Identification of brain nuclei implicated in cocaine-primed reinstatement of conditioned place preference: a behaviour dissociable from sensitization.

Relapse prevention represents the primary therapeutic challenge in the treatment of drug addiction. As with humans, drug-seeking behaviour can be precipitated in laboratory animals by exposure to a small dose of the drug (prime). The aim of this study was to identify brain nuclei implicated in the cocaine-primed reinstatement of a conditioned place preference (CPP). Thus, a group of mice were conditioned to cocaine, had this place preference extinguished and were then tested for primed reinstatement of the original place preference. There was no correlation between the extent of drug-seeking upon reinstatement and the extent of behavioural sensitization, the extent of original CPP or the extinction profile of mice, suggesting a dissociation of these components of addictive behaviour with a drug-primed reinstatement. Expression of the protein product of the neuronal activity marker c-fos was assessed in a number of brain regions of mice that exhibited reinstatement (R mice) versus those which did not (NR mice). Reinstatement generally conferred greater Fos expression in cortical and limbic structures previously implicated in drug-seeking behaviour, though a number of regions not typically associated with drug-seeking were also activated. In addition, positive correlations were found between neural activation of a number of brain regions and reinstatement behaviour. The most significant result was the activation of the lateral habenula and its positive correlation with reinstatement behaviour. The findings of this study question the relationship between primed reinstatement of a previously extinguished place preference for cocaine and behavioural sensitization. They also implicate activation patterns of discrete brain nuclei as differentiators between reinstating and non-reinstating mice.

A differential role for the adenosine A2A receptor in opiate reinforcement vs opiate-seeking behavior.

The adenosine A(2A) receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A(2A) receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine self-administration and breakpoint in A(2A) knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A(2A) knockout mice. In support of this finding, a place preference to morphine was not observed in A(2A) knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A(2A) knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A(2A) knockout was similar to wild-type mice, yet A(2A) knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A(2A) receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A(2A) receptors in opiate reinforcement compared to opiate-seeking.

Intravenous insulin-like growth factor-I receptor antisense treatment reduces angiotensin receptor expression and function in spontaneously hypertensive rats.

The present study investigated the effects of a functional deficit in insulin-like growth factor-I signaling via chronic intravenous administration of insulin-like growth factor-I (IGF-I) receptor antisense in the conscious spontaneously hypertensive rat cardiovascular system. Insulin-like growth factor-I receptor (IGF-IR) antisense, but not full mismatch treatment, decreased IGF-IR expression in both conductance and resistance blood vessels. Aortic IGF-IR density was reduced by 67.4 +/- 6.0% in antisense-treated spontaneously hypertensive rat (SHR) compared with untreated animals, whereas mismatch treatment had no effect (analysis of variance, n = 3, P < 0.01). Aortic and tail artery angiotensin II type 1 receptor expression was significantly reduced by IGF-IR antisense treatment, whereas angiotensin II type 2 receptor expression was unaffected by administration of antisense and mismatch oligonucleotides. IGF-I receptor antisense treatment caused a significant decrease in pressor responses to angiotensin II in comparison with full-length mismatch treatment (E(max) was reduced to 65 +/- 7 mm Hg compared with 99 +/- 6 mm Hg, p < 0.05). Likewise, a reduction in pressor responses to noradrenaline was observed in hypertensive rats treated with IGF-IR antisense compared with full mismatch-treated rats (E(max) was reduced to 60 +/- 6 mm Hg compared with 108 +/- 5 mm Hg, p < 0.01). There was no clear antisense effect on resting blood pressure and no effect at on aortic medial thickness. These results suggest that although the proliferative and vasodilator effects of IGF-I are impaired in SHR, the effects on angiotensin receptor expression remain profound.

Comparison of ethanol preference and neurochemical measures of mesolimbic dopamine and adenosine systems across different strains of mice.

BACKGROUND: To extend the known phenotype of strains commonly used in the development of mutant mice, ethanol, saccharin, and caffeine preferences were examined in C57Bl/6J, CD-1, and hybrid C57Bl/6J x CD-1 mice. As dopaminergic mechanisms are inherently involved in the neuronal processing of many drugs of abuse (including ethanol), and an important role for adenosine-dopamine interactions has also been reported, the dopaminergic and purinergic neurochemical profiles of mice were compared against the consummatory phenotype observed. METHODS: Ethanol (5% v/v), saccharin (0.1% w/v), and caffeine (0.1% w/v) consumption and preference were examined using a 2-bottle free-choice paradigm. Dopamine and adenosine receptor and transporter mRNA and protein density were quantified using in situ hybridization histochemistry and in vitro autoradiography, respectively. RESULTS: C57Bl/6J and hybrid C57Bl/6J x CD-1 mice demonstrated a clear ethanol preference, voluntarily consuming large quantities of ethanol when given the choice between drinking vessels containing either ethanol or water. Conversely, CD-1 mice were characterized as ethanol-avoiding under the present paradigm. Differences in D(1) receptor mRNA between the strains were consistent with the observed behavioral differences in ethanol preference. The high ethanol-preferring phenotype of C57Bl/6J mice could not be directly linked to alterations in dopamine transporter neurochemistry and/or enkephalin levels as proposed by earlier researchers. Ethanol-seeking behavior appeared to correlate with D2 receptor expression, however, with evidence that ethanol-preferring mice also exhibit an increased density of D2 receptors within limbic dopaminergic projection nuclei. Interestingly, strain differences in the expression of the ethanol-sensitive nucleoside transporter paralleled differences in ethanol consumption, a novel finding consonant with purinergic involvement in dopamine-related behaviors. CONCLUSIONS: This study has highlighted the relevance of alterations in dopamine receptor expression and purinergic modulation within the mesolimbic pathway and predisposition toward the development of ethanol-seeking behavior.

Receptor crosstalk: characterization of mice deficient in dopamine D1 and adenosine A2A receptors.

Here we report the development of D1A2A receptor knockout mice to investigate whether interactions between dopamine D1 and adenosine A2A receptors participate in reward-related behavior. The combined deletion of D1 and A2A receptors resulted in mice with decreased weight and appetitive processes, reduced rearing and exploratory behaviors, increased anxiety, and a significantly poorer performance on the rotarod, compared to wild-type littermates. D1A2A receptor knockout mice shared phenotypic similarities with mice deficient in D1 receptors, while also paralleling behavioral deficits seen in A2A receptor knockout mice, indicating individual components of the behavioral phenotype of the D1A2A receptor knockout attributable to the loss of both receptors. In contrast, ethanol and saccharin preference in D1A2A receptor knockout mice were distinctly different from that observed in derivative D1 or A2A receptor-deficient mice. Compared to wild types, preference and consumption of ethanol were decreased in D1A2A receptor knockout mice, the reduction in ethanol consumption greater even than that seen in D1 receptor-deficient mice. Preference and consumption of saccharin were also reduced in D1A2A receptor knockout mice, whereas saccharin preference was similar in wild-type, D1, and A2A receptor knockout mice. These data suggest an interaction of D1 and A2A receptors in the reinforcement processes underlying the intake of rewarding substances, whereby the A2A receptor seems involved in goal-directed behavior and the motor functions underlying the expression of such behaviors, and the D1 receptor is confirmed as essential in mediating motivational processes related to the repeated intake of novel substances and drugs.