Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction

Abstract

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions.

3d Synaptic Organization of the Rat Ca1 and Alterations Induced by Cocaine Self-Administration

“…Thus, electron microscopy with serial section reconstruction is the gold standard method for studying the normal synaptic organization and its possible alterations. Here, we used Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) technology to perform a three-dimensional (3D) analysis of the synaptic organization in the neuropil in the stratum radiatum of the CA1 region of Lewis rats -an inbred rat strain that is prone to the reinforcing effects of drugs of abuse 26 . This hippocampal layer receives most afferents from the Schaffer collaterals of the CA3 pyramidal neurons -a synaptic connection that has a key role in the learning-induced synaptic potentiation of the hippocampus 27 .…”

Reduced Levels of mGlu2 Receptors within the Prelimbic Cortex Are Not Associated with Elevated Glutamate Transmission or High Alcohol Drinking

“…A previous study indicated that basal extracellular glutamate levels within the PFC and NAC were lower in Lewis than Fischer 344 rats (Selim and Bradberry, ). EtOH has been shown to be more reinforcing in Lewis than Fischer 344 rats, and Lewis rats self‐administer more EtOH than Fischer 344 rats (Cadoni, ). These findings, along with the current results, suggest that extracellular glutamate levels may be associated with alcohol self‐administration and drinking.…”

Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor‐mediated signaling in roman high‐ and roman low‐avoidance rats

“…These neuroadaptations are hypothesized to underlie the development and maintenance of drug dependence and to contribute to relapse to drug seeking (Koob & Le Moal, ; Nestler, ). However, the behavioral, structural and neurochemical effects of drugs appear not only to be determined by the pharmacological properties of the drug itself, but to be also influenced by nonpharmacological factors, such as genetic susceptibility and environmental factors, (Cadoni, ; Giorgi, Piras, Lecca, & Corda, ), which play a pivotal role in modulating neuroadaptive responses to chronic drug use. Supporting this idea, many studies in different rodent strains have reported the existence of between‐strain differences in the sensitivity and in the response to drugs such as cocaine (Orsini, Bonito‐Oliva, Conversi, & Cabib, ), ethanol (Rose, Calipari, Mathews, & Jones, ), opiates (Kirkpatrick & Bryant, ), and nicotine (Freund & Wehner, ).…”