Characterization of the genetic basis for autosomal recessive hereditary nephropathy in the English Springer Spaniel.

BACKGROUND: Autosomal recessive hereditary nephropathy (ARHN) was diagnosed in 2 English Springer Spaniels (ESS), a breed not previously reported to be affected by hereditary nephropathy (HN). OBJECTIVE: To identify and characterize the genetic cause of ARHN in ESS. ANIMALS: Sixty-three ESS (2 with ARHN, 2 obligate carriers, and 59 others), 2 mixed-breed dogs with X-linked HN, and 2 English Cocker Spaniels (ECS) with ARHN were included. METHODS: ARHN was diagnosed based on transmission electron microscopy and immunostaining of kidney. DNA from affected dogs was screened for the mutation known to cause ARHN in ECS. Quantities of COL4A3, COL4A4, and COL4A5 mRNA transcripts in renal cortex were determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for ARHN-affected dogs and 7 other dogs. The coding regions of COL4A3 and COL4A4 were sequenced for the 2 ARHN-affected ESS and an unaffected dog. Exon 30 of COL4A4 was sequenced for all 63 ESS. RESULTS: qRT-PCR indicated a significant reduction in transcript levels of both COL4A3 and COL4A4 mRNA in the kidney of ARHN-affected ESS. Sequencing identified a single nucleotide substitution in COL4A4 at base 2806 resulting in a premature stop codon. Thirteen of 25 related dogs were identified as carriers. CONCLUSIONS AND CLINICAL IMPORTANCE: A mutation highly likely to cause ARHN in ESS has been identified.

D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption.

Although interference with dopamine (DA) systems can suppress lever pressing for food reinforcement, it is not clear whether this effect occurs because of a general disruption of food motivation. One way of assessing this has been a choice procedure in which a rat responds on an fixed ratio 5 (FR5) schedule for preferred Bioserve pellets while a less preferred lab chow is concurrently available in the operant chamber. Untreated rats consume little of the chow, preferring to respond for the Bioserve pellets. Previous studies have shown that depleting DA in the accumbens substantially decreased lever pressing while increasing chow consumption. In the present study, low doses (0.0625-1.0 microg) of the D1 antagonist SCH 23390 or the D2 antagonist raclopride were injected into the either the core or shell subregions of nucleus accumbens, and rats were tested on the concurrent lever pressing/feeding task. Analysis of the dose response curves showed that injections of SCH 23390 into the core were more potent than injections into the shell for suppressing lever pressing (i.e., the ED(50) was lower in the core). Nevertheless, injections of either drug into either site suppressed lever pressing and increased intake of the concurrently available chow. Across both drugs and at both sites, the amount of chow consumed was negatively correlated with the total number of responses. Neither drug significantly increased response duration, suggesting that accumbens DA antagonism did not produce the type of motor impairment that leads to severe alterations in the form of lever pressing. In summary, the blockade of D1 or D2 receptors in nucleus accumbens core or shell decreased lever pressing for food reinforcers, but rats remained directed toward the acquisition and consumption of food. These results indicate that accumbens D1 antagonism does not decrease lever pressing because of a general reduction in food motivation. Nevertheless, interference with accumbens DA does appear to set constraints upon which responses are selected for obtaining food, and may impair the ability of animals to overcome work-related response costs in order to obtain food.

Nucleus accumbens dopamine depletions and time-constrained progressive ratio performance: effects of different ratio requirements.

Two experiments were conducted to determine the effects of accumbens dopamine (DA) depletions on progressive ratio responding for food reinforcement. In one version of this schedule, ratio requirement increased by one response after each reinforcer was obtained (PROG1). In the other version, ratio requirement increased by five responses after each reinforcer was obtained (PROG5). For both versions, 60-min sessions were conducted. Accumbens DA depletions produced by local injections of 6-OHDA substantially decreased the number of responses on both schedules. The deficits in the response number induced by DA depletions persisted through the two weeks of postsurgical testing for both the PROG1 and PROG5 schedules. However, there were differences between the effects of DA depletions on the two schedules in terms of the time to complete the last ratio. Although time to complete the last ratio was significantly reduced by DA depletions only in the first week of testing on the PROG1 schedule, rats recovered on this measure by the second week after surgery. In contrast, DA-depleted rats on the PROG5 schedule showed a more persistent suppression of the time to complete the last ratio, which lasted through both weeks of postsurgical testing. Performance on schedules that generate low baseline rates of responding (e.g., continuous, fixed, and variable interval) is relatively unaffected by accumbens DA depletions; nevertheless, accumbens DA depletions substantially impair progressive ratio response output. The high work output necessary for responding on the PROG5 schedule may make these animals more sensitive to the effects of accumbens DA depletions.