Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.
Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life.
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Maurício
M
dos Santos Pereira
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Matheus Figueiredo
MF
Sathler
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Thais da Rosa
Tda R
Valli
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Richard Souza
RS
Marques
Laboratório de Neuroquímica, Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Ana Lucia Marques
AL
Ventura
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Ney Ronner
NR
Peccinalli
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Mabel Carneiro
MC
Fraga
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Alex C
AC
Manhães
Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, RJ, Brazil.
Regina
R
Kubrusly
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism; D001692:Biological Transport; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017447:Receptors, Dopamine D1 / Q000378:metabolism
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D008774:Methylphenidate; D000242:Cyclic AMP; D003042:Cocaine; D004298:Dopamine