Effects of environmental enrichment on sensitivity to cocaine in female rats: importance of control rates of behavior.

Environmental enrichment produces functional changes in mesolimbic dopamine transmission and alters sensitivity to psychomotor stimulants. These manipulations also alter the control rate of many behaviors that are sensitive to stimulant administration, which can make comparison of drug effects between isolated and enriched subjects difficult. The purpose of this study was to examine the effects of environmental enrichment on control rates of behavior and on sensitivity to cocaine in tests of locomotor activity, drug self-administration, conditioned place preference, and toxicity. In the locomotor activity test, isolated rats exhibited greater activity after the administration of cocaine, but also had higher control rates of activity. When locomotor activity was expressed as a percentage of saline control values, enriched rats exhibited a greater increase relative to their own control than isolated rats. In the drug self-administration procedure, isolated rats had higher breakpoints on a progressive-ratio schedule of reinforcement when responding was maintained by cocaine; however, isolated rats also had higher breakpoints in saline substitution tests and higher rates of inactive lever responding. When the self-administration data were expressed as a percentage of these control values, enriched rats exhibited a greater increase in responding relative to their own control rates than isolated rats. No differences were observed between isolated and enriched rats under control conditions in the place preference and toxicity studies. In both of these procedures, enriched rats were more sensitive than isolated rats to all the doses of cocaine tested. These data emphasize the importance of considering control rates of behavior in studies examining environmental enrichment and drug sensitivity, and suggest that environmental enrichment increases sensitivity to cocaine across a range of dependent measures when differences in control rates of behavior are taken into account.

Chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.

The purpose of this study was to determine whether chronic exercise alters sensitivity to the conditioned rewarding effects of cocaine. Female rats were obtained at weaning and randomly assigned to either sedentary or exercise conditions. After 6 weeks under these conditions, the effects of cocaine were examined in the conditioned place preference procedure. Cocaine produced a dose-dependent conditioned place preference in both groups of rats. Exercising rats were more sensitive than sedentary rats to cocaine in this procedure, and this effect was most pronounced at the highest dose of cocaine. These data suggest that chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.

Effects of environmental enrichment on sensitivity to mu, kappa, and mixed-action opioids in female rats.

Several studies report that environmental enrichment enhances sensitivity to opioid receptor agonists in male rats. Very few studies have examined the effects of enrichment in female rats, and thus it is not clear whether females are similarly sensitive to these effects. Consequently, the purpose of the present study was to examine the effects of environmental enrichment on sensitivity to representative mu, kappa, and mixed-action opioids in female rats. Following a protocol established in males, females were obtained at weaning and randomly assigned to two groups immediately upon arrival: isolated rats were housed individually with no visual or tactile contact with other rats; enriched rats were housed in groups of four in large cages and given various novel objects on a regular basis. After 6 weeks under these conditions, the antinociceptive effects of mu (morphine, levorphanol), kappa (spiradoline, U69,593), and mixed-action (buprenorphine, butorphanol) opioids were examined in a warm-water, tail-withdrawal procedure. All the opioids examined produced dose-dependent increases in antinociception; however, no differences in opioid sensitivity were observed between the two groups. To determine whether these findings were consistent across behavioral endpoints, the antidiuretic effects of representative mu opioids, and the diuretic effects of representative kappa opioids, were examined in female rats reared under isolated or enriched conditions for 10 weeks. Similar to that seen in the antinociceptive experiment, no significant differences in opioid sensitivity were observed between groups. These data indicate that environmental enrichment does not alter sensitivity to the effects of opioid receptor agonists in female rats, and suggest that females may respond differently to environmental enrichment than males.

The motor-impairing effects of GABA(A) and GABA(B) agonists in gamma-hydroxybutyrate (GHB)-treated rats: cross-tolerance to baclofen but not flunitrazepam.

gamma-Hydroxybutyrate (GHB) is believed to function as a neurotransmitter in the mammalian brain by binding to a GHB-specific binding site. In addition, GHB may also indirectly enhance the neuroinhibitory actions of gamma-aminobutyric acid (GABA) by converting to GABA at neuronal synapses. The purpose of the present study was to examine the effects of representative GABA(A) and GABA(B) receptor agonists in rats treated chronically with GHB. Using a rotorod apparatus, the motor-impairing effects of GHB, the indirect GABA(A) receptor agonist, flunitrazepam, and the direct GABA(B) receptor agonist, baclofen, were examined before, during and after chronic treatment with 1000 mg/kg GHB, b.i.d. Prior to chronic treatment, all three drugs produced dose-dependent decreases in motor performance at low (8 rpm) and high (32 rpm) rotational speeds. Chronic treatment with GHB significantly decreased the potency of baclofen at both speeds, but did not alter the potency of either GHB or flunitrazepam. Following termination of chronic treatment, the potency of baclofen increased significantly at both speeds and returned to that observed prior to chronic treatment. These data indicate that chronic treatment with GHB confers tolerance to a GABA(B) receptor agonist under conditions in which tolerance is not conferred to a GABA(A) receptor agonist. These findings are consistent with the in vivo behavioral profile of GHB, which reveals a greater role for GABA(B) receptors than for GABA(A) receptors in its behavioral effects.