Involvement of neural substrates in reward and aversion to methamphetamine addiction: Testing the reward comparison hypothesis and the paradoxical effect hypothesis of abused drugs.

Clinical studies of drug addiction focus on the reward impact of abused drugs that produces compulsive drug-seeking behavior and drug dependence. However, a small amount of research has examined the opposite effect of aversion to abused drugs to balance the reward effect for drug taking. An aversive behavioral model of abused drugs in terms of conditioned taste aversion (CTA) was challenged by the reward comparison hypothesis (Grigson, 1997). To test the reward comparison hypothesis, the present study examined the rewarding or aversive neural substrates involved in methamphetamine-induced conditioned suppression. The behavioral data showed that methamphetamine induced conditioned suppression on conditioning and reacquisition but extinguished it on extinction. A higher level of stressful aversive corticosterone occurred on conditioning and reacquisition but not extinction. The c-Fos or p-ERK immunohistochemical activity showed that the cingulated cortex area 1 (Cg1), infralimbic cortex (IL), prelimbic cortex (PrL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) of the hippocampus were overexpressed in aversive CTA induced by methamphetamine. These data may indicate that the Cg1, IL, PrL, BLA, NAc, and DG probably mediated the paradoxical effect-reward and aversion. Altogether, our data conflicted with the reward comparison hypothesis, and methamphetamine may simultaneously induce the paradoxical effect of reward and aversion in the brain to support the paradoxical effect hypothesis of abused drugs. The present data implicate some insights for drug addiction in clinical aspects.

Dissociating effects of spatial learning from locomotor activity for ouabain-induced bipolar disorder-like rats.

Whether ouabain, a Na+ - and K+-activated adenosine triphosphatase inhibitor, mimics cognitive impairments that can be dissociated from motor effects in the bipolar disorder-like animal model remains unclear. Ouabain and the vehicle aCSF were microinjected into the left lateral ventricle immediately, after 4h, and after 24h. The results showed that (a) locomotion responses of the Immediate group were significantly decreased compared to those of the aCSF group, particularly the first five minutes. (b) The ouabain-treated rats have longer latency and total distance traveled in the water maze task; however, the velocity was not affected for the ouabain group. (c) The analysis of covariance showed that the latency time (but not the total distance traveled and velocity) of the ouabain group was more impaired than that of the aCSF group, regardless of omitting total distance traveled and cross movement in the open field test. The latency might be more sensitive than the distance traveled and the velocity for assessing spatial learning. Dissociating the spatial learning from the movement may allow testing drug treatments of cognitive deficits independent of locomotor effects associated with bipolar disorder.

Effects of lithium and carbamazepine on spatial learning and depressive behavior in a rat model of bipolar disorder induced by ouabain.

Lithium (LiCl) and carbamazepine (CBZ), the common mood stabilizers, are thought to be effective treatments for bipolar disorder. The aim of the present study was to investigate whether LiCl as well as CBZ has similar effects on the bipolar disorder-associated cognitive dysfunctions in rats, particularly the spatial learning and depressive responses. Adult male Wistar rats were administered intracerebroventricularly with 5µl of 10(-3)M ouabain on session 1, and then received an intraperitoneal injection of LiCl or CBZ for 4 sessions (1 session/2days). For the behavioral tests, all rats were subjected to the water maze 15min for spatial learning and the forced swimming test 5min for depression on each session. The present results showed that ouabain resulted in increased latency and longer distance traveled to reach the hidden platform in the water maze, indicating that ouabain impaired the spatial learning. However, ouabain did not affect swimming velocity in the water maze and depressive responses in the forced swimming test. LiCl treatment decreased the ouabain-enhanced latency and the total distance, but not the velocity, swam to reach the hidden platform in the water maze task. Additionally, LiCl did not result in changes of any depressive indices, such as struggling behavior, swimming behavior, and floating behavior. Likewise, CBZ did not affect any behavioral indices of spatial learning and depression. A linear regression analysis suggested that LiCl, but not CBZ, could predict the decreased latency and total distance traveled except the velocity of swimming in the water maze and depressive behaviors. In summary, the present results suggested that lithium provided a better therapeutic effect than CBZ for ouabain-caused dysfunctions of spatial learning in a rat model of bipolar disorder.