Combined exposure to nicotine and ethanol in adolescent mice: effects on the central cholinergic systems during short and long term withdrawal.
Relapse to drug use is a major public health problem. In this sense, understanding the biological substrates that are affected during withdrawal may provide information to prevent relapse. Both smoking and alcoholic beverage consumption usually begin during adolescence, however, little is known about the basic neurobiology of the combined adolescent exposure, particularly during withdrawal. Since nicotine is a cholinergic agonist and it has been shown that ethanol interferes with nicotinic acetylcholine receptors (nAChRs), the current study focused on the effects of drug withdrawal on the central cholinergic system. From the 30th to the 45th postnatal day (PN), C57BL/6 male and female mice were exposed to nicotine free base (NIC) and/or ethanol (ETOH). Four groups were analyzed: (1) concomitant NIC (50 microg/ml in 2% saccharin to drink) and ETOH (25%, 2 g/kg i.p. injected every other day) exposure; (2) NIC exposure; (3) ETOH exposure; (4) vehicle. We assessed nAChR binding, choline acetyltransferase (ChAT) activity and [(3)H]hemicholinium-3 (HC-3) binding in the cerebral cortex and midbrain of mice at short (PN50) and long term (PN75) withdrawal. NIC and NIC+ETOH promoted nAChR upregulation during a short-term withdrawal. NIC short-term withdrawal elicited an increase in ChAT activity that was reversed by ETOH withdrawal. In addition, NIC+ETOH elicited a decrease in ChAT activity at long term withdrawal. Regarding HC-3, ETOH and NIC+ETOH promoted a decrease that persisted at long-term withdrawal. The present study provides experimental evidence that nicotine and ethanol during adolescence interact resulting in cholinergic system alterations during withdrawal.
Ribeiro-Carvalho
A
A
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. Prof. Manoel de Abreu 444, 5 andar, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil.
Lima
C S
CS
Medeiros
A H
AH
Siqueira
N R
NR
Filgueiras
C C
CC
Manhães
A C
AC
Abreu-Villaça
Y
Y
D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003367:Cotinine / Q000097:blood; D004326:Drinking / Q000187:drug effects; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000009:adverse effects / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D013997:Time Factors
D015415:Biomarkers; D026901:Membrane Transport Proteins; D011978:Receptors, Nicotinic; C065637:choline transporter; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol; D009538:Nicotine; D002795:Choline O-Acetyltransferase; D003367:Cotinine