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1.
J Extracell Vesicles ; 12(1): e12301, 2023 01.
Article in English | MEDLINE | ID: mdl-36691887

ABSTRACT

Cocaine, an addictive psychostimulant, has a broad mechanism of action, including the induction of a wide range of alterations in brain metabolism and mitochondrial homeostasis. Our group recently identified a subpopulation of non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin (mitovesicles) and developed a method to isolate mitovesicles from brain parenchyma. We hypothesised that the generation and secretion of mitovesicles is affected by mitochondrial abnormalities induced by chronic cocaine exposure. Mitovesicles from the brain extracellular space of cocaine-administered mice were enlarged and more numerous when compared to controls, supporting a model in which mitovesicle biogenesis is enhanced in the presence of mitochondrial alterations. This interrelationship was confirmed in vitro. Moreover, cocaine affected mitovesicle protein composition, causing a functional alteration in mitovesicle ATP production capacity. These data suggest that mitovesicles are previously unidentified players in the biology of cocaine addiction and that target therapies to fine-tune brain mitovesicle functionality may be beneficial to mitigate the effects of chronic cocaine exposure.


Subject(s)
Cocaine , Extracellular Vesicles , Mice , Animals , Cocaine/metabolism , Cocaine/pharmacology , Extracellular Vesicles/metabolism , Brain/metabolism , Mitochondria/metabolism , Biology
2.
Neurochem Res ; 47(8): 2263-2277, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35501523

ABSTRACT

In multiple neurodevelopmental and neurodegenerative disorders, endosomal changes correlate with changes in exosomes. We examined this linkage in the brain of mice that received cocaine injections for two weeks starting at 2.5 months of age. Cocaine caused a decrease in the number of both neuronal early and late endosomes and exosomes in the brains of male but not female mice. The response to cocaine in ovariectomized females mirrored male, demonstrating that these sex-differences in response to cocaine are driven by hormonal differences. Moreover, cocaine increased the amount of α-synuclein per exosome in the brain of females but did not affect exosomal α-synuclein content in the brain of males, a sex-difference eliminated by ovariectomy. Enhanced packaging of α-synuclein into female brain exosomes with the potential for propagation of pathology throughout the brain suggests a mechanism for the different response of females to chronic cocaine exposure as compared to males.


Subject(s)
Cocaine , Exosomes , Animals , Cocaine/pharmacology , Endosomes , Female , Male , Mice , Neurons/pathology , alpha-Synuclein
3.
Neurochem Res ; 46(11): 2909-2922, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34245421

ABSTRACT

Cocaine is a highly addictive stimulant with diverse effects on physiology. Recent studies indicate the involvement of extracellular vesicles (EVs) secreted by neural cells in the cocaine addiction process. It is hypothesized that cocaine affects secretion levels of EVs and their cargos, resulting in modulation of synaptic transmission and plasticity related to addiction physiology and pathology. Lipids present in EVs are important for EV formation and for intercellular lipid exchange that may trigger physiological and pathological responses, including neuroplasticity, neurotoxicity, and neuroinflammation. Specific lipids are highly enriched in EVs compared to parent cells, and recent studies suggest the involvement of various lipids in drug-induced synaptic plasticity during the development and maintenance of addiction processes. Therefore, we examined interstitial small EVs isolated from the brain of mice treated with either saline or cocaine, focusing on the effects of cocaine on the lipid composition of EVs. We demonstrate that 12 days of noncontingent repeated cocaine (10 mg/kg) injections to mice, which induce locomotor sensitization, cause lipid composition changes in brain EVs of male mice as compared with saline-injected controls. The most prominent change is the elevation of GD1a ganglioside in brain EVs of males. However, cocaine does not affect the EV lipid profiles of the brain in female mice. Understanding the relationship between lipid composition in EVs and vulnerability to cocaine addiction may provide insight into novel targets for therapies for addiction.


Subject(s)
Brain/drug effects , Cocaine/toxicity , Dopamine Uptake Inhibitors/toxicity , Extracellular Vesicles/drug effects , Lipid Metabolism/drug effects , Sex Characteristics , Animals , Brain/metabolism , Brain/pathology , Cocaine/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Extracellular Vesicles/metabolism , Extracellular Vesicles/pathology , Female , Injections, Intraperitoneal , Lipid Metabolism/physiology , Male , Mice , Mice, Inbred C57BL
4.
Transl Psychiatry ; 8(1): 167, 2018 08 24.
Article in English | MEDLINE | ID: mdl-30143609

ABSTRACT

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL-/- deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/- mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.


Subject(s)
Dendritic Spines/metabolism , Nerve Tissue Proteins/physiology , Neurofilament Proteins/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Synapses/physiology , Synaptic Transmission/physiology , Animals , Behavior, Animal , Female , Glutamic Acid/metabolism , Hippocampus/pathology , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Knockout
5.
Neurochem Res ; 41(1-2): 398-408, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26857796

ABSTRACT

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol(®)) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development.


Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Models, Animal , Phencyclidine/administration & dosage , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Corpus Striatum/metabolism , Locomotion/drug effects , Male , Mice , Mice, Inbred C57BL , Serine/blood , Serine/metabolism , Serine/pharmacology
6.
J Neurosci ; 34(28): 9222-34, 2014 Jul 09.
Article in English | MEDLINE | ID: mdl-25009256

ABSTRACT

Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.


Subject(s)
Behavior, Animal/drug effects , Calcium-Binding Proteins/administration & dosage , Calpain/antagonists & inhibitors , Longevity/drug effects , Tauopathies/prevention & control , Tauopathies/physiopathology , Animals , Calpain/metabolism , Cysteine Proteinase Inhibitors/administration & dosage , Female , Male , Mice , Mice, Transgenic , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Nerve Degeneration/prevention & control , Survival Rate , Tauopathies/pathology , Treatment Outcome , tau Proteins/drug effects , tau Proteins/genetics
7.
J Pharmacol Exp Ther ; 343(2): 413-25, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22895898

ABSTRACT

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.


Subject(s)
Benztropine/pharmacology , Cocaine/analogs & derivatives , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Conditioning, Operant/drug effects , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Indicators and Reagents , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Neocortex/cytology , Neocortex/drug effects , Neocortex/metabolism , Neurons/drug effects , Neurons/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Pregnancy , Protein Binding , Protein Conformation , Radioligand Assay , Serotonin Plasma Membrane Transport Proteins/metabolism , Sodium/metabolism , Sodium Channels/metabolism , Structure-Activity Relationship , Swimming/psychology , Veratridine/pharmacology
8.
Brain Struct Funct ; 216(4): 347-56, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21512897

ABSTRACT

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression.


Subject(s)
Aggression/physiology , Brain/metabolism , Catechol O-Methyltransferase/metabolism , Gene Expression Regulation/physiology , Social Dominance , Tyrosine 3-Monooxygenase/metabolism , Analysis of Variance , Animals , Brain/anatomy & histology , Immunoblotting , Male , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction
9.
Neurochem Res ; 33(5): 902-11, 2008 May.
Article in English | MEDLINE | ID: mdl-17999181

ABSTRACT

Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the alpha-synuclein gene and mutant alpha-synuclein expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T alpha-synuclein (alpha-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if mutant human alpha-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single, sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the alpha-syn tg and ntg mice. In the olfactory bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the alpha-syn tg mice. In addition, we identified a significant increase in dopamine metabolism in the alpha-syn transgenic, but not ntg mice. Finally, MPTP treatment of alpha-syn tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with alpha-synuclein. Cumulatively, the data support the hypothesis that mutant alpha-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress. The alpha-syn tg line is therefore useful to study the genetic and environmental inter-relationship in PD.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Dopamine/metabolism , Neurons/drug effects , alpha-Synuclein/metabolism , Animals , Blotting, Western , Chromatography, High Pressure Liquid , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Mice , Mice, Transgenic , Mutation , Neurons/metabolism , alpha-Synuclein/genetics
10.
Neuropsychopharmacology ; 30(4): 649-56, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15688094

ABSTRACT

Traditional models of schizophrenia have focused primarily upon dopaminergic (DA) dysregulation. In contrast, more recent models focus on dysfunction of glutamatergic systems, acting particularly through N-methyl-D-aspartate (NMDA) receptors. NMDA receptors in brain are regulated by glycine, acting via a strychnine-insensitive regulatory site, and by glycine (GlyT1) transporters that maintain low glycine levels in the immediate vicinity of the NMDA receptor complex. The present study investigates the role of NMDA receptors in the modulation of striatal dopamine release in vitro, and of glycine transport inhibitors (GTIs) as potential psychotherapeutic agents in schizophrenia. In striatum, NMDA receptors exert dual excitatory/inhibitory effects, with inhibition reflecting activity of local GABAergic feedback regulation. We have previously demonstrated effectiveness of glycine in regulating [3H]DA release both in vivo and in vitro, consistent with its beneficial clinical effects. In the present study, similar effects were observed for the high-affinity GTI (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy-)propyl]sarcosine (NFPS), and for a range of high-affinity GTIs with appropriate rank order of potency. In addition, (+)NFPS significantly stimulated NMDA-induced [3H]GABA release. Effects, of GTIs, were blocked by the glycine-site antagonists L689,560 and HA-966, and the GABA(B) antagonists phaclofen and CGP 52432, confirming the roles of both the NMDA-associated glycine-site and presynaptic GABA(B) receptors in NMDA receptor-mediated regulation of striatal DA release in vitro. Endogenous DA hyperactivity is associated with prominent positive symptoms in schizophrenia. The present results are consistent with recent clinical studies showing significant effectiveness of glycine-site agonists and GTIs in reduction of persistent positive, as well as negative, symptoms in schizophrenia.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Biphenyl Compounds/pharmacology , Corpus Striatum/metabolism , Dopamine/metabolism , Glycine/metabolism , Presynaptic Terminals/metabolism , Sarcosine/analogs & derivatives , Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Animals , Corpus Striatum/drug effects , Excitatory Amino Acid Agonists/pharmacology , GABA Antagonists/pharmacology , GABA-B Receptor Antagonists , Glycine Plasma Membrane Transport Proteins , Mice , Mice, Inbred BALB C , N-Methylaspartate/pharmacology , Organ Culture Techniques , Presynaptic Terminals/drug effects , Receptors, GABA-B/metabolism , Receptors, Glycine/antagonists & inhibitors , Receptors, Glycine/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Sarcosine/pharmacology , Schizophrenia/drug therapy , Schizophrenia/metabolism , Schizophrenia/physiopathology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology
11.
Neurochem Res ; 29(7): 1391-8, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15202770

ABSTRACT

The effects of acute lorazepam challenges on plasma (p) HVA, MHPG, and 5-HIAA, and their relationship to drug-induced cognitive and motor deficits and the apolipoprotein (APOE)-epsilon4 allele were examined. Eighteen healthy elderly (8 epsilon4 carriers) received placebo or acute oral lorazepam doses (0.5 mg or 1 mg) in random sequence, 1-week apart. Cognitive assessment and plasma levels of pHVA, pMHPG, and p5-HIAA were determined at baseline and at 1, 2.5, and 5 h postchallenge. There was no drug-to-placebo difference in monoamine levels and no consistent relationship between changes in monoamine levels and cognitive performance, regardless of epsilon4 status. However, the 1.0 mg dose increased p5-HIAA in epsilon4 carriers, whereas it caused a reduction in noncarriers. Higher baseline pMHPG and p5-HIAA levels were associated with better baseline memory. The epsilon4 allele may modulate the effect of lorazepam on p5-HIAA, but further studies are needed to confirm this finding and elucidate its possible significance.


Subject(s)
Anti-Anxiety Agents/pharmacology , Apolipoproteins E/genetics , Apolipoproteins/genetics , Cognition Disorders/genetics , Cognition/physiology , Lorazepam/pharmacology , Motor Activity/physiology , Aged , Analysis of Variance , Apolipoprotein E4 , Apolipoproteins E/drug effects , Cognition/drug effects , Genotype , Homovanillic Acid/blood , Humans , Hydroxyindoleacetic Acid/blood , Lorazepam/blood , Lorazepam/pharmacokinetics , Methoxyhydroxyphenylglycol/blood , Middle Aged , Motor Activity/drug effects , Regression Analysis
12.
Neurochem Res ; 27(3): 253-61, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11958525

ABSTRACT

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D1: SCH 23390, D2: eticlopride), and NMDA glutamatergic (MK 801) and GABAB (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABAB (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D1 (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.


Subject(s)
Dopamine/metabolism , Nicotine/pharmacology , Nucleus Accumbens/physiology , Receptors, Neurotransmitter/physiology , Ventral Tegmental Area/physiology , Animals , Atropine/pharmacology , Benzazepines/pharmacology , Cocaine/pharmacology , Dizocilpine Maleate/pharmacology , Kinetics , Male , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/drug effects , Receptors, Dopamine/physiology , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/physiology , Receptors, Neurotransmitter/drug effects , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/physiology , Ventral Tegmental Area/drug effects
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