Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia

Abstract

The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

Figure 1

Experimental time line. Vertical arrows indicate age of rat in weeks when surgeries and experimentation were conducted. Approximate duration of each of seven experimental phases is listed below the line. Asterisks indicate times when lever-press response rates were either habituated or extinguished to similar baseline levels prior to further testing.

Figure 2

Hemi-coronal representations showing the extent of neonatal ibotenic acid-induced lesions. Striped areas represent largest extent of the lesion (on either side) in the bilaterally lesioned group, while the black areas represent the smallest lesion area. The majority of lesioned rats had lesion sizes closer to the large extreme. Numbers below the sections indicate distance of sections posterior to bregma based on stereo-taxic coordinates of Paxinos and Watson.

Figure 3

Profile of spontaneous and sucrose-reinforced responding in NVHL and sham rats. NVHL rats show non-significant trends for (A) increased spontaneous lever-press responses in an initial 1-h test, and (B) latency to reach habituation criterion (number of sessions to ≤ 10 total lever responses/hour). C. NVHL animals acquire sucrose pellet self-administration (FR3) with shorter latencies to criterion (three consecutive sessions receiving the maximum 100 sucrose pellets) relative to shams. D. Response rates during the initial two extinction tests are similar in NVHL and sham rats at both sucrose-paired and inactive levers. E. The latency to reach extinction criterion is also similar (number of sessions to reach ≤ 15 responses on sucrose-paired lever). Data are presented as the mean ± SEM, *p < .05 by 2-tailed t-test.

Figure 4

Acquisition of cocaine self-administration (FR1:TO 14 s) in NVHL and sham rats over four weeks of ascending dose availability. A. NVHL rats respond more at the active lever beginning the second week at an injection dose of 0.2 mg/kg, and continue through weeks 3 and 4 (0.4 mg/kg/injection). B. Increases in total active lever responding in NVHL rats shown in (A) are reflected by increases in average daily time-out (TO) responses during the 14-s injection/time out periods, and not by increases in the number of injections taken. C. Average daily cocaine intake (mg/kg) increased in both groups, with a non-significant trend for early escalation in NVHL rats (but see Figure 6). D. More than 50% of NVHL rats reach criterion for acquisition of cocaine self-administration (≥ 30 cocaine injections/session for three consecutive sessions) by the end of the second test week, while shams require three weeks and a higher injection dose to achieve 50% acquisition. E. However, the mean latency to acquire cocaine self-administration was not significantly shorter in NVHL rats. Data are presented as the mean ± SEM, *p < .05 by 2-way ANOVA with repeated measures on test day or week.

Figure 5

Incidence of binge-like cocaine self-administration and response perseveration at the inactive lever in NVHL and sham rats. A. NVHL rats show a greater incidence of obtaining the maximum number of cocaine injections available (120 per session) than shams over the 4-week acquisition period. Data are expressed as the mean ± SEM percentage of total tests/animal. B. The incidence of response perseveration at the inactive lever during active cocaine self-administration is similar between NVHL and sham rats (≥ 100 responses concomitant with ≥ 30 cocaine injections). *p < .05 by Mann-Whitney U test.

Figure 6

Baseline cocaine self-administration (0.4 mg/kg/inj.) prior to extinction/reinstatement testing in NVHL and sham rats. A. NVHL rats continue to exhibit response perseveration at the active lever, with no difference in the number of injections taken compared with shams. B. Representative response records illustrating regularity in patterns of cocaine intake concomitant with response perseveration during the injection/time-out periods in an NVHL rat over a 30-min period compared with a sham animal. Hatch marks represent active lever responses that elicit a single drug injection. Arrows denote numbers of time-out responses in the 14-s time period after start of drug injection. Data in (A) are presented as the mean ± SEM, *p < .05 by 2-way ANOVA with repeated measures on test day.

Figure 7

Drug-paired lever responding during extinction and reinstatement testing. A. NVHL rats show significantly higher rates of cocaine-paired, but not inactive, lever responses during first two extinction test sessions relative to shams. B. The latency to reach extinction is prolonged in NVHL rats criteria (≤ 15 responses on cocaine-paired lever, ≤ 30 total on both levers in 2hr). C. Following achievement of extinction criteria, reinstatement induced by i.p. priming injections of cocaine is enhanced in NVHL relative to sham rats. Priming injections of saline or cocaine (5 and 15 mg/kg) were delivered after 2 h of additional extinction conditions in the test chambers. Two NVHL and one sham animal were excluded from the analysis due to high baseline responding (>30 total on both levers in second baseline hour). Data are presented as the mean ± SEM, *p < .05, **p < .01 by 2-way ANOVA, or by 2-tailed t-test.