Conditioned place preference

It has been reported that dopamine D3 receptor (D3R) knockout mice display similar ethanol (EtOH) consumption compared to wild types. In addition, studies with D3R pharmacological targeting were inconclusive. In the current study, we used both gain- and loss-of-function approaches to test the effects of central D3R manipulation on voluntary alcohol intake and EtOH-induced conditioned place preference (CPP) in rats. To this aim, we developed a lentiviral-mediated gene transfer approach to examine whether D3R knockdown (LV-siD3R) or overexpression (LV-D3R) in the nucleus accumbens (NAcc) is sufficient to modulate voluntary alcohol consumption and EtOH-CPP. Using the standard 2-bottle choice drinking paradigm and an unbiased CPP procedure, our results indicated that, like the D3R selective antagonist SB-277011-A, LV-siD3R attenuated voluntary alcohol consumption. In contrast, LV-D3R increased EtOH intake with no effect on total fluid intake. Similarly, the D3R agonist 7-OH-DPAT also ex...

Introduction: This study investigated the effect of the environmental enrichment during
adolescence on morphine-induced Conditioned Place Preference (CPP) and locomotor
sensitization in maternally separated male and female rat pups.
Methods: Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were
separated from them 3 hours per day during 2–14 days postnatal. All pups were weaned at 21
Postnatal Day (PND) and reared in standard environment or enriched environment from 21 to
50 PND with litter-mates of the same sex. The CPP and behavioral sensitization to morphine
were assessed by an unbiased place conditioning paradigm and open filed method.
Results: The results showed that the maternal separation enhanced morphine-induced CPP
in both sexes, locomotor sensitization in male pups and tolerance to morphine-induced motor
activity in female pups during adolescence. While, male and female pups reared in an EE
exhibited a decrease in morphine-induced CPP, locomotor sensitization and tolerance induced
by maternal separation compared to their control pups.
Conclusion: Access to enriched environment during adolescence may have a protective effect
against morphine-induced reward, locomotor sensitization and tolerance in adolescent male
and female rats following maternal separation.

Orexinergic projection originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) has an important role in the acquisition of morphine conditioned place preference (CPP). However, little if any is known about the function and/or effect of orexin on CPP in rats. In the present study, we investigated the direct effect of orexinergic neurons on acquisition of CPP by chemical stimulation of LH and involvement of orexin-A and CB1 receptors within the VTA in development of reward-related behaviors. 129 adult male albino Wistar rats weighing 220–320 g were unilaterally implanted by two separate cannulae into the LH and VTA. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that unilateral intra-LH administration of carbachol (62.5, 125 and 250 nmol/0.5 μl saline) as a cholinergic agonist, during conditioning phase, induced CPP in a dose-dependent manner. The maximal effect was shown at the dose of 250 nmol (P < 0.001) compared to vehicle (saline) group. However, intra-VTA administration of SB334867 as a selective orexin-A receptor antagonist (0.1, 1 and 10 nmol/0.3 μl DMSO) and AM251 (5, 25 and 125 nmol/0.3 μl DMSO) as a CB1 receptor antagonist, just 5 min before carbachol during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP in the rats. It is supposed that the orexinergic projection from LH to VTA is involved in LH chemical stimulation-induced CPP and orexin-A receptor in the VTA has a substantial role in this phenomenon. Our findings also suggest the existence of cross-talk between cannabinoid and orexinergic systems within the VTA in conditioned place preference paradigm.▶ Chemical stimulation of the lateral hypothalamus (LH) produced conditioned place preference in the rats. ▶ Administration of OX1 receptor antagonist in the VTA inhibited the development of LH stimulation-induced conditioned place preference. ▶ It seems that stimulation of LH orexinergic neurons could directly induce the reward-related behaviors in part, via excitation of VTA neurons in the rats. ▶ Intra-VTA administration of CB1 receptor antagonist could inhibit conditioned place preference similar to OX1 receptor antagonist. ▶ It seems that OX1 receptor and CB1 receptor have a common pathway in reward-related behaviors processing in animal models.

Endomorphin-1 (EM-1) is a recently isolated endogenous peptide having potent analgesic activity and high affinity and selectivity for the mu-opioid receptor. The present study was designed to investigate the rewarding and psychomotor stimulant effects of EM-1 in specific brain regions. We found that rats would learn without priming or response shaping to lever-press for microinjections of EM-1 into the ventral tegmental area (VTA); responding was most vigorous for high-dose injections into the posterior VTA. Rats did not learn to lever-press for microinjections of EM-1 into the nucleus accumbens (NAS) or regions just dorsal to the VTA. Lever-pressing for EM-1 in the VTA was extinguished when vehicle was substituted for the peptide and was reinstated when EM-1 reinforcement was re-established. Conditioned place preference was established by EM-1 injections into the posterior but not the anterior VTA or the NAS. Injection of EM-1 (0.1-1.0 nmol) into the posterior VTA induced robust in...

The mesolimbic dopaminergic system that projects from the ventral tegmental area (VTA) to the nucleus accumbens is critical for initiation of opioid reinforcement and reward-related effects of drugs of abuse. In the present study, the effects of reversible inactivation of VTA on acquisition and expression of morphine-induced conditioned place preference (CPP) were investigated in rats. One hundred and eighty-one adult male albino Wistar rats were used in these experiments. Reversible inactivation of VTA was done through the unilateral and bilateral intra-VTA microinjection of 2% lidocaine during the acquisition and expression of morphine (5 mg/kg; s.c.)-induced CPP. Animal displacement, conditioning score and locomotor activity were recorded by Ethovision software. The results showed that bilateral but not unilateral intra-VTA administration of lidocaine significantly decreases the acquisition (P < 0.01) and expression (P < 0.05) of morphine-induced CPP compared to their respective saline-microinjected groups. Moreover, intra-VTA administration of lidocaine had no effect on locomotor activity in these experiments. Our results further support the idea that VTA may play an important role in the acquisition of morphine-induced CPP. In addition, there is no functional lateralization in the VTA for acquisition and/or expression of morphine-induced CPP in the rat.

Experimental evidence indicates that chemical stimulation of lateral hypothalamus (LH) by carbachol can produce conditioned place preference (CPP) in rats. Several lines of evidence have shown that cAMP-response element binding protein (CREB), extracellular signal-regulated kinase (ERK), and c-fos have pivotal role in CPP induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated-CREB (p-CREB) and -ERK (p-ERK), and c-fos induction within ventral tegmental area (VTA), hippocampus and prefrontal cortex (PFC) after the acquisition of CPP induced by intra-LH administration of carbachol. Animals were unilaterally implanted by cannula into LH. For chemical stimulation of LH, carbachol (250 nmol/0.5 μl saline) was microinjected once each day, during 3-day conditioning phase (acquisition period) of CPP paradigm. After the acquisition period, the brains were removed, and p-CREB and p-ERK, and c-fos induction in the ipsilateral VTA, hippocampus and PFC were measured by Western blot analysis. The results indicated a significant increase in level of phosphorylated CREB (P < 0.01) in VTA, and PFC (P < 0.05), during LH stimulation-induced CPP, while its level decreased in hippocampus (P < 0.05). Also, in aforementioned regions, an increase in c-fos level was observed, but this enhancement in PFC was not significant. Moreover, p-ERK changed in these areas, but not significantly. Our findings suggest that studying the intracellular signals and their changes, such as phosphorylated-CREB, can elucidate a functional relationship between LH and other brain structures involved in reward processing in rats.► p-CREB in the VTA and PFC significantly increased after LH stimulation-induced CPP. ► LH stimulation-induced CPP could decrease CREB phosphorylation in the hippocampus. ► There was no significant change in p-ERK after CPP in the VTA, hippocampus and PFC. ► After LH stimulation-induced CPP, c-fos induction increased in these three regions.

Recent evidence suggests that a variety of molecule products play critical roles in the transitions from recreational drug use to drug abuse, and then to drug dependence. Elucidation of the roles of specific molecules in the development of drug dependence can come from preclinical animal models and/or from clinical data. Among animal models, behavioral sensitization, conditioned place preference, drug discrimination, drug self-administration, and extensions of these basic procedures have been widely used to identify molecule products that might be involved in psychostimulant dependence. Repeated exposure to psychostimulants causes cellular adaptations in specific neuronal populations that are likely to contribute to dependence in some humans. In animal models, molecules that include shati, piccolo, tumor necrosis factor-alpha, and glial cell line-derived neurotrophic factor can act as antiaddictive factors. In some of these models, other molecules including matrix metalloproteinase and tissue plasminogen activator can act as proaddictive factors. We review evidence that the balance between levels of anti- and proaddictive factors induced by addictive drugs could play important roles in developing drug dependence. We focus on potential risk molecules in animal models for the development of methamphetamine dependence and their relevance to abusers. We propose that dynamic changes in the balance between levels of antiaddictive and proaddictive factors in the brain provide some of the determinants of susceptibility to drug dependence. Exploration of the roles that candidate molecules play in an appropriate repertoire of animal behavioral models, especially drug self-administration and extensions thereof, should thus help us to understand human stimulant dependence.