were accumulated for an additional 2 h. Intra-accumbal PTX sensitized rats to the locomotor-activating effects of a single cocaine challenge which was dose-dependent. After behavioral testing, brains were removed and processed for in vitro receptor autoradiography using the D(1) receptor ligand [3H] SCH 23390. No changes in D(1) dopamine receptor binding were observed. These findings suggest a role for inhibitory proteins (G(i)/G(o)) within the nucleus acumbens in locomotor activity and also cocaine-induced behavioral sensitization.     

Differential effects of methamphetamine and cocaine on conditioned place preference and locomotor activity in adult and adolescent male rats

Human and animal laboratory studies show that adolescents and adults respond differently to drugs and that drug administration during adolescence leads to different behavioral effects than during adulthood. Although there are a number of studies on the effects of cocaine, little is known about the effects of methamphetamine in adolescent vs adult rats. In the present study, sensitivity to the conditioned reward of multiple doses of methamphetamine or cocaine was evaluated in male adolescent (PND 34) and adult (PND 66) rats using a conditioned place preference (CPP) paradigm. In addition, the locomotor-activating effects of methamphetamine were determined across a 5-day period of administration. After 3 days of training with cocaine, both adolescent and adult male rats developed CPP to cocaine, however, the dose-effect curve for cocaine CPP was shifted to the left in adolescent compared to adult rats. In contrast to the development of CPP to cocaine in both groups after 3 days of conditioning, methamphetamine CPP occurred only in adolescent, and not in adult rats. After 5 days of training, however, both adolescent and adult rats exhibited identical responses to multiple doses of methamphetamine and a significant CPP was observed in both groups. Daily administration of methamphetamine increased locomotor activity in both adolescent and adult rats, with a greater effect seen in the adults. In neither group, was there evidence of a significant sensitization to the locomotor-activating effects of methamphetamine. These data show that adolescents are more sensitive to psychostimulant reward and thus to the conditioned rewarding properties of cocaine or methamphetamine than adults. A better understanding of this difference may lead to age-specific preventions and treatments for psychostimulant abuse.     

Repeated cocaine treatments induce distinct locomotor effects in crayfish

A repeated injection of cocaine regime is known to induce complex locomotion alterations in both vertebrate and invertebrate models of drug addiction. However, the specific effect of cocaine on behaviorally distinct locomotion and non locomotion parameters is not well known. The present experiments determined whether cocaine has distinct effect on multifarious locomotor activity of crayfish (Orconectes rusticus). Following repeated injections of 2.5 μg/g or 10.0 μg/g dose of cocaine for three days, videotaped recordings of locomotion were analyzed to determine whether repeated injections of cocaine produced distinct effect on multifarious locomotor activity of crayfish. Cocaine decreased immobility in day 1 when compared with saline. Thereafter, cocaine increased immobility in days 2 and 3. Repeated injections of cocaine increased distance traveled, average speed, mobility and decreased lingering episodes. These findings indicate that cocaine has distinct action on movement and non-movement behavioral activities, suggesting that locomotion as a unitary phenomenon comprised of assemblage of multifarious components, which can be manipulated and separated by cocaine in crayfish.     

A single pretreatment with MK-801 or cocaine enhances their locomotor stimulant effects in rats

A single dose of MK-801 (1.0 mg/kg, s.c.) induces an enhanced locomotor response to a subsequent lower dose of MK-801 (0.3 mg/kg) administered 4, 7 or 14 days later in young adult rats (>90 days). MK-801 (1.0 mg/kg) administration did not significantly enhance the effects of cocaine (10, 20 mg/kg) administered 7 days later. Cocaine (20 mg/kg) enhanced the effect of a subsequent dose of 10 mg/kg cocaine, but did not significantly alter the response to a higher dose cocaine (20 mg/kg) or of MK-801 (0.1 or 0.3 mg/kg) again given 7 days later. MK-801 (1.0 mg/kg) did not significantly enhance the locomotor response to a second dose of MK-801 (0.3 mg/kg) in 28-day-old rats tested 7 days after the initial dose, but did enhance the effects of a lower (0.1 mg/kg) dose. These findings indicate that even a single dose of a stimulant such as MK-801 and cocaine can induce enduring changes in sensitivity to subsequent doses of the same stimulants in young adult rats. The lack of significant effects seen in cross-sensitization studies suggests that separate mechanisms maybe involved in the sensitization to cocaine and MK-801. The more pronounced enhancement of activity in the older animals is in accord with previous findings that sensitization processes are developmentally regulated.     

Central ventilatory effects of thyrotropin-releasing hormone in the conscious rat

Thyrotropin-releasing hormone was shown to exert potent ventilatory effects after central administration. These data, however, were derived from studies using anesthetized animal preparations. Since TRH elicits strong arousal reactions, the observed ventilatory effects of TRH under anesthesia may have been due to nonspecific reduction in the anesthetic state of the animals. In order to clarify the extent to which the reversal of anesthesia may change ventilatory parameters after TRH application, we investigated the effect of TRH on ventilation rate, relative tidal volume, relative respiratory minute volume, CO2 production CO2 consumption, and locomotor activity in the conscious, unrestrained rat. Intracerebroventricular application of TRH induced a dose-dependent, sustained increase in ventilation rate, relative tidal volume, and relative respiratory minute volume of maximally 128%, 890%, and 235%, respectively. In addition, CO2 production and O2 consumption were elevated by 4.6 and 11.7 fold, while no significant changes in locomotor activity were observed. The results suggest that TRH stimulates ventilation by a mechanism independent of its analeptic properties.     

The effects of carbamazepine on the thyrotropin response to thyrotropin-releasing hormone

A thyrotropin (thyroid-stimulating hormone; TSH) stimulation test with thyroid-releasing hormone (TRH) was performed on six patients with a DSM-III diagnosis of major depressive disorder, both before and during a trial of carbamazepine. Carbamazepine, an anticonvulsant effective in the treatment of affective illness, caused a reduction in the TSH response to TRH. This finding suggests that carbamazepine may decrease thyroid function primarily at the level of the pituitary in affectively ill patients.     

Aging blocks the thermoregulatory action of thyrotropin-releasing hormone in anaesthetized rats

The influence of aging on the thermoregulatory effect of thyrotropin-releasing hormone (TRH) was studied in young (3-month-old) and aged (24-month-old) chloral hydrate-treated rats subjected either to normothermic (23 degrees C) or cold (4 degrees C) environment. Cerebroventricular injection of TRH (1 or 10 micrograms) or the TRH analog, CG 3509 (0.1 or 1 microgram), significantly enhanced the decline of body temperature in the young, anaesthetized rats, both in the normal and cold environments, but had no effect whatsoever on the decrease in body temperature in the chloral hydrate-treated aged animals. These results suggest that aging impairs the central mechanism(s) involved in the thermoregulatory action of TRH.     

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.     

Involvement of both opiate and catecholaminergic receptors of ventromedial hypothalamus in the locomotor stimulant action of thyrotropin-releasing hormone

Summary To explore the mode of the locomotor stimulant action of thyrotropin-releasing hormone (TRH), rats with or without administration of opiate or catecholaminergic receptor antagonists were infused with TRH through previously implanted hypothalamic cannula. Administration of TRH, but not the normal saline or TSH, into the ventromedial hypothalamus caused an enhancement in both the gross movements (including stimulation of forward locomotion, head and body rearing) and fine movements (including increased grooming and head swaying). The locomotor stimulant action provoked by TRH was antagonized by pretreatment of ventromedial hypothalamus with either an alpha-adrenergic receptor antagonist (yohimbine), a dopaminergic receptor antagonist (haloperidol) or an opiate receptor antagonist (naloxone), but not with a beta-adrenergic receptor antagonist (propranolol). The results indicate that all the adrenergic, dopaminergic and opiate receptors in the ventromedial hypothalamus are involved in the TRH-induced hyperactivity in the rat.     

Acute and chronic cocaine behavioral effects in novel versus familiar environments: open-field familiarity differentiates cocaine locomotor stimulant effects from cocaine emotional behavioral effects

Cocaine is a potent stimulant drug, but its stimulant effects can be substantially modulated by environmental novelty versus familiarity. In this report, we varied exposures to a novel environment as a way to assess the impact of environmental familiarity versus novelty upon the locomotor activation induced by acute and chronic cocaine treatments. In experiment 1, the effects of 1 (PE1) versus 0 (PE0) pre-exposures to the test environment were compared for their impact upon the locomotor stimulant, central zone entry and grooming effects induced by an acute cocaine (10 mg/kg) treatment. In experiment 2, the effects of 10 (PE10) versus 0 (PE0) pre-exposures upon the cocaine effects were compared. Experiment 3 assessed the effects of nine cocaine treatments (10.0 mg/kg) initiated in a novel environment (PE0) versus familiar environment (PE10). In all experiments, cocaine had a potent locomotor stimulant effect in a novel environment, which was attenuated by environmental familiarity such that in PE10 groups, cocaine did not reliably induce an acute locomotor stimulant effect. Environmental novelty/familiarity, however, did not reliably alter cocaine effects upon central zone penetration, grooming behavior, or the neurochemical effects induced by cocaine. In the chronic treatment regimen, the PE0 group exhibited a tolerance-like decrease in locomotor activation, but the PE10 group exhibited a sensitization-like increase in locomotor activation. Despite the marked directional changes in the locomotor stimulant effects of cocaine treatments, initiated in a novel (PE0) versus familiar (PE10) environment, the same asymptotic levels of locomotor activation were achieved. In contrast, the behavioral measures of central zone activity progressively increased with repeated treatments regardless of whether the environment was initially novel (PE0) or familiar (PE10). Thus, habituation factors can profoundly alter the locomotor stimulant effects of cocaine and can induce pseudo-tolerance phenomena. In contrast, central zone activity undergoes sensitization-like effects independent of habituation state and therefore appears to represent a more fundamental behavioral effect of cocaine. In that, central zone penetration in an open-field is linked to emotional processes; this finding is of substantial importance in understanding the effects of repeated cocaine usage.     

Effects of thyrotropin-releasing hormone (TRH) on status epilepticus in rats

Recent studies have demonstrated that intramuscular administration of thyrotropin-releasing hormone (TRH) or its analogue improves various clinical aspects of intractable epilepsy such as Lennox-Gastaut syndrome, West syndrome, and myoclonus epilepsy. Other clinical studies reported efficient property of intravenous TRH against status epilepticus. However, it is also true that intravenous TRH produces epileptic seizures in patients with epilepsy or organic brain damage. Thus, the utility of intravenous TRH for the treatment of status epilepticus seems to be equivocal. To further explore the problem in this regard, we examined the effect of TRH on limbic status epilepticus in rats. Thirty-eight male Wistar rats weighing 180-220g were used. Status epilepticus was induced by intracerebral injection of a combination of 200 micrograms of dibutyryl-cAMP (db-cAMP) and 67.2ng of ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM) through an implanted cannula. 30 min later, TRH or vehicle (distilled water) was administered intravenously (i.v.) or intracerebroventricularly (i.c.v.). Although 3 mg/kg of TRH (n = 9), when injected i.v., did not alter the pattern of electroclinical ictal responses induced by db-cAMP/EDTA, 25 mg/kg (n = 5) and 50 mg/kg (n = 5) of TRH significantly exaggerated EEG and/or behavioral ictal seizures, beginning immediately after the injection and lasting for more than 30 min. With 50 mg/kg of TRH, the exaggerated seizure patterns were followed by marked suppression of electroclinical seizures. 50 micrograms of i.c.v. TRH (n = 5), like higher doses of i.v. TRH, caused a slight, but not a significant, build up of electroclinical ictal seizures, beginning immediately after the injection and lasting for about 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunological blockade of endogenous thyrotropin-releasing hormone produces hypothermia in rats

Administration of anti-serum to thyrotropin-releasing hormone (TRH) into the lateral cerebral ventricle of rats produces a dose-dependent hypothermia. Neutralization of anti-TRH serum with excess TRH abolishes this hypothermic effect. These results suggest a thermoregulatory role for endogenous TRH in the rat central nervous system.     

Individual differences in cocaine conditioned taste aversion are developmentally stable and independent of locomotor effects of cocaine

Drugs of abuse induce complex motivational states in their users which have been shown to vary developmentally. In addition to developmental variation, interindividual variation in the rewarding and aversive effects of drugs of abuse is an important consideration. A rat model was used to assess whether the conditioned rewarding/aversive effects of cocaine were maintained as individuals matured from adolescence into adulthood. We tested rats in the cocaine conditioned taste aversion task as adolescents and again in adulthood. We observed a wide range of approach/avoidance behaviors in this task, and also observed that the relative interindividual differences in approach/avoidance are remarkably stable across the two developmental stages. Furthermore, we observed that these interindividual differences are not attributable to individual differences in cocaine-induced locomotor effects or individual differences in blood or brain cocaine levels. Taken together, these findings indicate that sensitivity to cocaine's motivational effects is stable across development and part of a unique neurological process.     

Effect of thyrotropin-releasing hormone on cerebral blood flow in conscious rat

The effect of thyrotropin-releasing hormone (TRH) was studied on local CBF (LCBF) in normal conscious rats. LCBF was measured by the autoradiographic [14C]iodoantipyrine method 5 min after TRH (5 mg/kg, i.v.) administration. TRH significantly increased LCBF in 22 of 33 brain regions. This increase of LCBF exceeded 100% of the control values in the cerebral cortices, whereas there was no significant increase in white matter or in some gray matter structures. The increase of CBF following TRH administration was abolished by pretreatment with indomethacin (5 mg/kg, i.v.). The mechanisms underlying the increase of CBF following TRH administration are discussed in relation to prostaglandin metabolism.     

Effect of amitriptyline on the thyrotropin response to thyrotropin-releasing hormone in endogenous depression

Patients with endogenous depression whose depressive episodes were clinically resolved after electroconvulsive therapy were divided into two groups: one in which patients remained well (n = 16) and another in which patients relapsed within 6 months (n = 11). Treatment with amitriptyline for 3 weeks did not affect the median thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) in recovered patients, whereas that in relapsed patients was significantly enhanced. The data suggest that amitriptyline affects the TSH response to TRH differently in stably recovered and relapsed patients. If this effect is maintained beyond the 3-week period studied, treatment with amitriptyline will invalidate the predictive value of the TRH test.     

Strain and sex differences in the locomotor response and behavioral sensitization to cocaine in hyperactive rats

Individual variability in the behavioral responsiveness to psychostimulant drugs is due, in part, to genetic factors. The present study investigated the effects of acute and repeated administrations of cocaine (0, 5, 10 or 20 mg/kg, i.p.) on locomotor activity in male and female rats from genetically distinct strains often used as a model of human childhood hyperactivity/attentional deficit disorder: Wistar Kyoto Hyperactive (WKHA) rats, Spontaneous Hypertensive rats (SHR) and their control Wistar Kyoto (WKY). The results, expressed as percent change in locomotor activity relative to respective control groups, showed that cocaine elicits a dose-dependent hyperactivity in all strains and revealed neither strain nor sex differences in acute sensitivity to moderate doses of the drug. Nevertheless, across repeated administrations, strain and sex differences appeared: WKHA rats displayed a moderate extent of sensitization to psychomotor stimulant effects of cocaine and female rats showed more robust sensitization than males, whatever the strain. These findings support the genotype-dependence in the development of behavioral sensitization to cocaine and confirm the robustness of the sexual dimorphism across different inbred rat strains. Interestingly, the present results demonstrate that sensitization to psychostimulant drugs occurs in genetically hyperactive strains as well as in their normoactive control strain.     

Effect of septohippocampal lesions on thyrotropin-releasing hormone antagonism of pentobarbital narcosis

Thyrotropin-releasing hormone (TRH) has been shown to antagonize pentobarbital narcosis in a variety of mammalian phylogeny, and many lines of evidence indicate that TRH action in the septum to modulate the septohippocampal system may be the neuroanatomical substrate mediating this effect. To further examine this hypothesis, the analeptic response following injection of TRH into the lateral ventricles or ventromedial septum was measured after lesions of the septum, fimbria or hippocampus. Lesions were induced using either radiofrequency current, aspiration or microinjection of kainic acid. Bilateral electrolytic lesions of the fimbria were found to block the antagonism of pentobarbital narcosis by intraseptal injection of 500 ng TRH, indicating that intraseptal TRH is acting via the septohippocampal system. In contrast, complete aspiration of the dorsal hippocampi did not attenuate intracerebroventricular (i.c.v.) administration of TRH. However, large electrolytic septal lesions effectively blocked i.c.v. TRH. These findings indicate first that i.c.v. TRH can cause arousal from pentobarbital narcosis via interaction with alternative neuroanatomical substrates from the septohippocampal system, and secondly, that these alternative substrates have axons which either synapse in or pass through the septum. The fact that injection of kainic acid into the ventromedial septum did not antagonize i.c.v. TRH supports the likelihood that the effectiveness of electrolytic septal lesions results from disruption of fibers in passage and not destruction of neuron perikarya in the septum.