Pharmacological analysis of the interaction of antimuscarinic drugs at M(2) and M(3) muscarinic receptors in vivo using the pithed rat assay.

Muscarinic receptor antagonists form the mainstay of the therapeutic options for airway, bladder, and gastrointestinal smooth muscle disorders. Both M(2) and M(3) muscarinic receptors are involved in mediating smooth muscle contractility, although the relative functional contribution of each subtype, especially in the disease state, is unclear. Because the potency and selectivity of compounds for a given receptor in an in vivo setting can be dissimilar to that observed in an in vitro system, we developed an in vivo assay to simultaneously determine the absolute potency and selectivity of muscarinic receptor antagonists at M(2) and M(3) receptors using the pithed rat.

Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.

The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.

Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization.

The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine.

Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent effects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the vicinity of developing DA neurons have been reported to support survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons.

Sensitization to the locomotor activating effects of cocaine following cocaethylene-preexposure.

The present study assessed the ability of cocaethylene to induce sensitization to the behavioral activating effects of cocaine in the male Sprague-Dawley rat. Preexposure to cocaethylene (15 or 25 mg/kg) significantly enhanced the locomotor activating effects of a subsequent cocaine (15 mg/kg) challenge injection. In addition, acute intraperitonecal administration at several doses (10, 15, or 25 mg/kg) confirmed previous reports of increased bioavailability of cocaine in brain and plasma relative to cocaethylene.

Blockade of FG 7142-induced increased dopamine utilization by the glycine/NMDA receptor antagonist (+)-HA 966.

Systemic administration of the anxiogenic benzodiazepine inverse agonist FG 7142 has been shown to increase selectively dopamine utilization in the medial prefrontal cortex and the shell, but not core, subregion of the nucleus accumbens. In the present study, we examined the functional interaction between benzodiazepine and N-methyl-D-aspartate receptor influences on dopamine utilization in these areas. Male Sprague-Dawley rats were pretreated with the glycine receptor antagonist (+)-HA 966 (15 mg/kg, i.

The role of mesoprefrontal dopamine neurons in stress.

While several catecholaminergic systems are activated by stressful stimuli, the mesoprefrontal dopamine (DA) system appears to be particularly vulnerable to stress. Low intensity stressors that do not produce detectable effects in most ascending catecholaminergic systems activate mesoprefrontal DA neurons. Mesoprefrontal DA neurons are unique in that they lack or have decreased densities of specific autoreceptors affecting autoregulatory capabilities, which could contribute to the fact that mesoprefrontal DA neurons exhibit increased rates of burst firing and DA turnover relative to other midbrain dopaminergic projections.

Selective increase in dopamine utilization in the shell subdivision of the nucleus accumbens by the benzodiazepine inverse agonist FG 7142.

We examined the effects of the benzodiazepine inverse agonist FG 7142 on dopamine metabolism in the core and shell subdivisions of the nucleus accumbens. FG 7142 (15 mg/kg i.p.

Preexposure to, but not cotreatment with, the neurotensin antagonist SR 48692 delays the development of cocaine sensitization.

This study examined the role of neurotensin (NT) in the development of cocaine sensitization using the novel nonpeptide NT antagonist SR 48692. Male Sprague-Dawley rats received five daily administrations of SR 48692 (80 micrograms/kg, IP or PO) or vehicle. Following a 7 day drug-free period, cocaine-induced (15 mg/kg, IP) locomotor activity was assessed.

Interactions between caffeine and cocaine in tests of self-administration.

Interactions between the effects of cocaine and caffeine have been demonstrated in tests of motor activity and drug discrimination. Since both drugs are widely consumed by humans, the present study was undertaken to determine whether a similar interaction between the reinforcing effects of these drugs could be demonstrated. Experienced cocaine self-administering rats were treated with caffeine either as an i.

Augmentation of the neurochemical effects of cocaine in the ventral striatum and medial prefrontal cortex following preexposure to amphetamine, but not nicotine: an in vivo microdialysis study.

This study assessed the ability of cocaine to increase synaptic levels of dopamine (DA) in the ventral striatum (VS) and medial prefrontal cortex (mPFC) following repeated daily exposure to amphetamine or nicotine. In vivo microdialysis was used to assay DA levels in the awake freely moving male Sprague-Dawley rats. Three days following guide cannula implantation, subjects received 9 daily preexposure injections of amphetamine (1.

Development and expression of sensitization to cocaine's reinforcing properties: role of NMDA receptors.

Acquisition of cocaine self-administration (0.125, 0.25 or 0.

Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine.

The acquisition of low-dose (0.25 mg/kg/infusion) intravenous cocaine self-administration was measured in rats that had received nine daily injections of amphetamine (1.0 mg/kg, IP), nicotine (0.

Effects of cadmium on cocaine-induced changes in activity.

Adult male rats were exposed to a diet that contained 100 parts per million added cadmium or a control diet for 72 days before being tested in a Digiscan activity monitor. During the 1-hr test period, each animal's baseline activity levels were recorded for 20 min. Animals then received intraperitoneal injections of 0, 10, 20, or 40 mg/kg cocaine HCl, and their activity levels were recorded for the remaining 40 min of the test session.

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats.

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.

Caffeine exposure sensitizes rats to the reinforcing effects of cocaine.

The present study examined the effect of pre-exposure to a moderate dose of caffeine (20 mg kg-1) on the acquisition of self-administration of cocaine (0.125 mg kg-1/infusion or 0.25 mg kg-1/infusion) in the rat.

Pre-exposure to amphetamine but not nicotine sensitizes rats to the motor activating effect of cocaine.

Rats were pretreated with nine daily injections of either d-amphetamine SO4(1.0 mg/kg, 1P), nicotine bitartrate (0.6 mg base/kg, SC) or saline.

Preexposure sensitizes rats to the rewarding effects of cocaine.

During a preexposure period rats were injected once daily with either cocaine HCI (10 mg/kg, IP) or the saline vehicle for 12 consecutive days. Rats that were chronically exposed to cocaine during the pretreatment phase were more responsive to the motor activating effects of a subsequent injection of cocaine than were rats chronically treated with saline. In self-administration testing, saline-pretreated groups did not exhibit a significant preference for a lever producing a cocaine infusion relative to an inactive lever, suggesting that the doses tested (0.

Caffeine preexposure sensitizes rats to the motor activating effects of cocaine.

Rats were preexposed to caffeine or to water vehicle with nine daily injections (20 mg/kg, i.p.).

The effects of naltrexone on cadmium-induced increases in oral ethanol self-administration.

Adult male rats were exposed to a standard laboratory diet (N = 20), or an adulterated diet containing 100 ppm added cadmium (N = 20), for 60 days. On Day 61, half the animals from each dietary condition received subcutaneous implants of two 30 mg naltrexone pellets, and the remaining half the animals received identical implants of 30 mg placebo pellets. One week later, animals from groups created by this interaction (Groups Control-Placebo, Control-Naltrexone, Cadmium-Placebo, Cadmium-Naltrexone) were tested in an ethanol self-administration paradigm that presented a 10% ethanol solution (v/v) in both a choice and nonchoice format.