Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate. Corticofugal PFC neurons, which are inhibited by VTA ...DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC D1 receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC D1 stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC D1 receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.
1. Low dose dopaminergic agonist effects have been used as a behavioral screen for identifying compounds with selective autoreceptor activity. 2. However, results from several recent investigations ...suggest that these behaviors may not be generated from an autoreceptor substrate but rather from a subpopulation of postsynaptic dopamine receptors with a high affinity for the agonist. 3. In support of this hypothesis, the present investigation reports that both hypomotility and yawning, induced in the rat with 0.07 mg/kg apomorphine, were not paralleled by autoreceptor-induced reductions in transmitter metabolism from either mesolimbic or neostriatal dopamine regions.
Animals were treated either acutely, or chronically for 21 days, with a low dose (0.1 mg/kg) of haloperidol, then sacrificed to obtain trunk blood for radioimmunoassay of prolactin (PRL) level. PRL ...concentrations on day 21 of chronic treatment were greater than two-fold those produced by acute neuroleptic. Challenge with apomorphine to rats withdrawn for 48 hours revealed similar PRL reductions as a group withdrawn from chronic vehicle injections.
When treated chronically with haloperidol, rats show progressively enhanced behavioral suppression, mimicking the delay of onset seen clinically with neuroleptics. To investigate potential ...neurochemical mechanisms underlying this delay, low-dose apomorphine treatment was administered after withdrawal from 21 days of 0.1 mg/kg haloperidol, to probe for depolarization inactivation or autoreceptor supersensitivity. This haloperidol treatment was subthreshold for inducing either dopamine autoreceptor supersensitivity or postsynaptic supersensitivity as evidenced by equivalent metabolic reductions in chronically treated neuroleptic versus vehicle groups, and an absence of stereotypical responding in either condition. However, haloperidol treated rats appeared subsensitive to yawning induced by 0.07 mg/kg apomorphine. This latter response appears to be generated from an as yet unidentified postsynaptic dopaminergic substrate. The present observation suggests that, within a therapeutically relevant dose range, repeated neuroleptic administration induces a complex set of neuroadaptive processes (both up- and down-regulation of pre- and postsynaptic sites) in the underlying substrate for these drugs' behavioral and biochemical effects.
Animals responding for biphasic square wave stimulation to the VTA were treated for 26 days with a low dose (0.07 mg/kg) of the neuroleptic haloperidol and tested at 1 h post-injection. Initially the ...drug induced a pronounced lateral displacement of the baseline rate-intensity function, concomitant with a depression in slope. Over the course of chronic treatment, partial tolerance was observed to the drug-induced increases in threshold concomitant with the onset of a significant suppression in peak response rate. Biochemical tolerance to stimulated dopamine metabolism (as per cent non-drug control) was significant only for mesolimbic (versus neostriatal) regions, in animals receiving haloperidol according to pre- and post-test administration schedules. The observation of sensitization to peak rate reductions parallels previous reports for spontaneous locomotor activity measures and is compatible with depolarization inactivation mechanisms proposed to account for delayed-onset clinical effects. Further, selective biochemical tolerance in mesolimbic regions supports suggestions that mesolimbic dopamine is important as a substrate for subtle low dose neuroleptic effects which may be relevant for studying pharmacotherapeutic treatment issues.
Early postlesion amphetamine-induced contralateral rotation has been linked to intraneuronal dopamine (DA) accumulation and transmitter release associated with axonal degeneration. Animals in the ...present study sustained severe unilateral depletion of striatal DA with or without a near-complete loss of ipsilateral mesolimbic DA. Contralateral rotation to 1.0 mg/kg (+)-amphetamine was observed on days 1 and 4 postlesion, and was greatly enhanced in mesolimbic-lesioned animals on day 4. On days 7 and 14, very little contralateral turning was observed and there was an emergence of low-rate ipsilateral rotation. These changes in direction and magnitude of rotational response suggest neurochemical adaptations which continue beyond initial periods of intraneuronal accumulation and degeneration-induced release.
Bilateral lesions of mesolimbic dopamine (DA) reliably produce an attenuated response to amphetamine's locomotor stimulatory effects when administered after two weeks of surgical recovery. Several ...studies have revealed enhanced amphetamine-induced hyperactivity during the first postlesion week, however. In the present study, animals with bilateral 6-OHDA lesions of nucleus accumbens and olfactory tubercle DA showed an exaggerated response to 1.0 mg/kg amphetamine during this early period but were hypoactive in the absence of drug treatment. Neurochemical assay at 5 days revealed increased DA metabolism in the tubercle. Shifting patterns of postlesion amphetamine response under conditions of reduced mesolimbic DA are suggestive of dynamic adaptations in nondopaminergic systems.
The effect of direct intrastriatal injection of three organophosphate cholinesterase inhibitors, DFP (diisopropylphosphorofluoridate), soman (pinacolyl methylphosphonofluoridate) and sarin (isopropyl ...methylphosphonofluoridate) has been studied on locomotor activity in the rat. The degree of ChE inhibition has been monitored in the striatum, as well as in surrounding brain areas and blood, in order to verify the selectivity of the treatment and rule out effects attributable to actions in these areas and/or the periphery. It has been determined that while enzyme activity is inhibited in the striatum by all three compounds, only DFP significantly reduces locomotor activity at doses that produce no other observable behavioral deficits, or significant leakage into the periphery. Behavioral recovery occurs before enzyme activity returns to control levels. Possible contributions of DFP's action on other neurotransmitters and on ChE in other brain areas to the inhibition of locomotor activity are discussed.
A rapid latex agglutination slide test for group A beta-hemolytic streptococcal throat infections was prospectively evaluated. Resident physicians, working in an adult non-acute emergency room, ...recorded clinical data and collected throat swabs from 729 adult patients with sore throats. Research assistants obtained throat swabs from 329 control patients. Sensitivity and specificity, compared with routine cultures, were 96% and 97%, respectively. Analyses of clinical predictions and of test results for control patients, however, suggest that this test may perform better than routine culture. The test provides a rapid, accurate, potentially useful alternative for diagnosing group A beta-hemolytic streptococcal pharyngitis in adults.
