Genetic differences in the rewarding and activating effects of morphine and ethanol

Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future.

Section: Discussionsupporting

confidence: 42%

Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

Nuutinen

Lintunen

Vanhanen

et al. 2011

“…This dose is somewhat lower than those previously reported to induce CPP in mice. Cunningham et al (1992a) reported a maximal conditioning effect with doses of 3 and 4 g/kg using DBA/2J mice, whereas demonstrated significant CPP in Swiss-Webster mice with ethanol doses of 1 and 2 g/kg. The higher potency of ethanol in our study compared with the previous reports might be explained by the shorter conditioning trials used in the present study (20 min) compared with 30 and 60 min in the cited study .…”

Section: Discussionmentioning

confidence: 44%

CB1 Receptor Knockout Mice Display Reduced Ethanol-Induced Conditioned Place Preference and Increased Striatal Dopamine D2 Receptors

Houchi

Babovic

Pierrefiche

et al. 2004

174

145

Cannabinoids and ethanol activate the same reward pathways, and recent advances in the understanding of the neurobiological basis of alcoholism suggest that the CB 1 receptor system may play a key role in the reinforcing effects of ethanol and in modulating ethanol intake. In the present study, male CB 1 receptors knockout mice generated on a CD1 background displayed decreased ethanol-induced conditioned place preference (CPP) compared to wild-type (CB 1 þ / þ ) mice. Ethanol (0.5, 1.0, 1.5, and 2.0 g/kg) induced significant CPP in CB 1 þ / þ mice at all doses tested, whereas it induced significant CPP only at the highest dose of ethanol (2.0 g/kg) in CB 1 À/À mice.However, there was no genotypic difference in cocaine (20 mg/kg)-induced CPP. There was also no genotypic difference, neither in cocaine (10-50 mg/kg) nor in D-amphetamine (1.2-5 mg/kg)-induced locomotor effects. In addition, mutant and wild-type mice did not differ in sensitivity to the anxiolytic effects of ethanol (1.5 g/kg) when tested using the elevated plus maze. Interestingly, this decrease in ethanol efficacy to induce CPP in CB 1 À/À mice was correlated with an increase in D2/D3 receptors, as determined by [ 3 H]raclopride binding, whereas there was no difference in D1-like receptors, as determined by [ 3 H]SCH23390 binding, measured in the striatum from drug-naïve mice. This increase in D2/D3 binding sites observed in CB 1 knockout mice was associated with an altered locomotor response to the D2/D3 agonist quinpirole (low doses 0.02-0.1 mg/kg) but not to an alteration of quinpirole (0.1-1.0 mg/kg)-induced CPP compared to wild-type mice. Altogether, the present results indicate that lifelong deletion of CB 1 receptors reduced ethanol-induced CPP and that these reduced rewarding effects of ethanol are correlated to an overexpression of striatal dopamine D2 receptors.

“…The floor of the open field consisted of two interchangeable halves made of one of two textures: either a 'grid' made from stainless-steel rods (2.3 mm stainless-steel rods mounted 6.4 mm apart) or 'hole' floor (16-gauge stainless steel perforated with 6.4-mm diameter holes). This combination of floor textures was selected on the basis of unpublished pilot studies using commercially acquired C57BL/6 mice and studies by others (Cunningham et al, 1992;Cunningham, 1995) showing that mice spend an average of about 50% time on each floor type during (preconditioning) bias/preference tests. Thus, the apparatus allowed for an 'unbiased' place preference procedure to be used (see 'Results').…”

Section: Apparatusmentioning

confidence: 44%

Narp Deletion Blocks Extinction of Morphine Place Preference Conditioning

Crombag

Dickson

Dinenna

et al. 2008

As drug abuse can be viewed as a maladaptive form of neuronal plasticity, attention has focused on defining the synaptic plasticity mechanisms that mediate the long-term effects of these drugs. As Narp is secreted at synaptic sites and binds to the extracellular surface of AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. Accordingly, to assess its potential role in the long-lasting behavioral effects of drugs of abuse, we have investigated the impact of Narp deletion on sustained behavioral responses elicited by repeated morphine administration. Narp knockout mice display normal locomotor sensitization and conditioned place preference, but are markedly resistant to extinction of place preference. Thus, these findings indicate that Narp plays a selective role in extinction, possibly by its effects on AMPA receptor trafficking.