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Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies.

Abstract

It is well known that cocaine's psychomotor stimulant properties derive from enhanced monoamines via synaptic transporter/reuptake inhibition and release mechanisms. However, to further understand mechanisms of action for cocaine, which may be receptor-related, ketanserin, a selective 5-HT(2A/2C) antagonist was used to ascertain a possible mediation for 5-HT(2A//2C) receptors in the monoamine and behavioral responses to cocaine. The studies were performed in the freely moving and behaving animal with In Vivo Microvoltammetry. Miniature carbon sensors, BRODERICK PROBE microelectrodes detected dopamine (DA) and serotonin (5-HT) concentrations in Nucleus Accumbens (NAcc) of male, Sprague-Dawley laboratory rats in separate signals and within seconds while at the same time, locomotor behavior was monitored with infrared photobeams. Synaptic release of each monoamine was detected because separate studies showed that the depolarization blocker, gamma-butyrolactone (gamma BL), decreased steady-state values [Pharmacol. Biochem. Behav. 40 (1991) 969]. Acute studies (Day 1) were performed; the animals received single injection of drug(s) in the faradaic behavioral chamber after a stable baseline during habituation behavior was achieved. After completion of the study, the animals were returned to their home cages. Subacute studies (Day 2) were also performed; these took place 24 h later in the faradaic behavioral chamber; same animal control was used and no further drug was administered. Day 2 data were compared to baseline (habituation data) on Day 1. Results showed that (1) Acute administration of Cocaine (10 mg/kg, i.p.) (N=5) increased DA and 5-HT release above baseline (p<0.001) while locomotion was also increased above baseline (p<0.001). (2) In Subacute studies in the cocaine group, when no further drug was administered, DA release decreased (p<0.001) and decreases in 5-HT release also occurred throughout the time course (p<0.05). Locomotor behavior increased above baseline and showed a trend toward statistical significance (p<0.07). (3) Acute administration of Ketanserin/Cocaine (3 mg/kg s.c. and 10 mg/kg i.p., respectively) (N=6) showed that ketanserin antagonized DA and 5-HT release (p<0.001), while locomotion was antagonized as well (p<0.001). (4) In Subacute studies, in the ketanserin/cocaine group, when no further drug was administered, DA decreased (p<0.001), but 5-HT increased (p<0.001), while locomotor activity increased above baseline and a trend toward statistical significance was seen (p<0.07). Additional saline controls were without effect (p>0.05). In summary, Acute studies showed that cocaine produced its psychostimulant responses on monoamines and behavior and ketanserin antagonized these responses, likely via a 5-HT(2A/2C) receptor mediation. Presynaptic and postsynaptic responses were not distinguished, suggesting, in addition, a role for 5-HT-ergic modulation of DA, likely DA(2) postsynaptic modulation Subacute cocaine studies showed that on Day 2, deficiencies in monoamines occurred, reflecting cocaine withdrawal mechanisms neurochemically, while locomotor behavior did not show such dramatic deficiencies. Indeed, behavior increased above baseline. Moreover, ketanserin reversed 5-HT-related and not DA-related cocaine monoamine responses, while locomotion continued to be insignificantly increased above baseline as was seen in the Subacute cocaine group. The data suggest that presynaptic 5-HT(2A/2C) receptor mechanisms may be important during withdrawal from single injection of cocaine.

Authors+Show Affiliations

Department of Physiology and Pharmacology, CUNY Medical School, New York, NY 10031, USA. drpabroderick@cs.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15093963

Citation

Broderick, Patricia A., et al. "Cocaine Acts On Accumbens Monoamines and Locomotor Behavior Via a 5-HT2A/2C Receptor Mechanism as Shown By Ketanserin: 24-h Follow-up Studies." Progress in Neuro-psychopharmacology & Biological Psychiatry, vol. 28, no. 3, 2004, pp. 547-57.
Broderick PA, Olabisi OA, Rahni DN, et al. Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):547-57.
Broderick, P. A., Olabisi, O. A., Rahni, D. N., & Zhou, Y. (2004). Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies. Progress in Neuro-psychopharmacology & Biological Psychiatry, 28(3), 547-57.
Broderick PA, et al. Cocaine Acts On Accumbens Monoamines and Locomotor Behavior Via a 5-HT2A/2C Receptor Mechanism as Shown By Ketanserin: 24-h Follow-up Studies. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):547-57. PubMed PMID: 15093963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies. AU - Broderick,Patricia A, AU - Olabisi,Opeyemi A, AU - Rahni,David N, AU - Zhou,Yueping, PY - 2004/01/30/accepted PY - 2004/4/20/pubmed PY - 2004/6/18/medline PY - 2004/4/20/entrez SP - 547 EP - 57 JF - Progress in neuro-psychopharmacology & biological psychiatry JO - Prog. Neuropsychopharmacol. Biol. Psychiatry VL - 28 IS - 3 N2 - It is well known that cocaine's psychomotor stimulant properties derive from enhanced monoamines via synaptic transporter/reuptake inhibition and release mechanisms. However, to further understand mechanisms of action for cocaine, which may be receptor-related, ketanserin, a selective 5-HT(2A/2C) antagonist was used to ascertain a possible mediation for 5-HT(2A//2C) receptors in the monoamine and behavioral responses to cocaine. The studies were performed in the freely moving and behaving animal with In Vivo Microvoltammetry. Miniature carbon sensors, BRODERICK PROBE microelectrodes detected dopamine (DA) and serotonin (5-HT) concentrations in Nucleus Accumbens (NAcc) of male, Sprague-Dawley laboratory rats in separate signals and within seconds while at the same time, locomotor behavior was monitored with infrared photobeams. Synaptic release of each monoamine was detected because separate studies showed that the depolarization blocker, gamma-butyrolactone (gamma BL), decreased steady-state values [Pharmacol. Biochem. Behav. 40 (1991) 969]. Acute studies (Day 1) were performed; the animals received single injection of drug(s) in the faradaic behavioral chamber after a stable baseline during habituation behavior was achieved. After completion of the study, the animals were returned to their home cages. Subacute studies (Day 2) were also performed; these took place 24 h later in the faradaic behavioral chamber; same animal control was used and no further drug was administered. Day 2 data were compared to baseline (habituation data) on Day 1. Results showed that (1) Acute administration of Cocaine (10 mg/kg, i.p.) (N=5) increased DA and 5-HT release above baseline (p<0.001) while locomotion was also increased above baseline (p<0.001). (2) In Subacute studies in the cocaine group, when no further drug was administered, DA release decreased (p<0.001) and decreases in 5-HT release also occurred throughout the time course (p<0.05). Locomotor behavior increased above baseline and showed a trend toward statistical significance (p<0.07). (3) Acute administration of Ketanserin/Cocaine (3 mg/kg s.c. and 10 mg/kg i.p., respectively) (N=6) showed that ketanserin antagonized DA and 5-HT release (p<0.001), while locomotion was antagonized as well (p<0.001). (4) In Subacute studies, in the ketanserin/cocaine group, when no further drug was administered, DA decreased (p<0.001), but 5-HT increased (p<0.001), while locomotor activity increased above baseline and a trend toward statistical significance was seen (p<0.07). Additional saline controls were without effect (p>0.05). In summary, Acute studies showed that cocaine produced its psychostimulant responses on monoamines and behavior and ketanserin antagonized these responses, likely via a 5-HT(2A/2C) receptor mediation. Presynaptic and postsynaptic responses were not distinguished, suggesting, in addition, a role for 5-HT-ergic modulation of DA, likely DA(2) postsynaptic modulation Subacute cocaine studies showed that on Day 2, deficiencies in monoamines occurred, reflecting cocaine withdrawal mechanisms neurochemically, while locomotor behavior did not show such dramatic deficiencies. Indeed, behavior increased above baseline. Moreover, ketanserin reversed 5-HT-related and not DA-related cocaine monoamine responses, while locomotion continued to be insignificantly increased above baseline as was seen in the Subacute cocaine group. The data suggest that presynaptic 5-HT(2A/2C) receptor mechanisms may be important during withdrawal from single injection of cocaine. SN - 0278-5846 UR - https://www.unboundmedicine.com/medline/citation/15093963/Cocaine_acts_on_accumbens_monoamines_and_locomotor_behavior_via_a_5_HT2A/2C_receptor_mechanism_as_shown_by_ketanserin:_24_h_follow_up_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-5846(04)00024-7 DB - PRIME DP - Unbound Medicine ER -