Environmental Enrichment and Drug Action. Fig. 1. Mean number of active lever responses for oral 10% ethanol across five consecutive 30-min sessions in EC, SC and IC rats using a two-lever operant conditioning procedure. There was a main effect of group, with EC rats self-administering significantly less ethanol than IC rats; SC rats did not differ significantly from the two other groups. There was no difference between EC and IC rats in the number of responses on the inactive lever (which had no programmed consequence), although the number of inactive responses was negligible (~2 responses per session-results not shown). (From Deehan et al. 2007.)

(0.03 mg/kg/infusion) on a ► continuous reinforcement schedule, EC rats self-administered less amphetamine than IC rats; there were no differences between EC and IC rats at higher unit doses. A separate group of rats was trained to lever press for amphetamine on a ► progressive ratio schedule in which the number of lever presses required to earn a drug infusion increased until the rats stopped responding (i.e., breakpoint). As shown in Fig. 2, the ► breakpoint was significantly lower for EC than IC rats at the low unit dose, but not at the higher unit dose. These results suggest that enrichment decreases the reinforcing effect of amphetamine, but only at low unit doses.

It is possible that the difference between EC and IC rats in amphetamine self-administration using low unit doses may reflect a difference in the rate of extinction or a difference in the ► reinstatement threshold. The rationale behind this possibility is that, at the beginning of each drug self-administration session, rats begin responding in a drug-free state. If a unit dose is too low, the responding may simply extinguish similar to what occurs when saline is substituted for drug. However, if several low dose infusions are earned in rapid succession, total drug intake may accumulate beyond some minimum threshold, thus engendering reliable responding within the session. Based on this notion, the decrease in amphetamine self-administration at a low unit dose in EC rats could represent either an accelerated rate of extinction within the session or an increase in the reinstatement threshold. A recent study using the reinstatement procedure found that EC rats extinguished responding faster than IC rats when amphetamine was replaced with saline (Stairs et al. 2006). When responding was reinstated following a noncontin-gent amphetamine priming injection, IC rats reinstated drug-seeking responses following a low dose prime, whereas EC rats only reinstated drug-seeking responses following a high dose prime. The higher reinstatement threshold in EC rats, taken together with a more rapid rate of extinction, may result in a loss of responding within the session, thus explaining the enrichment-induced reduction in drug intake.

Effects on Neurobiology Involved in Drug Action

Numerous studies have explored the neurobiological mechanisms that contribute to the ability of enrichment to decrease the reinforcing effect of drugs of abuse. Environmental enrichment increases thickness of the cortex, primarily by enlarging the size of neuronal cell bodies, increasing the density of dendritic spines and increasing the number of glial astrocytes. Metabolic activity is also enhanced, as revealed by an increase in the number of mitochondria and oxygenated capillary blood volume (Renner and Rosenzweig 1987). While these cellular changes also occur in subcortical regions such as the striatum, ► hippocampus, and ► nucleus accumbens, the ► prefrontal cortex appears to be especially sensitive to enrichment.

The ► medial prefrontal cortex (mPFC) has been implicated in the reinforcing effect of abused drugs, likely due to its inter-connections with limbic structures such as the anterior cingulate cortex and ► nucleus accumbens. Recent work has demonstrated that dopamine activity in mPFC is altered in EC rats compared to IC rats (Zhu et al. 2005). These investigators examined functional activity of the ► dopamine transporter (DAT). Compared to IC rats, EC rats have decreased DAT function as indexed by the velocity of uptake of [3H] dopamine uptake into mPFC tissue slices. Measurements of DAT protein expression revealed that EC rats have less DAT than IC rats at the cell surface. Additionally, a recent study has shown that EC rats display a reduction in postsynaptic dopamine D1 receptors in mPFC (Del Arco et al. 2007). The enrichment-induced reduction in pre- and postsynaptic dopa-minergic cellular processes in mPFC may reflect a compensatory decrease due to repeated stimulation of this cortical system by enriching stimulation.

Studies have shown that environmental enrichment also alters the neurochemical effects of various drugs of abuse. For example, when challenged with acute

Environmental Enrichment and Drug Action. Fig. 2. Mean number of amphetamine infusions earned by EC, SC and

IC rats on a PR schedule of reinforcement using a unit dose of either 0.03 mg/kg/infusion (left panel) or 0.1 mg/kg/infusion (right panel). Asterisk (*) represents a significant difference from IC rats tested at the same unit dose, p < 0.05. (From Bardo and Dwoskin 2004.)

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Anxiety and Depression 101

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