<P> ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise . Natural rewards, like drugs of abuse, induce ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression . Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward . Research on the interaction between natural and drug rewards suggests that psychostimulants and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess cross-sensitization effects that are mediated through ΔFosB . </P> <P> Similar to drug rewards, non-drug rewards also increase the level of extracellular dopamine in the NAcc shell . Drug - induced dopamine release in the NAcc shell and NAcc core is usually not prone to habituation (i.e., the development of drug tolerance: a decrease in dopamine release from future drug exposure as a result of repeated drug exposure); on the contrary, repeated exposure to drugs that induce dopamine release in the NAcc shell and core typically results in sensitization (i.e., the amount of dopamine that is released in the NAcc from future drug exposure increases as a result of repeated drug exposure). Sensitization of dopamine release in the NAcc shell following repeated drug exposure serves to strengthen stimulus - drug associations (i.e., classical conditioning that occurs when drug use is repeatedly paired with environmental stimuli) and these associations become less prone to extinction (i.e., "unlearning" these classically conditioned associations between drug use and environmental stimuli becomes more difficult). After repeated pairing, these classically conditioned environmental stimuli (e.g., contexts and objects that are frequently paired with drug use) often become drug cues which function as secondary reinforcers of drug use (i.e., once these associations are established, exposure to a paired environmental stimulus triggers a craving or desire to use the drug which they've become associated with). </P> <P> In contrast to drugs, the release of dopamine in the NAcc shell by many types of rewarding non-drug stimuli typically undergoes habituation following repeated exposure (i.e., the amount of dopamine that is released from future exposure to a rewarding non-drug stimulus normally decreases as a result of repeated exposure to that stimulus). </P> <Table> Summary of addiction - related plasticity <Tr> <Th> Form of neuroplasticity or behavioral plasticity </Th> <Th_colspan="6"> Type of reinforcer </Th> <Th> Sources </Th> </Tr> <Tr> <Th> Opiates </Th> <Th> Psychostimulants </Th> <Th> High fat or sugar food </Th> <Th> Sexual intercourse </Th> <Th> Physical exercise (aerobic) </Th> <Th> Environmental enrichment </Th> </Tr> <Tr> <Td> ΔFosB expression in nucleus accumbens D1 - type MSNs </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> </Td> </Tr> <Tr> <Th_colspan="8"> Behavioral plasticity </Th> </Tr> <Tr> <Td> Escalation of intake </Td> <Td> Yes </Td> <Td> Yes </Td> <Td> Yes </Td> <Td> </Td> <Td> </Td> <Td> </Td> <Td> </Td> </Tr> <Tr> <Td> Psychostimulant cross-sensitization </Td> <Td> Yes </Td> <Td> Not applicable </Td> <Td> Yes </Td> <Td> Yes </Td> <Td> Attenuated </Td> <Td> Attenuated </Td> <Td> </Td> </Tr> <Tr> <Td> Psychostimulant self - administration </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↓ </Td> <Td> </Td> <Td> ↓ </Td> <Td> ↓ </Td> <Td> </Td> </Tr> <Tr> <Td> Psychostimulant conditioned place preference </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> ↓ </Td> <Td> ↑ </Td> <Td> ↓ </Td> <Td> ↑ </Td> <Td> </Td> </Tr> <Tr> <Td> Reinstatement of drug - seeking behavior </Td> <Td> ↑ </Td> <Td> ↑ </Td> <Td> </Td> <Td> </Td> <Td> ↓ </Td> <Td> ↓ </Td> <Td> </Td> </Tr> <Tr> <Th_colspan="8"> Neurochemical plasticity </Th> </Tr> <Tr> <Td> CREB phosphorylation in the nucleus accumbens </Td> <Td> ↓ </Td> <Td> ↓ </Td> <Td> ↓ </Td> <Td> </Td> <Td> ↓ </Td> <Td> ↓ </Td> <Td> </Td> </Tr> <Tr> <Td> Sensitized dopamine response in the nucleus accumbens </Td> <Td> No </Td> <Td> Yes </Td> <Td> No </Td> <Td> Yes </Td> <Td> </Td> <Td> </Td> <Td> </Td> </Tr> <Tr> <Td> Altered striatal dopamine signaling </Td> <Td> ↓ DRD2, ↑ DRD3 </Td> <Td> ↑ DRD1, ↓ DRD2, ↑ DRD3 </Td> <Td> ↑ DRD1, ↓ DRD2, ↑ DRD3 </Td> <Td> </Td> <Td> ↑ DRD2 </Td> <Td> ↑ DRD2 </Td> <Td> </Td> </Tr> <Tr> <Td> Altered striatal opioid signaling </Td> <Td> No change or ↑ μ - opioid receptors </Td> <Td> ↑ μ - opioid receptors ↑ κ - opioid receptors </Td> <Td> ↑ μ - opioid receptors </Td> <Td> ↑ μ - opioid receptors </Td> <Td> No change </Td> <Td> No change </Td> <Td> </Td> </Tr> <Tr> <Td> Changes in striatal opioid peptides </Td> <Td> ↑ dynorphin No change: enkephalin </Td> <Td> ↑ dynorphin </Td> <Td> ↓ enkephalin </Td> <Td> </Td> <Td> ↑ dynorphin </Td> <Td> ↑ dynorphin </Td> <Td> </Td> </Tr> <Tr> <Th_colspan="8"> Mesocorticolimbic synaptic plasticity </Th> </Tr> <Tr> <Td> Number of dendrites in the nucleus accumbens </Td> <Td> ↓ </Td> <Td> ↑ </Td> <Td> </Td> <Td> ↑ </Td> <Td> </Td> <Td> </Td> <Td> </Td> </Tr> <Tr> <Td> Dendritic spine density in the nucleus accumbens </Td> <Td> ↓ </Td> <Td> ↑ </Td> <Td> </Td> <Td> ↑ </Td> <Td> </Td> <Td> </Td> <Td> </Td> </Tr> </Table>

Dopamine and drug addiction the nucleus accumbens shell connection