Biomedical subjects

J D Salamone

Publications and source records attributed to J D Salamone.

At least 19 recordsLinked to original sources

PubMed2007

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits.

BACKGROUND: Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. OBJECTIVE: The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. RESULTS: The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. CONCLUSIONS: Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression.

Animals↗

PubMed2005

The cannabinoid CB1 antagonist AM 251 produces food avoidance and behaviors associated with nausea but does not impair feeding efficiency in rats.

RATIONALE: A growing body of evidence suggests that cannabinoid CB1 receptor antagonists have potential therapeutic utility as appetite suppressants. However, the specific mechanisms underlying the reduction in food intake produced by these drugs are not well understood. OBJECTIVE: Considering the known antiemetic and motor-suppressive effects of CB1 agonists, the present studies were conducted to determine if the reductions in food intake induced by the CB1 antagonist AM 251 could result from nausea or impairments in intake-related motor control, rather than solely from appetite suppression. METHODS: Three experiments were conducted to examine the effects of AM 251 (2.0, 4.0, or 8.0 mg/kg or vehicle) on detailed parameters of food intake, on the development of conditioned taste avoidance, and on taste reactivity. RESULTS: In the first experiment, acute administration of AM 251 dose-dependently decreased food intake; nevertheless, feeding rate (grams consumed per time spent eating) and food handling were unaffected, which suggests that food intake was not reduced because of severe motor impairments. In the second experiment, AM 251 dose-dependently reduced intake of a flavor with which it had previously been associated, indicating that conditioned taste avoidance had developed. Lastly, AM 251 was found to induce conditioned rejection reactions in a dose-dependent manner. CONCLUSIONS: The CB1 antagonist AM 251 may reduce food intake in part by inducing nausea or malaise, but not because of incoordination or motor slowing related to feeding.

Animals↗

PubMed2005

Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine.

According to the dopamine (DA) hypothesis of reward, DA systems in the brain, particularly in the nucleus accumbens, are thought to directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food, water and sex, as well as various drugs of abuse. However, there are numerous problems associated with this hypothesis. Interference with accumbens DA transmission does not substantially blunt primary motivation for natural rewards such as food, but it does disrupt the propensity of animals to engage in effortful responding to obtain food. Electrophysiological and voltammetric studies indicate that novel stimuli, conditioned stimuli that predict reward, and instrumental behaviors that deliver natural rewards all act to stimulate DA activity. Accumbens DA acts as a modulator of several functions related to motivated behavior, and can influence normal and pathological cognitive function, activational aspects of motivation, anergia or psychomotor slowing in depression, the impact of conditioned stimuli, plasticity and a variety of sensorimotor functions.

Animals↗

PubMed2005

The novel cannabinoid agonist AM 411 produces a biphasic effect on accuracy in a visual target detection task in rats.

Cannabinoid agonists have been shown to produce dose-related impairments in several measures of cognitive performance. However, it is unclear if low doses of cannabinoid CB1 agonists, or CB1 antagonists, can facilitate aspects of stimulus detection. The present study employed an operant procedure involving visual stimulus detection in rats. The task was found to be sensitive to the muscarinic acetylcholine antagonist scopolamine. The CB1 antagonist AM 251 did not affect stimulus detection processes across a broad range of doses. However, the novel CB1 agonist AM 411 produced a biphasic effect, with the two lowest doses (0.25 and 0.5 mg/kg) enhancing accuracy. AM 411 changed patterns of responding toward runs of consecutive errors on only one of the two levers. It produced a biphasic effect on consecutive errors on the lever associated with a higher level of errors, with decreases in errors following the lower doses (0.25 and 0.5 mg/kg) and increases following the highest dose (2.0 mg/kg). These effects were not accompanied by changes in measures of bias commonly used to uncover such patterns in rodent operant models of cognitive performance. In contrast to the cognitive impairment seen after administration of moderate to high doses of CB1 agonists, it appears that low doses of some CB1 agonists may be capable of enhancing stimulus detection processes.

Adamantane↗

PubMed2004

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats.

RATIONALE: Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. OBJECTIVE: The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. METHODS: The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. RESULTS: Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED50 for suppression of jaw movements divided by the ED50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. CONCLUSIONS: On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.

Animals↗

PubMed2004

Behavioral effects of inhibition of cannabinoid metabolism: The amidase inhibitor AM374 enhances the suppression of lever pressing produced by exogenously administered anandamide.

Biochemical investigations have identified putative enzymatic pathways for the synthesis and metabolism of endogenous cannabinoids. Anandamide amidase is an enzyme that metabolizes anandamide into arachadonic acid and ethanolamine. Using in vitro methods, various inhibitors of amidase have been identified. The present studies were undertaken to determine if the amidase inhibitor AM 374 could enhance the effects of intraperitoneal (IP) injections of anandamide. Three studies were conducted to investigate the effects of various drug treatments on fixed ratio 5 operant lever pressing for food reinforcement. In the first study, the effects of different doses of anandamide were assessed, and it was demonstrated that 5.0 and 10.0 mg/kg anandamide IP significantly suppressed lever pressing, while 2.5 mg/kg produced very little effect. The second study tested the effects of intraventricular (ICV) injections of AM 374, and it was observed that doses up to 10.0, 20.0 and 40 microg AM 374 had no significant effect upon lever pressing. The third study investigated the combined effect of AM374 with a low dose of anandamide. Rats received two drug injections: one ICV and one IP. Four different drug treatments were assessed: 1) ICV vehicle + IP vehicle, 2) ICV vehicle + 2.5 mg/kg anandamide IP, 3) ICV 20.0 microg AM 374 + IP vehicle, and 4) ICV 20 microg AM 374 + 2.5 mg/kg anandamide IP. Combined administration of AM 374 plus anandamide led to a significant decrease in lever pressing compared to either AM374 or anandamide administered alone. Observations of the animals treated with the combination of AM374 plus anandamide indicated that the drug combination resulted in motor slowing, which is consistent with the notion that stimulation of cannabinoid receptors produced a motor deficit that interfered with lever pressing. Although AM374 produced no effect on its own, this amidase inhibitor did enhance the behavioral effect of a low dose of anandamide. These results are consistent with the notion that AM 374 inhibited the enzymatic breakdown of exogenously injected anandamide. This type of procedure can be used to assess a variety of different compounds for their ability to inhibit cannabinoid metabolism.

Amidohydrolases↗

PubMed2004

The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism.

Recent evidence indicates that adenosine A2A receptors modulate the activity of striatal neurons, and that antagonists of this receptor may have actions in various animal models related to motor function. Four experiments were conducted to study the effects of systemic injections of the adenosine A2A antagonist KF17837 on the behavioral effects produced by repeated administration of the dopamine (DA) antagonist haloperidol. In the first two experiments, it was shown that repeated 0.5 mg/kg haloperidol severely suppressed open-field locomotor activity, and that KF17837 (0.0-20.0 mg/kg) did not significantly increase open-field locomotor activity. The third experiment demonstrated that injections of KF17837 (0.0-20.0 mg/kg) completely reversed the suppression of locomotion induced by haloperidol, and also increased rearing behavior in haloperidol-treated rats. Previous research has reported that haloperidol induces tremulous jaw movements that have many of the characteristics of parkinsonian tremor. The fourth experiment demonstrated that i.p. injections of KF17837 (0.0-20.0 mg/kg) also suppressed haloperidol-induced tremulous jaw movements. Taken together, the results of these experiments indicate that adenosine A2A antagonism can reverse the locomotor suppression and tremulous movements induced by DA antagonism. This profile of activity is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in an antiparkinsonian effect in animal models.

Adenosine A2 Receptor Antagonists↗

PubMed2003

Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate.

The typical response to acute peripheral administration of low to high doses of ethanol in rats is a dose-dependent depression of motor activity. Nevertheless, recent studies indicate that intraventricular (ICV) injections of ethanol can produce signs of behavioral activation. In addition, considerable evidence indicates that brain metabolism of ethanol is involved in modulating some of the behavioral effects of this drug, which suggests that ethanol may have active metabolites with central actions. The present study was undertaken to investigate the effects of ICV ethanol, and its two major metabolites acetaldehyde and acetate, on open field locomotor activity in rats. Male Sprague-Dawley rats received different doses of ethanol, acetaldehyde or acetate ICV and immediately were placed in an open field chamber in which locomotion was measured. Rats injected with ICV ethanol or acetaldehyde showed an inverted U-shaped dose-response curve, with moderate doses increasing motor activity. In contrast, acetate produced a dose-dependent decrease in motor activity. These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats, and suggest that acetaldehyde may be an active metabolite of ethanol that also can facilitate locomotor activity. Moreover, it is possible that some of the motor suppression or sedation produced by ethanol is due to the central actions of acetate.

Acetaldehyde↗

PubMed2003

Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration.

RATIONALE: Low doses of ethanol stimulate locomotion in mice, but in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of locomotion. Moreover, chronic ethanol administration fails to produce signs of locomotor sensitization in rats. OBJECTIVE: The present study was undertaken to determine whether intraventricular (i.c.v.) infusions of low doses of ethanol (as determined by comparisons with systemic doses, and by analyses of brain extract ethanol levels) could increase locomotor activity in rats after acute or repeated administration. METHODS: Male rats received acute doses of ethanol i.p. (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) or i.c.v. (0.0, 0.7, 1.4, or 2.8 micromol) and were tested for motor activity. In a third experiment, repeated i.c.v. vehicle or ethanol (2.8 micromol) was administered for 15 sessions over a 30-day period, and motor activity was recorded. This phase was followed by a single challenge session, in which a low dose of ethanol (0.7 micromol) was injected i.c.v. to both groups of rats. RESULTS: Rats injected with i.p. ethanol showed no increase in activity at low doses, with higher doses suppressing activity. In contrast, i.c.v. injections of low doses of ethanol increased motor activity. After repeated administration, ethanol-treated rats were more sensitive than control-treated rats to the locomotor stimulant effect of ethanol. CONCLUSIONS: These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats and suggest that i.c.v. ethanol can produce some signs of motor sensitization, a characteristic that has been related to the potential addictive properties of many drugs.

Animals↗

PubMed2003

Substantia nigra pars reticulata GABA is involved in the regulation of operant lever pressing: pharmacological and microdialysis studies.

Substantia nigra pars reticulata (SNr) is an important mesencephalic nucleus that functions as a relay area for basal ganglia output. SNr receives GABAergic inputs from the neostriatum and globus pallidus, and in turn sends projections to a variety of motor areas. Although a large number of studies have focused upon the behavioral functions of basal ganglia dopamine, much less is known about the behavioral functions of SNr GABA. The present studies were undertaken to investigate the role of SNr GABA in lever pressing behavior. In the first experiment, the GABA(A) antagonist bicuculline was infused locally into SNr to determine if blockade of GABA receptors interfered with the performance of lever pressing on a fixed ratio 5 schedule. SNr injections of bicuculline produced a dose-related suppression of operant responding. Analysis of interresponse time bins showed that SNr bicuculline produced a response slowing characterized by a relative reduction in the number of fast interresponse times, and an increase in the relative number of pauses. In an additional experiment, microdialysis methods were used to determine if extracellular GABA is elevated during the performance of fixed ratio five lever pressing. During the 30 min lever pressing session, extracellular GABA showed a significant and substantial increase relative to baseline levels. These data support the hypothesis that SNr GABA is involved in the regulation of motor output, and indicate that GABA release in this structure is increased during behavioral stimulation.

Animals↗

PubMed2003

Brain implantations of engineered GABA-releasing cells suppress tremor in an animal model of Parkinsonism.

Traditional approaches in the treatment of Parkinson's disease have typically been directed at restoring dopaminergic tone in the neostriatum of the basal ganglia. Nevertheless, the vast majority of neostriatal efferent projections use GABA as their neurotransmitter. Substantia nigra pars reticulata (SNr) is a major basal ganglia output area that is a target of these GABAergic projections, and research from animal models has indicated that stimulation of GABA receptors in SNr can produce motor effects consistent with an antiparkinsonian action. In the present study, implantation of engineered GABA-releasing cells into SNr reduced tremulous movements in an animal model of parkinsonian tremor. These results suggest that implantation of GABA cells into SNr, or possibly into other basal ganglia structures, could provide an alternative transplantation strategy for the treatment of Parkinsonism.

Animals↗

PubMed2003

The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats.

Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.

Animals↗

PubMed2003

Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse.

For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food, as well as drugs of abuse. Yet, several fundamental aspects of primary food reinforcement, motivation, and appetite are left intact after interference with accumbens DA transmission. Recent studies have shown that accumbens DA is involved in responsiveness to conditioned stimuli and activational aspects of motivation. In concurrent choice tasks, accumbens DA depletions cause animals to reallocate their choice behavior in the direction of instrumental behaviors that involve less effort. Also, an emerging body of evidence has demonstrated that the effects of accumbens DA depletions on instrumental food-seeking behavior can vary greatly depending upon the task. For example, some schedules of reinforcement are insensitive to the effects of DA depletions, whereas others are highly sensitive (e.g., large fixed ratios). Accumbens DA depletions slow the rate of operant responding, blunt the rate-facilitating effects of moderate-sized ratios, and enhance the rate-suppressing effects of very large ratios (i.e., produce ratio strain). Accumbens DA may be important for enabling rats to overcome behavioral constraints, such as work-related response costs, and may be critical for the behavioral organization and conditioning processes that enable animals to engage in vigorous responses, such as barrier climbing, or to emit large numbers of responses in ratio schedules in the absence of primary reinforcement. The involvement of accumbens DA in activational aspects of motivation has implications for energy-related disorders in psychiatry, as well as aspects of drug-seeking behavior.

Animals↗

PubMed2002

Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studies with a putative model of Parkinsonian tremor.

RATIONALE: Atypical antipsychotics such as clozapine and olanzapine have a low liability for producing motor side effects. In addition to being D2 antagonists, these drugs have a complex binding profile that includes affinity for muscarinic, alpha, H1, and various serotonin receptors. Previous work in rats has shown that atypical antipsychotics suppress tremulous jaw movements induced by the anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a putative model of parkinsonian tremor, and the ability of antipsychotic drugs to suppress these movements in rats is correlated with motor side-effect liability in humans. OBJECTIVE: The present work was undertaken to study the role of central serotonin receptors in the generation of cholinomimetic-induced jaw movements. RESULTS: Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements, with an ED(50) of 2.77 mg/kg. Local injections of mianserin directly into substantia nigra pars reticulata (SNr) also suppressed tacrine-induced jaw movements. Injections into ventrolateral neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw movement activity. CONCLUSIONS: These studies suggest that atypical antipsychotics may act both on striatal muscarinic receptors and nigral serotonin receptors to suppress jaw movement activity. It is possible that the unique motor properties of atypical antipsychotics result from actions on multiple receptors in several brain areas. The precise serotonin receptor subtype involved in these effects is unknown, and future work will examine the effects of drugs that act selectively on 5-HT(2A) and 5-HT(2C) receptors.

Analysis of Variance↗

PubMed2002

Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task.

RATIONALE: Dopamine is important for enabling organisms to overcome work-related response costs. One way of investigating this function has been with concurrent choice procedures using food reinforcement. In the present study, rats were given a choice between pressing a lever for preferred Bioserve pellets, or approaching and consuming a less-preferred laboratory chow that was concurrently available. In previous work with this task, dopamine antagonists and accumbens dopamine depletions decreased lever pressing but increased chow consumption. OBJECTIVE: The present study assessed three drugs (two dopamine antagonists and one appetite suppressant) using the lever pressing/chow feeding task. RESULTS: Under baseline conditions, rats pressed the lever at high rates (1,300-1,500 responses) to obtain the preferred food, and little of the laboratory chow was eaten (1-2 g). Selective D1 and D2 antagonists (SKF 83566 and raclopride) reduced fixed ratio 5 lever pressing, but substantially increased chow consumption. In contrast, the serotonergic appetite suppressant fenfluramine reduced both lever pressing and chow consumption. With the dopamine antagonists, lever pressing and chow consumption were inversely correlated across treatments, while these two measures were unrelated in the fenfluramine experiment. CONCLUSIONS: Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2001

Interactions between dopamine D1 receptors and gamma-aminobutyric acid mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies.

RATIONALE: Several studies have shown that dopamine D1 agonists act on forebrain dopamine terminal regions to exert many of their behavioral effects. Yet, there is also a large number of D1 receptors in the substantia nigra pars reticulata (SNr), and these receptors are located mainly on terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. OBJECTIVE: The present studies were undertaken to determine the behavioral and neurochemical effects of local administration of the D1 agonist SKF 82958 and to study the interactions between D1 and GABA mechanisms in SNr. METHODS: Microdialysis methods were used to characterize the effect of SKF 82958 on extracellular GABA, and several experiments studied the effects of nigral D1 stimulation on motor activity and investigated the behavioral significance of D1/GABA interactions in SNr. RESULTS: Local infusion of 10(-6) M SKF 82958 increased extracellular levels of SNr GABA, and this effect was blocked by co-infusion of the D1 antagonist SCH 23390. Bilateral SNr injections of SKF 82958 increased locomotor activity, and this effect was blocked by the GABA-A antagonist bicuculline. Intranigral bicuculline reduced motor activity, while the GABA-A agonist muscimol increased various motor activities in a manner similar to SKF 82958. CONCLUSIONS: The present results suggest that the D1 agonist SKF 82958 acts on D1 receptors in SNr to increase extracellular levels of GABA, and the increase in motor activity produced by nigral D1 stimulation is dependent on stimulation of GABA-A receptors. D1/GABA interactions in SNr are important for the modulation of basal ganglia output, which may have important implications for Parkinson's disease.

Animals↗

PubMed2001

Neostriatal muscarinic receptor subtypes involved in the generation of tremulous jaw movements in rodents implications for cholinergic involvement in parkinsonism.

Several studies have shown that a number of pharmacological and neurochemical conditions in rats can induce jaw movements that are described as "vacuous" or "tremulous". For several years, there has been some debate about the clinical significance of various drug-induced oral motor syndromes. Nevertheless, considerable evidence now indicates that the non-directed, chewing-like movements induced by cholinomimetics have many of the characteristics of parkinsonian tremor. These movements are characterized largely by vertical deflections of the jaw, which occur in the same 3-7 Hz peak frequency that is typical of parkinsonian tremor. Cholinomimetic-induced tremulous jaw movements are suppressed by a number of different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, ropinirole, pergolide, amantadine, diphenhydramine and clozapine. A combination of anatomical and pharmacological research in rats has implicated M4 receptors in the ventrolateral neostriatum in the generation of tremulous jaw movements. Mice also show cholinomimetic-induced jaw movements, and M4 receptor knockout mice demonstrate subtantially reduced levels of jaw movement activity, as well as increased locomotion. Taken together, these data are consistent with the hypothesis that a centrally-acting M4 antagonist may be useful as a treatment for parkinsonian symptoms, including tremor.

Acetylcholine↗

PubMed2001

Substantia nigra pars reticulata is a highly potent site of action for the behavioral effects of the D1 antagonist SCH 23390 in the rat.

RATIONALE: Considerable evidence indicates that dopaminergic drugs, including drugs that act on D1 receptors, exert their effects by actions on forebrain dopamine terminal regions. Nevertheless, anatomical studies also have demonstrated that there is a high concentration of D1 receptors in the substantia nigra pars reticulata (SNr). The D1 receptors in SNr are located largely on the terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 antagonist SCH 23390 was effective if locally injected into SNr and to compare the results of SNr injections with those obtained from other brain sites. Fixed ratio 5 (FR5) lever pressing and open-field locomotion were used as the behavioral tests because these tasks are sensitive to systemic SCH 23390. METHODS: Rats received bilateral implantations of guide cannulae into either nucleus accumbens, neostriatum, SNr, or control sites in the cortex or brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 microl per side): vehicle, 0.25, 0.5, 1.0, or 2.0 microg SCH 23390. RESULTS: In the FR5 study, the SNr was by far the most potent site for suppression of lever pressing, with an ED50 (dose that produces half maximal response) of 0.33 microg per side. Nucleus accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open-field locomotion, the SNr, nucleus accumbens, and neostriatum were approximately equipotent sites, and all three were more potent than the control sites. CONCLUSIONS: SNr was a very potent site for suppression of lever pressing and open-field locomotion. These data suggest that D1 antagonists have multiple sites of action, including not only the forebrain dopamine terminal regions but also the SNr. It is possible that blockade of SNr D1 receptors modulates GABA release from striatonigral neurons.

Animals↗