Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction

Abstract

By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix MICROARRAY SUITE 4 and MICROARRAY SUITE 5, which use perfect-match-minus-mismatch models, and DCHIP and RMA, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy.release machinery ͉ ␦-catenin ͉ Glu receptor-interacting protein 2 ͉ PKC␥ ͉ fractalkine A current challenge for the neuroscience of drug addiction is to understand the molecular mechanisms responsible for the development of compulsive drug use (1). Such a transition is generally associated with a pattern of escalating drug use whereby consumption increases over time and becomes increasingly difficult to control. In the present study, we investigated gene expression changes associated with drug addiction by using an animal model that demonstrates escalation of cocaine intake. In this model, drug intake gradually escalates when daily access to the drug is increased to Ն6 h [long access (LgA)] (2, 3), whereas with only 1 h of access per day [short access (ShA)], drug intake remains low and stable over time. The difference in cocaine consumption between ShA and LgA animals has been hypothesized to model the difference drawn by clinicians between controlled and compulsive drug use (2, 3). This view is supported by recent results showing that escalation in cocaine intake in LgA animals is associated with an increased motivation to seek and to take cocaine and with a persistent downregulation of brain reward function when compared with ShA animals (3-5). Therefore, escalation of cocaine intake in LgA rats appears to replicate the behavioral and neuroadaptive changes assoc...

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…Additional support for the idea that incubation of drug craving involves early withdrawal neuroadaptations that decrease cue-induced drug seeking comes from cocaine studies in which the duration of the training session and number of training days were manipulated (Pacchioni et al, 2011;Sorge et al, 2005). These studies indicate that extended cocaine exposure, which presumably leads to more profound neuroadaptations (Ahmed et al, 2005;Ben-Shahar et al, 2009), does not increase cue-induced drug seeking during late withdrawal but instead decreases cocaine seeking during early withdrawal. This idea is also supported by recent molecular studies that have documented differential transcriptional and translational adaptations at early and late withdrawal times after methamphetamine self-administration in rats (Krasnova et al, 2013).…”

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite

“…As early as 1964, Wolf (38) showed that bilateral lesions in the lateral hypothalamus greatly reduced the drinking response to sodium deficiency, although he commented that such lesions might damage structures nearby (e.g., zona incerta and median forebrain bundle). Another study reported it as a brain subregion with particularly dynamic gene regulation in cocaineaddicted rats (39).…”

The incentive sensitization theory of addiction: some current issues

“…This is presumably because extended access facilitates greater drug intake than limited access, and produces greater corresponding changes in the brain responsible for addiction-like behaviour (Mantsch et al 2004;Ahmed et al 2005;Ferrario et al 2005;.…”