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Neural activity in the central gray during defense has also been measured by C-deoxyglucose metabolism. Morton et al. (1984) compared C-deoxyglucose uptake in attackers vs attacked mice, i.e. offense vs. defense. Defense produced greater activity in the dorsal central gray. Also using C-deoxyglucose, Roberts and Nagel (1996) measured increased activity in many areas during flight and attack in rats, finding the correlation of central gray activity with flight stronger than with attack. Their attack results are difficult to evaluate because attack was produced by electrical stimulation of the brain which may activate both offensive and defensive attack simultaneously, as discussed below.
Both electrical and chemical stimulation of the midbrain central gray produce the various motor patterns of defense, as reviewed in 1979 (Adams, 1979a) and confirmed by many studies since then. Data from discrete brain lesions support the proposition that the motivational mechanism is located in the dorsal but not the ventral central gray of the midbrain: lesions of the ventral central gray do not abolish freezing and flight elicited from the dorsal central gray (Vianna, et al., 2001). Despite this, several recent studies claim that the ventral central gray is involved in the freezing component of defense. Although the behavior of the intruder under attack (escape and upright postures, crouch and supine postures) was not altered by local injection of morphine in the ventrolateral central gray, the duration of time subsequently spent in the crouch posture was increased (Vivian and Miczek, 1999). While chemical stimulation of the dorsal central gray produces reactions "similar to the natural reactions of a rat or cat when threatened or attacked," stimulation of the ventral gray produces "a profound hyporeactivity" (Bandler and Shipley, 1994). Along the same lines, lesions of the dorsal central gray enhance freezing by a rat following exposure to a cat or footshock, while lesions of the ventral central gray reduce freezing (DeOca et al., 1998) and cholinergic stimulation of the ventral central gray prolongs the duration of tonic immobility in guinea pigs (Monassi et al., 1999).
As proposed on the basis of neuronal recording (Adams, 1968a, 1968b) and lesion studies (Edwards and Adams, 1974), the neurons of the defense motivational mechanism are located both within and lateral to the central gray, which may be considered as a continuous anatomical structure (Edwards and Adams, 1974) that is artificially separated by the penetration of myelinated fibers (Adams, 1979a). In the rat, chemical stimulation of the region lateral to the dorsal central gray, including the deep layers of the superior colliculus, the adjacent mesencephalic reticular formation and the intercollicular nucleus, also produces the various motor patterns of defense, including escape locomotion, squealing and biting (Shehab et al., 1995a). Some of the defense obtained by electrical and chemical stimulation of the superior colliculus and inferior colliculus may involve this region (Brandao et al., 1999).
Considerable research has been directed in recent years to the neurotransmitters affecting midbrain central gray neurons that are related to defense. These midbrain central gray neurons are facilitated by excitatory amino acids (EAA), in particular glutamate, in the cat (Bandler, 1982) and rat (Krieger and Graeff, 1985) and by substance P in the cat (Gregg and Siegel, 2003) and inhibited by the opioid neurotransmitter enkephalin (Siegel et al., 1997) and the transmitter GABA (gamma amino-butyric acid) in the cat (Siegel et al., 1999) and rat (Schmitt et al., 1986). Another possible neurotransmitter facilitating these neurons is cholecystokinin, apparently originating from neurons in the adjacent dorsolateral midbrain tegmentum, according to recent research by Luo et al. (1998). Earlier studies, reviewed in 1979 (Adams, 1979a), identified cholinergic facilitation of central gray defense neurons (e.g. Baxter, 1968). Not only the neurotransmitters, but also the receptors for these transmitters are increasingly distinguished. Hence, Carobrez et al. (2001) distinguish short-term and long-term effects of EAA synaptic transmission on three types of receptors on central gray neurons of the rat which are abbreviated as AMPA, KAIN and NMDA.
Origins of the neurotransmitters are less well known. Some of the EAA-mediated facilitation of central gray neurons responsible for defense is said to come from neurons located in the dorsomedial and anteromedial hypothalamus where electrical stimulation can produce coordinated defense behavior in the cat (Siegel et al, 1997). Some of the EAA-mediated facilitation may also come from projections to the central gray from neurons located in the basal amygdala (Shaikh et al., 1994). The origin of fibers that facilitate with the neurotransmitter substance P is not known. Some inhibition, perhaps that of GABA, comes from local circuits, as suggested by studies in which bicuculline injections produced defense (DiScala et al., 1984) and in which single neurons were inhibited by nearby electrical stimulation (Sandner et al., 1986). According to data in the cat, some of the opioid enkephalin-mediated inhibition may come from projections from the central amygdala (Siegel et al., 1997), while other may come from local circuits within the central gray (Siegel et al., 1999). Although there are reports that the neurotransmitter serotonin has both inhibitory and excitatory effects on the defense neurons of the central gray (Graeff et al., 1993, Shaikh et al., 1997), there remain questions about the mechanism involved (Siegel et al., 1999). Presumably the neurotransmitters correspond to inputs from various analyzers and synthesizers of motivating stimuli to be discussed in the following section of this review, but functional correspondence has yet to be demonstrated.