Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

Zayara, Avi E.; McIver, Gregor; Valdivia, Paola N.; Lominac, Kevin D.; McCreary, Andrew C; Szumlinski, Karen K.

doi:10.1007/s00213-010-1996-3

ScienceOpen: research and publishing network

For Publishers

For Researchers

Blog
About

Search
Advanced search

views

recommends

Record: found
Abstract: found
Article: not found

Blockade of nucleus accumbens 5-HT _2A and 5-HT _2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

research-article

Author(s): Avi E. Zayara ¹ , Gregor McIver ¹ , Paola N. Valdivia ¹ , Kevin D. Lominac ¹ , Andrew C. McCreary ² , Karen K. Szumlinski ¹ ^, ³ ^,

Publication date (Electronic): 3 September 2010

Journal: Psychopharmacology

Publisher: Springer-Verlag

Keywords: 5-HT2A receptor, 5-HT2C receptor, Cocaine, Sensitization, Glutamate, Dopamine, Nucleus accumbens, Addiction, Psychosis

Read this article at

ScienceOpenPublisher PMC

Bookmark

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Rationale

The serotonin 5-HT _2A and 5-HT _2C receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine’s addictive and psychotogenic properties.

Objectives

In the present study, we tested the hypothesis that NAC 5-HT _2A and 5-HT _2C receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days 1 and 7, 15 mg/kg; days 2–6, 30 mg/kg, i.p.).

Methods

The effects of intra-NAC infusions of the 5-HT _2A antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500 nM) or the 5-HT _2C antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500 nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100 nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC.

Results

Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization.

Conclusions

These data provide the first evidence that NAC 5-HT _2A and 5-HT _2C receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.

Related collections

Most cited references 70

Record: found
Abstract: found
Article: not found

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies.

L. J. M. J. Vanderschuren, P Kalivas (2000)

Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and mu-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

0 comments Cited 157 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Atypical antipsychotics: mechanism of action.

Philip Seeman (2002)

Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs. This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.

0 comments Cited 134 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The psychology and neurobiology of addiction: an incentive-sensitization view.

Philip C. Robinson, Kent C. Berridge (2000)

The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentive-sensitization theory of addiction", which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.

0 comments Cited 92 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

: +1-805-8936124 , +1-805-8934303 , szumlinski@psych.ucsb.edu

Journal

Journal ID (nlm-ta): Psychopharmacology (Berl)

Title: Psychopharmacology

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 0033-3158

ISSN (Electronic): 1432-2072

Publication date (Electronic): 3 September 2010

Publication date PMC-release: 3 September 2010

Publication date (Print): February 2011

Volume: 213

Issue: 2-3

Pages: 321-335

Affiliations

[1 ]Department of Psychology and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660 USA

[2 ]Solvay Pharmaceuticals Research Laboratories, CJ van Houtenlaan 36, 1380 DA Weesp, The Netherlands

[3 ]Department of Psychology, University of California at Santa Barbara, Santa Barbara, CA 93106-9660 USA

Article

Publisher ID: 1996

DOI: 10.1007/s00213-010-1996-3

PMC ID: 3032203

PubMed ID: 20814782

SO-VID: 4e884fda-adea-461e-aec8-d3c223c970f7

History

Date received : 26 January 2010

Date accepted : 8 June 2010

Custom metadata

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: 5-ht2a receptor,5-ht2c receptor,addiction,cocaine,glutamate,psychosis,dopamine,nucleus accumbens,sensitization

Data availability:

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: 5-ht2a receptor, 5-ht2c receptor, addiction, cocaine, glutamate, psychosis, dopamine, nucleus accumbens, sensitization