Dopamine D4 receptor deficiency in mice alters behavioral responses to anxiogenic stimuli and the psychostimulant methylphenidate.

An allele of the human dopamine D4 receptor (D4R) gene (DRD4), containing seven tandem repeats of a 48-base nucleotide sequence (DRD4.7), has been reproducibly found in novelty seekers, substance abusers, and individuals with attention-deficit hyperactivity disorder. One hypothesis predicts the resultant protein product of the DRD4.7 polymorphism is deficient in G protein-coupled signaling. If attenuated D4R signaling contributes to these complex behaviors, then wild-type (WT) mice and mice completely lacking D4Rs (D4R KO) might be expected to display significantly different behavioral responses to stimuli known to affect dopamine signaling, such as novelty or psychostimulants. Adolescent male D4R KO mice exhibited greater locomotor activity and spent less time in the anxiogenic center of a novel open field environment than WT littermates. The presence of D4Rs had no effect on emergence into a novel environment from a sheltered space or exploration of a novel object. Low doses of acute methylphenidate (MP) had no effect on the exploration of a novel object, but dose-dependently increased the latency to emerge into a novel environment from a sheltered space. WT and D4R KO mice responded differently to high doses of acute MP, displaying significantly elevated locomotor activity and reduced stereotypy relative to WT mice. Chronic MP treatment produced enhanced locomotor sensitization in D4R KO mice, however this effect could not be fully recapitulated using the putative D4R antagonist L-745-870. These studies suggest that the roles of D4R signaling in novelty-seeking behaviors and the response to psychostimulants are not as clear as previously reported, and that some of these effects may be due to developmental compensatory effects as a consequence of lost D4R expression. If the DRD4.7 variant results in deficient D4R signaling in vivo, this may contribute to an elevated risk of sensitization to drugs of abuse including psychostimulants used to treat ADHD.

Characterization of rat prepro-orphanin FQ/nociceptin((154-181)): nociceptive processing in supraspinal sites.

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the orphan receptor-like/kappa(3)-like opioid receptor clone, produces a variety of behavioral responses, including those associated with pronociception and antinociception. The OFQ/N precursor rattus-proOFQ (rppOFQ/N) contains several paired basic amino acids, which raises the possibility that post-translational processing can be responsible for the production of a number of additional biologically active peptide fragments. One of these putative peptides, rppOFQ/N (rppOFQ/N(154-181)), was examined for antinociceptive and pronociceptive processes in four brain sites involved in pain inhibition: the ventrolateral periaqueductal gray (vlPAG), the amygdala, the locus coeruleus (LC), and the rostroventromedial medulla (RVM). Endogenous rppOFQ/N(154-181) was identified in each region. rppOFQ/N(154-181) produced a dose-dependent antinociception in all four sites using the tailflick assay. Injections into misplaced cannula sites failed to exert effects. Antinociception in the four sites differed in their response to the opioid antagonist naloxone. Naloxone pretreatment completely blocked rppOFQ/N(154-181)-induced antinociception in the vlPAG and the amygdala, but not in the LC or RVM. In contrast rppOFQ/N(154-181) was hyperalgesic in the LC and RVM, but not in the vlPAG or amygdala. rppOFQ/N(154-181) also was compared with either its N-terminal 17-amino acid peptide (rppOFQ/N(154-170), also known as OFQ2) or its 8-amino acid C-terminal fragment (rppOFQ/N(174-181)). Although both rppOFQ/N(154-181) and rppOFQ/N(154-170) produced antinociception, the latter was less effective because the C-terminal fragment was inactive. Thus, rppOFQ/N(154-181) has complex antinociceptive and pronociceptive actions within the brain, and the pharmacological specificity of its actions differs among supraspinal sites.