Adolescents Are More Vulnerable to Cocaine Addiction: Behavioral and Electrophysiological Evidence.

Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence.

J Neurosci. 2013 Mar 13; 33(11): 4913-22
Wong WC, Ford KA, Pagels NE, McCutcheon JE, Marinelli M

In humans, adolescence is a period of heightened propensity to develop cocaine addiction. It is unknown whether this is attributable to greater access and exposure to cocaine at this age, or whether the adolescent brain is particularly vulnerable to the addictive properties of cocaine. Here, we subjected male adolescent (P42) and adult (?P88) rats to a wide range of cocaine self-administration procedures. In addition, to determine whether behavioral differences are associated with developmental differences in dopaminergic activity, we examined and manipulated the activity of dopamine neurons. Relative to adults, adolescent rats took cocaine more readily, were more sensitive to lower doses, showed greater escalation of cocaine intake, and were less susceptible to increases in price (i.e., were more “inelastic”). In parallel, adolescents also showed elevated activity of ventral tegmental area dopamine neurons, a feature known to be associated with increased self-administration behavior. Pharmacological manipulation of dopamine D2 receptor function with quinpirole (agonist) or eticlopride (antagonist), to alter dopamine neuron activity, eliminated age differences in cocaine self-administration. These data suggest a causal relationship between behavioral and electrophysiological determinants of cocaine addiction liability. In conclusion, adolescents show behavioral and electrophysiological traits of heightened addiction liability. HubMed – addiction


Locomotor Sensitization to Ethanol Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Nucleus Accumbens and Increases Ethanol Self-Administration.

J Neurosci. 2013 Mar 13; 33(11): 4834-42
Abrahao KP, Ariwodola OJ, Butler TR, Rau AR, Skelly MJ, Carter E, Alexander NP, McCool BA, Souza-Formigoni ML, Weiner JL

Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. The specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In this study, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss Webster mice were treated daily with saline or 1.8 g/kg ethanol for 21 d. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least 11 d of withdrawal, cohorts of saline- or ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanol-sensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long-term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol. HubMed – addiction


Water by the spoonful: Children of addiction.

Can Fam Physician. 2013 Mar; 59(3): e141-2
Koren G

Question I just saw for the first time a 7-year-old boy with severe attention deficit hyperactivity disorder and oppositional defiant disorder. He came with his grandmother, who has been his guardian for the past 2 years. His mother is addicted to cocaine and is in rehabilitation. There is no paternal involvement. What is known about the long-term effects of being raised by parents with addictions? Answer Being raised by parents addicted to cocaine, other drugs, or alcohol confers high risk of neglect, physical and mental abuse, poverty, and a long list of psychological and psychiatric disorders. These children must be considered to be at very high risk and should be followed appropriately; both the children and their families must be supported. HubMed – addiction


Carnitine-Acyltransferase System Inhibition, Cancer Cell Death, and Prevention of Myc-Induced Lymphomagenesis.

J Natl Cancer Inst. 2013 Mar 13;
Pacilli A, Calienni M, Margarucci S, D’Apolito M, Petillo O, Rocchi L, Pasquinelli G, Nicolai R, Koverech A, Calvani M, Peluso G, Montanaro L

BackgroundThe metabolic alterations of cancer cells represent an opportunity for developing selective antineoplastic treatments. We investigated the therapeutic potential of ST1326, an inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid (FA) import into mitochondria.MethodsST1326 was tested on in vitro and in vivo models of Burkitt’s lymphoma, in which c-myc, which drives cellular demand for FA metabolism, is highly overexpressed. We performed assays to evaluate the effect of ST1326 on proliferation, FA oxidation, and FA mitochondrial channeling in Raji cells. The therapeutic efficacy of ST1326 was tested by treating Eµ-myc mice (control: n = 29; treatment: n = 24 per group), an established model of c-myc-mediated lymphomagenesis. Experiments were performed on spleen-derived c-myc-overexpressing B cells to clarify the role of c-myc in conferring sensitivity to ST1326. Survival was evaluated with Kaplan-Meier analyses. All statistical tests were two-sided.ResultsST1326 blocked both long- and short-chain FA oxidation and showed a strong cytotoxic effect on Burkitt’s lymphoma cells (on Raji cells at 72 hours: half maximal inhibitory concentration = 8.6 ?M). ST1326 treatment induced massive cytoplasmic lipid accumulation, impairment of proper mitochondrial FA channeling, and reduced availability of cytosolic acetyl coenzyme A, a fundamental substrate for de novo lipogenesis. Moreover, treatment with ST1326 in Eµ-myc transgenic mice prevented tumor formation (P = .01), by selectively impairing the growth of spleen-derived primary B cells overexpressing c-myc (wild-type cells + ST1326 vs Eµ-myc cells + ST1326: 99.75% vs 57.5%, difference = 42.25, 95% confidence interval of difference = 14% to 70%; P = .01).ConclusionsOur data indicate that it is possible to tackle c-myc-driven tumorigenesis by altering lipid metabolism and exploiting the neoplastic cell addiction to FA oxidation. HubMed – addiction