We studied the influence of cocaine use on the structure of neurons in brain regions that contribute to its rewarding effects by allowing rats to self-administer cocaine (0.33 mg/infusion) for 1 h a day for 1 month. Control animals were left undisturbed or allowed to work for food for the same period of time. After an additional 1 month drug-free period the brains were processed for Golgi-Cox staining. In rats that self-administered cocaine, but not rats that worked for food, there was a significant increase in dendritic branching and in the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal (but not occipital) cortex. There was also a 2.6-fold increase in the incidence of spines with multiple heads (branched spines) on medium spiny neurons. Finally, in the prefrontal cortex some of the apical dendrites of pyramidal cells appeared misshaped, having large bulbous structures on their terminal tips. We speculate that cocaine self-administration experience alters patterns of synaptic connectivity within limbocortical circuitry that is thought to contribute to cocaine's incentive motivational effects and may have neuropathological effects in frontal areas involved in decision making and judgment. Together, these two classes of drug-induced neuroadaptations may contribute to the development of addiction.

We studied the influence of cocaine use on the structure of neurons in brain regions that contribute to its rewarding effects by allowing rats to self-administer cocaine (0.33 mg/infusion) for 1 h a day for 1 month. Control animals were left undisturbed or allowed to work for food for the same period of time. After an additional 1 month drug-free period the brains were processed for Golgi-Cox staining. In rats that self-administered cocaine, but not rats that worked for food, there was a significant increase in dendritic branching and in the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal (but not occipital) cortex. There was also a 2.6-fold increase in the incidence of spines with multiple heads (branched spines) on medium spiny neurons. Finally, in the prefrontal cortex some of the apical dendrites of pyramidal cells appeared misshaped, having large bulbous structures on their terminal tips. We speculate that cocaine self-administration experience alters patterns of synaptic connectivity within limbocortical circuitry that is thought to contribute to cocaine's incentive motivational effects and may have neuropathological effects in frontal areas involved in decision making and judgment. Together, these two classes of drug-induced neuroadaptations may contribute to the development of addiction. Synapse 39:257-266, 2001.

Although the preferential activation of the prefrontal cortical (PFC) dopaminergic system is generally observed in stress, limited exceptions to this have been observed. Certain non-escape behaviors have been demonstrated to attenuate physiological indices of stress (e.g., coping or displacement responses). One well-characterized non-escape behavior observed in stress is chewing, or gnawing, of inedible objects. Engagement in this behavior attenuates stress-related activation of the hypothalamopituitary-adrenal axis, in a variety of species. We examined the degree to which engagement in this non-escape behavior modulates stressor-induced activation of the PFC dopamine (DA) system. Rats and mice were exposed to a brightly lit novel environment (novelty stress) in the presence or absence of inedible objects. Following novelty exposure, various dopaminergic terminal fields were collected and dopamine and its major catabolite, DOPAC, were measured using HPLC with electrochemical detection. DOPAC/DA ratios were calculated as an index of DA utilization. In some cases serotonin (5-HT) and its major catabolite, 5-HIAA, were also measured. In animals that did not chew, novelty exposure elicited significant increases in DOPAC/DA levels within PFC, nucleus accumbens (shell and core subdivisions), and striatum (relative to quiet-controls). DOPAC/DA responses were greater in the right PFC than in the left PFC. Animals that chewed displayed significantly lower DOPAC/DA responses in PFC, but not other dopaminergic terminal fields. This effect of chewing was always observed in the right PFC and less consistently in the left PFC. Chewing did not alter novelty-induced increases in PFC 5-HIAA/5-HT responses. Thus, engagement in this non-escape behavior elicits a neuroanatomically and neurochemically specific attenuation of the PFC DA response in stress. Given the pivotal role of the PFC in certain cognitive and affective processes, behavioral regulation of PFC DA utilization may modulate cognitive and/or affective function in stress.

Although the preferential activation of the prefrontal cortical (PFC) dopaminergic system is generally observed in stress, limited exceptions to this have been observed. Certain non-escape behaviors have been demonstrated to attenuate physiological indices of stress (e.g., coping or displacement responses). One well-characterized non-escape behavior observed in stress is chewing, or gnawing, of inedible objects. Engagement in this behavior attenuates stress-related activation of the hypothalamopituitary-adrenal axis, in a variety of species. We examined the degree to which engagement in this non-escape behavior modulates stressor-induced activation of the PFC dopamine (DA) system. Rats and mice were exposed to a brightly lit novel environment (novelty stress) in the presence or absence of inedible objects. Following novelty exposure, various dopaminergic terminal fields were collected and dopamine and its major catabolite, DOPAC, were measured using HPLC with electrochemical detection. DOPAC/DA ratios were calculated as an index of DA utilization. In some cases serotonin (5-HT) and its major catabolite, 5-HIAA, were also measured. In animals that did not chew, novelty exposure elicited significant increases in DOPAC/DA levels within PFC, nucleus accumbens (shell and core subdivisions), and striatum (relative to quiet-controls). DOPAC/DA responses were greater in the right PFC than in the left PFC. Animals that chewed displayed significantly lower DOPAC/DA responses in PFC, but not other dopaminergic terminal fields. This effect of chewing was always observed in the right PFC and less consistently in the left PFC. Chewing did not alter novelty-induced increases in PFC 5-HIAA/5-HT responses. Thus, engagement in this non-escape behavior elicits a neuroanatomically and neurochemically specific attenuation of the PFC DA response in stress. Given the pivotal role of the PFC in certain cognitive and affective processes, behavioral regulation of PFC DA utilization may modulate cognitive and/or affective function in stress.