Neurocircuitry Targets in Ethanol Reward and Dependence

Abstract

Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol-sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA-A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin-releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.

Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol‐preferring and ‐nonpreferring rats

“…The largest number of differences was found in the nucleus accumbens, a structure that plays a key role in regulating alcohol intake [3,15]. The data suggest that there may be some basic differences in the mechanisms underlying synaptic transmission in the nucleus accumbens between the iP and iNP rats.…”

“…In addition, differences in γ-amino-n-butyric acid (GABA)-stimulated flunitrazepam binding were also observed in the hippocampus between the lines [14]. Because of the involvement of the nucleus accumbens in regulating alcohol intake [15], some of differences in the nucleus accumbens may be associated with the disparate alcohol drinking behaviors of these lines. Furthermore, the hippocampus is involved in the development of alcohol tolerance [16], and there are differences between the P and NP lines in the development of acute tolerance [17] and in the persistence of tolerance to a single dose of ethanol [18].…”

Excessive Ethanol Drinking Following a History of Dependence Animal Model of Allostasis

“…To date, there is evidence that changes in dopamine, GABA, endogenous opioids, glutamate and CRF may be associated with the transition from controlled alcohol use to alcohol dependence (Roberts and Koob 1997;Koob et al 1998). For example, CRF is increased in the amygdala during early ethanol withdrawal in rats (Merlo-Pich et al 1995) and the administration of CRF receptor antagonists into this brain region reverses the anxiety-like behaviors measured during early ethanol withdrawal (Rassnick et al 1993).…”

Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors

“…Ethanol dependence is a form of adaptive neuronal plasticity (13), and long-term administration of ethanol influences many neurotransmitter systems in the brain. However, the most specific and prominent changes are observed within several ligandgated ion channels, including excitatory NMDA and inhibitory GABA (A) receptors (4, 11, 40-43).…”