Modulation of the gating of auditory evoked potentials by norepinephrine: pharmacological evidence obtained using a selective neurotoxin.
Central mechanisms of sensory gating were assessed in Sprague-Dawley rats using an evoked potential technique similar to one that we have previously employed to show diminished sensory gating in psychotic patients. Gating mechanisms were examined using a conditioning-testing paradigm in which pairs of 74-dB clicks were delivered; the interval between the conditioning and test stimuli was 0.5 sec. A middle latency auditory evoked response (N50) recorded from the skull of unanesthetized, freely moving rats demonstrated significant suppression to the test click. Systemic administration of amphetamine (1 mg/kg, ip) significantly reduced the amount of suppression of the response to the test stimulus; haloperidol (1 mg/kg), injected after the amphetamine, returned the conditioning-testing suppression ratio toward normal values. Amphetamine also decreased the latency and amplitude of the conditioning response, an effect that was also reversed by haloperidol. Both decreased suppression of the test response and reduced amplitude and latency of the conditioning response have been observed in schizophrenia. To aid in determining the underlying mechanism of these effects, the animals were treated with two doses, given at a 1-week interval, of N-(2-chloroethyl-N-ethyl-2-bromobenzylamine) (DSP4; 50 mg/kg, ip), an agent that selectively depletes central norepinephrine. The extent and selectivity of the depletions were confirmed by chemical analysis. Following DSP4, the effects of amphetamine on the amplitude and latency of the conditioning response were largely unchanged. However, pretreatment with DSP4 significantly attenuated the reduction in conditioning-testing suppression observed following the administration of amphetamine. The data suggest a specific role for norepinephrine in the modulation of sensory processing.
Adler
L E
LE
Department of Psychiatry, University of Colorado Health Sciences Center, Denver 80262.
Pang
K
K
Gerhardt
G
G
Rose
G M
GM
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001288:Attention / Q000502:physiology*; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D009498:Neurotoxins; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects
D001596:Benzylamines; D009498:Neurotoxins; D000661:Amphetamine; D006220:Haloperidol; C012102:DSP 4; D009638:Norepinephrine