Charles F. Mactutus

Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia

Infection with the human immunodefiency virus (HIV) selectively targets the basal ganglia resulting in loss of dopaminergic neurons. Although frequently asymptomatic, some patients may develop signs of dopamine deficiency de novo. Accordingly, they are highly susceptible to drugs that act on dopaminergic systems. Both neuroleptics and psychostimulants may exacerbate these symptoms. Experimental evidence suggests that viral proteins such as gp120 and Tat can cause toxicity to dopaminergic neurons, and this toxicity is synergistic with compounds such as methamphetamine and cocaine that also act on the dopaminergic system. In addition, other neurotransmitters that modulate dopaminergic function, such as glutamate and opioids, may also modify the susceptibility of the dopamine system to HIV. Therefore, a thorough understanding of the mechanisms that lead to this selective neurotoxicity of dopaminergic neurons would also likely lead to the development of therapeutic modalities for patients with HIV dementia.

Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum

HIV-associated dementia complex is a serious disabling disease characterized by cognitive, behavioral and motor dysfunction. Basal ganglia involvement in HIV-1 infection may be responsible for some of the psychomotor symptoms associated with HIV dementia. The objectives of the present study were to determine: (1) whether gp120 and Tat produce striatal toxicity, and (2) whether gp120 and Tat show synergistic toxicity in the striatum. In these studies, the recombinant proteins gp120, Tat, or saline (0.9%) were stereotaxically injected in the striatum of adult male rats. The striatal sections were evaluated for area of tissue loss (Cresyl-violet stained sections) and the number of GFAP immunoreactive cells 7 days after the injections. Doses of gp120 250 ng/microl or higher and Tat 5 microg/microl or higher produced a significant area of tissue loss and significantly increased the number of GFAP reactive cells. We found no toxicity in animals treated with immunoabsorbed gp120 or Tat. Combined gp120 (100 ng/microl)+Tat (1 microg/microl) injections into the rat striatum significantly increased the area of tissue loss and altered morphology and increased number of GFAP reactive cells, as compared to controls. Thus, the present results suggest the involvement of gp120 and Tat in striatal toxicity and provide a model for further studies to fully characterize their role in HIV-1 toxicity and to develop therapeutic strategies for HIV-1 associated dementia complex.

Oxidative damage induced by the injection of HIV-1 Tat protein in the rat striatum.

Oxidative stress has been hypothesized to play a role in the pathogenesis of different neurodegenerative disorders, including HIV-related dementia. Tat, a nonstructural protein of HIV, is implicated in potentiation of neuronal apoptosis by mechanisms involving the disruption of calcium homeostasis and oxidative stress. The injection of Tat caused an increase of protein carbonyl formation in the rat striatum. Increased oxidative modification of proteins occurred early after Tat injection and preceded Tat-mediated astrogliosis. Immunostaining of brain sections demonstrated that an area of prominent protein carbonyl immunoreactivity surrounded an injection site in the striatum of Tat-injected rats. Intense protein carbonyl immunoreactivity was localized in cell bodies. Our study suggests that increased protein oxidation may be an important part of the mechanism of Tat neurotoxicity.

Prenatal cocaine exposure impairs selective attention: Evidence from serial reversal and extradimensional shift tasks

This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment.

Prenatal Intravenous Cocaine Adversely Affects Attentional Processing in Preweanling Rats

Perhaps the sole, clinically reported, deficit in infants of women that abused cocaine (COC) during pregnancy that persists through early childhood is that of an attentional disorder. Using the heart rate orienting response (HR-OR), a putative valid and reliable measure of attention, we examined the offspring of rats exposed to COC in utero via the clinically relevant intravenous (IV) route. Sprague-Dawley females, implanted with IV access ports prior to breeding, were administered saline or 3 mg/kg COC HC1, 1X/day on gestational day (GD) 8-14 and 2X/day on GD15-21. No significant effects of prenatal COC were apparent for maternal or litter parameters. Six pups/litter were tested: one of each sex on postnatal day (PD) 12, PD16, and PD21. Following 20 min of adaptation, pups were exposed to a novel odor (20 s amyl acetate) for a set of four acquisition trials; after a 4-h retention interval, the same procedure was again employed. At PD12, both prenatal COC and control pups demonstrated a significant HR-OR on the acquisition trials and both groups showed significant within-session habituation. Across the 4-h retention interval, prenatal COC-exposed pups showed habituation whereas control pups did not. At PD16, the magnitude of the HR-OR was significantly greater in prenatal COC-exposed pups relative to control pups. Within-session habituation also characterized the HR-OR of the COC, but not control, pups. For the retention data, within-subject and regression analyses suggested the COC-exposed pups displayed greater between and within-session habituation, respectively. At PD21, the prenatal COC-treated pups displayed an HR-OR that did not habituate across acquisition trials; the control pups displayed a significant HR-OR only during the initial 5 s of the first two trials. During the retention trials, regression analyses again suggested the COC-exposed pups displayed greater evidence of within-session habituation. Collectively, these data demonstrate that prenatal exposure to COC alters attention throughout the preweanling period of development. Given the putative role of norepinephrine, but not dopamine or serotonin, in central mediation of the HR-OR of preweanling rats, the effects of prenatal IV COC exposure in this task are consistent with a noradrenergically based attentional disorder.

REPEATED INTRAVENOUS COCAINE ADMINISTRATION : LOCOMOTOR ACTIVITY AND DOPAMINE D2/D3 RECEPTORS

The dopamine D3 receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D2 and D3 receptor density in the rat striatum and nucleus accumbens. Male Sprague‐Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60‐minute test sessions. Repeated cocaine treatment resulted in a significant dose‐dependent increase in striatal D3 receptors which was predicted by daily 60‐minute central locomotor activity. Conversely, D3 receptors in the nucleus accumbens exhibited a significant dose‐dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose‐dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D2 receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D3 receptor involvement in the expression of cocaine‐induced behavioral sensitization. Thus, the D3 receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D3) and reinforcing aspects (nucleus accumbens D3) of repeated cocaine administration.

Hypothermia-induced amnesia for newly acquired and old reactivated memories: Commonalities and distinctions

A series of six experiments compared the characteristics of hypothermia-induced amnesia for newly acquired and old reactivated memories. Old memory, when reactivated by cue exposure, was disrupted by mild or deep hypothermia treatment, while new memory was impaired only by deep cooling. Mild hypothermia had no disruptive influence on either new or old memories. Old, but not new, learning showed recovery from amnesia in a test-retest procedure. The onset of amnesia was more rapid for an old reactivated memory than for a newly acquired memory. The susceptibility of memory to disruption decreased over time following original learning or cue reactivation, although this decrease was, if anything, more rapid following the cuing procedure. Recovery from amnesia could be induced by a recooling reminder treatment and was similar for both new and old memories. It was suggested that activity of, or access to, memory rather than age per se determines susceptibility to disruption. The process of memory reactivation appears somewhat more sensitive, rapid, and brief than the processes) of memory formation. However, that the underlying old memory remains stable over time was supported by the strong retention when specific implicit or explicit reactivation cues were available.

Enduring Effects of Prenatal Cocaine Exposure on Attention and Reaction to Errors

Rats exposed to cocaine prenatally were administered a series of 3-choice visual attention tasks, with the most pronounced deficits seen in a task in which the onset time, location, and duration of a visual cue varied unpredictably between trials. The cocaine-exposed rats were less accurate than controls but did not differ in the rate of premature responses or omission errors. The pattern of errors, coupled with response latency data, implicated deficits in the ability to rapidly engage attention and maintain a high level of alertness to the task. The cocaine-exposed rats also exhibited a blunted reaction to an error on the previous trial, possibly reflecting an alteration in emotional regulation and/or error monitoring. Implications for underlying neuropathology are discussed.

Amnesia induced by hyperthermia: An unusually profound, yet reversible, memory loss

The present series of investigations was designed to evaluate whether hyperthermia, produced by whole body immersion in warm (45°C) water, could serve as an amnestic agent. In Experiment 1, previously shocked and experimentally naive rats received one-trial passive avoidance training followed by hyperthermia treatment after delays of either 30 sec, 5, 30, or 60 min. Each of three dependent measures indicated the retention of the experimentally naive rats was susceptible to disruption through treatment delay intervals of 1 hr. In the previously shocked animals, retention was impaired only at the 30-sec interval. No evidence for spontaneous recovery was observed 48 hr after training. Experiment 2 investigated whether hyperthermia or hypothermia would impair memory over multiple training/amnesic treatment/test sequences. On the initial test trial both groups were amnestic. However, over four test sequences each separated by 24 hr the amnestic effects of body cooling, but not of warming, diminished significantly. Anterograde effects of hyperthermia did not appear responsible for the repeated memory loss as good retention was observed 24 hr after a fifth training trial. In Experiment 3, noncontingent footshock produced substantial memory recovery from both hyperthermia- and hypothermia-induced amnesia relative to sham-trained controls which also received the reminder treatment. Despite the unusual potency of hyperthermia as an amnestic agent, the attenuation of the amnesia by reminder treatment suggested an interpretation consistent with a general retrieval-oriented theory.

Hypothermia-induced retrograde amnesia: Role of body temperature in memory retrieval

The relationship of body temperature to the onset, and the subsequent alleviation, of hypothermia-induced retrograde amnesia (RA) was investigated. In Experiment 1, the retention of a passive avoidance task and the body temperature at the time of testing were assessed at intervals of 4, 8, 12, and 16 h after training/amnesic treatment. While retention was evident for up to 12 h posthypothermia treatment, it was clear that body temperature did not index magnitude of RA. A second experiment examined the alleviation of hypothermia-induced RA as a function of body temperature and retention interval. Memory recovery was facilitated at both 1- and 7-day intervals when testing occurred at 29°-31°C but not at 33°–35°C. The possibility of different mechanisms underlying retention after hypothermia and retrieval after recooling was suggested. An alternative explanation in terms of contextual cues and cue utilization was also discussed.