Pretreatment with serotonin 5-HT3 receptor antagonists produces no observable blockade of long-term motor sensitization to cocaine in rats

Szumlinski, Karen K.; Frys, Kelly; Kalivas, Peter W.

doi:10.1007/s00213-002-1274-0

Cited by 18 publications

(19 citation statements)

References 41 publications

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“…Despite the dense innervation of the ventral tegmental area by the MRN (Vertes et al, 1999), the facilitation of cocaine-induced behavioral sensitization produced by DPAT into the MRN occurred in the absence of any DPAT effect upon the cocaine-sensitized increase in accumbens dopamine. This observation is consistent with a more critical role for mesoaccumbens dopamine transmission in the expression, rather than in the development, of cocaine-induced behavioral sensitization (eg, Mattingly et al, 1994;White et al, 1998;Szumlinski et al, 2003). Similar to the sensitization-like increase in the motor response to the first cocaine injection that was produced by intra-DRN pretreatment with DPAT, these MRN data pose enhanced glutamate transmission in the accumbens as a contributing factor mediating the potentiated behavioral sensitization produced by daily intra-MRN administration of DPAT with cocaine.…”

Section: Serotonin Projections From the Mrn Regulate The Development supporting

confidence: 60%

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

Szumlinski

Frys

Kalivas

2004

Neuropsychopharmacol

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A distinct role for serotonin transmission from the dorsal and median raphé nuclei (DRN and MRN, respectively) was identified in regulating the behavioral and neurochemical effects of acute and repeated cocaine administration. Serotonin 1A (5-hydroxytryptophan (5-HT)1A) receptors were stimulated by intraraphé microinjection of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT; 5 or 10 mg) and behavior, as well as extracellular neurotransmitter content in the nucleus accumbens was measured. Pretreatment of the DRN with DPAT caused a sensitization-like potentiation of acute cocaine-induced motor activity and an elevation in extracellular dopamine and glutamate. In contrast, DPAT microinjection into the MRN did not alter acute cocaine-induced motor activity or extracellular levels of dopamine or glutamate. Acutely, DPAT microinjection into either raphé nucleus reduced the basal and acute cocaine-stimulated levels of extracellular serotonin. Pretreatment with DPAT before systemic cocaine administration was continued for 5 days, and 3 weeks after the last injection, all rats were administered a cocaine challenge injection. The sensitized behavioral and neurochemical response produced by repeated cocaine in control subjects was unaffected by the intra-DRN administration of DPAT. However, in animals administered DPAT into the MRN, both the sensitized motor response and the increase in glutamate were augmented, while the sensitized serotonin response was blocked, without altering dopamine sensitization. These data show a differential role for 5-HT1A receptors in the DRN and MRN in the acute and sensitized effects of cocaine. While the DRN is involved in the acute effects of cocaine, neuroadaptations in the MRN may regulate the long-term consequences of repeated cocaine exposure.

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Section: Serotonin Projections From the Mrn Regulate The Development supporting

confidence: 60%

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

Szumlinski

Frys

Kalivas

2004

Neuropsychopharmacol

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“…Thus, under isoflurane anesthesia (4% for induction; 1.5–2.5% for maintenance), microinjector guide cannulae (26 gauge, 20 mm; Plastics One, Roanoke VA) were implanted bilaterally 2 mm over the NAC shell for animals slated for the behavioral experiments, and microdialysis guide cannulae (20 gauge, 20 mm, Plastics One) were implanted bilaterally 3 mm over the NAC shell for the neurochemical experiments using the following coordinates: AP, +1.1 mm; ML, ±2.5 mm; DV for behavior, −5.7 mm; DV for microdialysis, −4.7 mm; 6° angle from vertical (e.g., Szumlinski et al 2003, 2004). The coordinates were based on the rat brain atlas of Paxinos and Watson (2000).…”

Section: Methodsmentioning

confidence: 99%

“…Animals then received seven, once daily, injections of either saline or cocaine (days 1 and 7, 15 mg/kg; days 2–6, 30 mg/kg), using a repeated treatment regimen demonstrated previously to elicit robust long-term sensitization in rats (e.g., Szumlinski et al 2003, 2004). On injections 1 and 7, the locomotor activity of the animals was monitored for 2 h, while on injections 2–6, animals were returned to their home cages following injection.…”

Section: Methodsmentioning

confidence: 99%

“…A comparison of the total distance traveled from injections 1 to 7 of repeated treatment served to index the extent of locomotor habituation and locomotor sensitization exhibited respectively by repeated saline- and cocaine-treated animals (data not shown). A 2-h test for behavioral sensitization was conducted 3 weeks later (Szumlinski et al 2003, 2004), in which the effects of an intra-NAC infusion of 0, 50, 100, or 500 nM MDL 100907 or SB 242084 were assessed upon the capacity of a 15-mg/kg cocaine challenge injection to elicit locomotor activity. Assignment of rats to their intra-NAC pretreatments was such that each repeated saline and repeated cocaine group exhibited equivalent locomotor behavior prior to the test for sensitization (i.e., based on the change in locomotor activity from injections 1 to 7 of repeated treatment).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2010

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RationaleThe serotonin 5-HT2A and 5-HT2C 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.ObjectivesIn the present study, we tested the hypothesis that NAC 5-HT2A and 5-HT2C 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.).MethodsThe effects of intra-NAC infusions of the 5-HT2A antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500 nM) or the 5-HT2C 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.ResultsAlthough 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.ConclusionsThese data provide the first evidence that NAC 5-HT2A and 5-HT2C 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.

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“…Similarly, MDL72222 reduced methamphetamine-induced sensitization of its hyperactivating effects in mice [215]. However, in other work, although administration of 5-HT3 receptor antagonists partially blocked the acute locomotor activating effects of cocaine, the 5-HT3 antagonists did not block sensitization of cocaine-induced hyperlocomotion in rats [216a]. …”

Section: 5-ht3 Receptors In Animal Models Of Addictionmentioning

confidence: 99%

The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy

Engleman¹,

Rodd²,

Bell

et al. 2008

CNSNDDT

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Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5-HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5-HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol-associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5-HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.

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Pretreatment with serotonin 5-HT3 receptor antagonists produces no observable blockade of long-term motor sensitization to cocaine in rats

Cited by 18 publications

References 41 publications

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

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

The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy

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