Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse.
A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. Although addictive properties of drugs of abuse are generally considered to be mediated by an increased release of dopamine in the ventral striatum, recent pharmacological and genetic experiments indicate an implication of alpha1b-adrenergic receptors in behavioral and rewarding responses to psychostimulants and opiates. Later on, it was shown that not only noradrenergic but also serotonergic systems, through 5-HT(2A) receptors, were controlling behavioral effects of drugs of abuse. More recently, experiments performed in animals knockout for alpha1b-adrenergic or 5-HT(2A) receptors indicated that noradrenergic and serotonergic neurons, besides their activating effects, inhibit each other by means of the stimulation of alpha1b-adrenergic and 5-HT(2A) receptors and that this mutual inhibition vanishes in wild type mice with repeated injections of psychostimulants, opiates or alcohol. Uncoupling induced by repeated treatments with drugs of abuse installs a stable sensitization of noradrenergic and serotonergic neurons, thus explaining an increased reactivity of dopaminergic neurons and behavioral sensitization. We propose that noradrenergic/serotonergic uncoupling is a common stable neurochemical consequence of repeated drugs of abuse which may also occur during chronic stressful situations and facilitate the onset of mental illness. Drug consumption would facilitate an artificial re-coupling of these neurons, thus bringing a temporary relief.
Institut National de la Santé et de la Recherche Médicale Unité 114, Centre National de la Recherche Scientifique UMR 7148, Collège de France 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France. jean-pol.tassin@college-de-france.fr
Jean-Pol
JP
Tassin
D000818:Animals; D001519:Behavior / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D019966:Substance-Related Disorders / Q000209:etiology*; D014026:Nicotiana; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D003511:Cyclohexanols; D013287:Illicit Drugs; D009294:Narcotics; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D010133:p-Chloroamphetamine; D009020:Morphine; D000069470:Venlafaxine Hydrochloride; D003913:Dextroamphetamine; D004298:Dopamine