Cocaine- and alcohol-mediated expression of inducible transcription factors is blocked by pentobarbital anesthesia.

Identifying the neurocircuitry involved in behavioral responses to drugs of abuse is an important step towards understanding the mechanisms of drug addiction. The present study sought to distinguish brain regions involved in pharmacological effects of cocaine and ethanol from secondary effects by administering these drugs in the presence or absence of pentobarbital anesthesia. Changes in neuronal activity were assessed by immunohistochemical analysis of expression of an inducible transcription factor (ITF), c-Fos, in the brain of rats habituated to repeated pentobarbital anesthesia or saline administration. Cocaine administration (15 mg/kg, i.v.) in non-anesthetized animals produced a strong induction of c-Fos in the striatum and large number of other brain areas. Ethanol administration (2 g/kg, i.p.) induced c-Fos in a smaller number of characteristic brain areas, including the central nucleus of amygdala and paraventricular nucleus of hypothalamus. However, neither of these drugs was able to induce c-Fos in pentobarbital-anesthetized rats (50 mg/kg, i.v.). The suppressive effects of pentobarbital were not specific to c-Fos, such that pentobarbital also suppressed expression of ITFs FosB and Egr1 in the striatum of cocaine-treated rats. On the other hand, pentobarbital by itself strongly induced c-Fos expression in the lateral habenula of saline-, cocaine-, and ethanol-injected rats. It is not clear whether the suppressive effects of anesthesia on ITF expression in other areas are mediated by activation of lateral habenula, or are independent of this event. Our data suggest that in the absence of conscious awareness of drug-associated cues, cocaine and alcohol activate only a fraction of the neural elements engaged in the unanesthetized state.

Self-administration of cocaine increases the release of acetylcholine to a greater extent than response-independent cocaine in the nucleus accumbens of rats.

RATIONALE: The neurochemical effects of psychostimulant exposure may depend on how these drugs are encountered. A useful method for examining this issue is to compare neurotransmitter release following response-dependent, or self-administered, drug exposure and response-independent exposure. OBJECTIVES: This experiment examined the effect of active and passive cocaine administration on acetylcholine (ACh) efflux in the shell region of the nucleus accumbens (NAc) in rats. METHODS: One group of rats (CSA: cocaine self-administration) was trained to lever-press for intravenous infusions of cocaine (0.42 mg/kg per infusion) on a fixed-ratio-1 schedule of reinforcement. Cocaine infusions were accompanied by the onset of a stimulus light that signaled a 20-s time-out period. Control rats received intravenous cocaine (cocaine non-contingent: CNC) or saline (SAL) in a manner that was not contingent upon their behavior. Drug infusions in these groups were determined by the lever-press behavior of the animals in the CSA group, i.e. they were yoked to rats in the self-administration group such that CNC animals received equal amounts of cocaine as CSA rats. Animals received cocaine or saline in 3-h sessions for 13 consecutive days before testing. On day 14, extracellular ACh was measured in 15-min intervals before, during and after a 3-h session of cocaine exposure using unilateral microdialysis probes located in the NAc shell coupled with HPLC. RESULTS: ACh efflux was significantly increased above baseline in both groups of rats that received cocaine but CSA rats had significantly higher ACh levels during the self-administration period compared to their yoked counterparts. In addition, ACh efflux remained elevated longer in CSA animals relative to CNC rats following cessation of cocaine exposure. CONCLUSIONS: These results demonstrate that ACh interneurons in the NAc shell are responsive to cocaine exposure. In addition, these findings suggest that the manner in which the drug is administered (i.e. either by active self-administration or passive exposure) may be relevant to the magnitude of the neural response.